%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 146 0 R 161 0 R 169 0 R 183 0 R 210 0 R 238 0 R 266 0 R 371 0 R 451 0 R 453 0 R 455 0 R ] /Count 12 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 9 0 R /F3 10 0 R /F4 11 0 R >> /XObject << /I1 12 0 R /I2 13 0 R /I3 152 0 R /I4 163 0 R /I5 164 0 R /I6 165 0 R /I7 166 0 R /I8 167 0 R /I9 168 0 R /I10 187 0 R /I11 214 0 R /I12 221 0 R /I13 246 0 R /I14 249 0 R /I15 272 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20180721155510+00'00') /ModDate (D:20180721155510+00'00') /Title (Exercise is not beneficial and may accelerate symptom onset in a mouse model of Huntingtons disease PLOS Currents Huntington Disease) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 14 0 R 16 0 R 18 0 R 20 0 R 22 0 R 24 0 R 26 0 R 28 0 R 30 0 R 32 0 R 34 0 R 36 0 R 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 56 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R 78 0 R 80 0 R 82 0 R 84 0 R 86 0 R 88 0 R 90 0 R 92 0 R 94 0 R 96 0 R 98 0 R 100 0 R 102 0 R 104 0 R 106 0 R 108 0 R 110 0 R 112 0 R 114 0 R 116 0 R 118 0 R 120 0 R 122 0 R 124 0 R 126 0 R 128 0 R 130 0 R 132 0 R 134 0 R 136 0 R 138 0 R 140 0 R 142 0 R 144 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 29615 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Exercise is not beneficial and may accelerate symptom onset in )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(a mouse model of Huntingtons disease)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(December 7, 2010)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Michelle C Potter)] TJ ET 0.271 0.267 0.267 rg BT 111.319 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 116.740 663.247 Td /F1 9.8 Tf [(Chunyan Yuan)] TJ ET 0.271 0.267 0.267 rg BT 181.236 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.657 663.247 Td /F1 9.8 Tf [(Conwell Ottenritter)] TJ ET 0.271 0.267 0.267 rg BT 267.387 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 272.808 663.247 Td /F1 9.8 Tf [(Mohamed Mughal)] TJ ET 0.271 0.267 0.267 rg BT 350.837 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 356.258 663.247 Td /F1 9.8 Tf [(Henriette van Praag)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Potter MC, Yuan C, Ottenritter C, Mughal M, van Praag H. Exercise is not beneficial and may accelerate symptom onset in a )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(mouse model of Huntingtons disease. PLOS Currents Huntington Disease. 2010 Dec 7 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.RRN1201.)] TJ ET q 15.000 31.315 577.500 593.837 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Exercise benefits both general health and brain function in rodents and humans. However, it is less clear whether physical )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(activity prevents or ameliorates neurodegenerative diseases. The aim of the present study was to determine whether voluntary )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(wheel running can delay the onset or reduce the severity of Huntingtons disease \(HD\) in a mouse model. To investigate )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(whether running may delay HD symptoms lifespan, disease onset, locomotor activity, glucose levels, weight, striatal volume, )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(inclusions, cognition and hippocampal neurogenesis were studied in male N171-82Q transgenic HD mice. Running started in )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(pre-symptomatic \(441 days old\) male HD mice, did not improve function and appeared to accelerate disease onset. In )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(particular, HD runners had an earlier onset of disease symptoms \(shaking, hunched back and poor grooming\), reduced striatal )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(volume and impaired motor behavior, including a shorter latency to fall from the rotarod compared to sedentary controls. )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(Furthermore, weight loss, reduced lifespan, hyperglycemia, Morris water maze learning deficits, diminished hippocampal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions and decreased dentate gyrus volume were )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(refractory to physical activity. Taken together our research indicates that exercise is not beneficial, and may be detrimental to a )] TJ ET BT 26.250 447.524 Td /F1 9.8 Tf [(vulnerable nervous system.)] TJ ET BT 26.250 410.921 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program at the National Institute on Aging.)] TJ ET BT 26.250 361.865 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(Exercise benefits general health and brain function )] TJ ET 0.267 0.267 0.267 rg BT 247.906 341.910 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 258.749 341.910 Td /F1 9.8 Tf [( . In rodents, running increases hippocampal neurogenesis, spine density, )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(vascularization, neurotrophin levels, learning and long-term potentiation)] TJ ET 0.267 0.267 0.267 rg BT 334.594 330.006 Td /F1 9.8 Tf [( [2] [3] [4])] TJ ET 0.271 0.267 0.267 rg BT 375.251 330.006 Td /F1 9.8 Tf [( . However, it remains unclear whether )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(exercise delays or prevents neurodegenerative diseases and HD in particular. Initial research showed that environmental )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(enrichment delays symptom onset in R6/1 transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 281.466 306.196 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 292.308 306.196 Td /F1 9.8 Tf [( . An important component of enrichment is physical activity )] TJ ET 0.267 0.267 0.267 rg BT 551.327 306.196 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 562.168 306.196 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(Indeed, in R6/1 mice, running normalized rearing behavior and delayed the onset of deficits in rear-paw clasping, motor )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(coordination and spatial working memory. However, rotarod performance, ubiquitinated protein aggregates and hippocampal )] TJ ET BT 26.250 270.482 Td /F1 9.8 Tf [(BDNF protein levels were unchanged by exercise )] TJ ET 0.267 0.267 0.267 rg BT 242.456 270.482 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 266.851 270.482 Td /F1 9.8 Tf [( . In addition, running conferred some positive changes to )] TJ ET BT 26.250 258.577 Td /F1 9.8 Tf [(electrophysiological properties of medium-sized spiny neurons in the striatum of R6/2 mice)] TJ ET 0.267 0.267 0.267 rg BT 416.387 258.577 Td /F1 9.8 Tf [( [9])] TJ ET 0.271 0.267 0.267 rg BT 429.939 258.577 Td /F1 9.8 Tf [( . Thus, it is unclear whether )] TJ ET BT 26.250 246.672 Td /F1 9.8 Tf [(running enhances motor and cognitive function in HD mouse models.)] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(A biological correlate of exercise is increased hippocampal neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 340.541 227.268 Td /F1 9.8 Tf [( [4])] TJ ET 0.271 0.267 0.267 rg BT 354.094 227.268 Td /F1 9.8 Tf [( . Stimulation of endogenous dentate gyrus )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 84.779 215.363 Td /F1 9.8 Tf [( [10] [11])] TJ ET 0.271 0.267 0.267 rg BT 122.726 215.363 Td /F1 9.8 Tf [( may be a therapeutic intervention)] TJ ET 0.267 0.267 0.267 rg BT 269.591 215.363 Td /F1 9.8 Tf [( [12])] TJ ET 0.271 0.267 0.267 rg BT 288.564 215.363 Td /F1 9.8 Tf [( for HD related cognitive deficits. However, in R6/2 mice, )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(neurogenesis is reduced and refractory to exercise)] TJ ET 0.267 0.267 0.267 rg BT 245.177 203.458 Td /F1 9.8 Tf [( [13])] TJ ET 0.271 0.267 0.267 rg BT 264.150 203.458 Td /F1 9.8 Tf [( . It is unknown whether lack of an effect of running is limited to this )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(transgenic strain. R6/2 mice are mainly a model for the juvenile-onset form of HD, whereas R6/1 transgenic mice have a later )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(disease onset and longer lifespan )] TJ ET 0.267 0.267 0.267 rg BT 174.206 179.649 Td /F1 9.8 Tf [([14] [15])] TJ ET 0.271 0.267 0.267 rg BT 209.443 179.649 Td /F1 9.8 Tf [( . Interestingly, environmental enrichment enhanced neurogenesis in this mouse )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(model )] TJ ET 0.267 0.267 0.267 rg BT 55.510 167.744 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 71.773 167.744 Td /F1 9.8 Tf [( . Effects of running on cell genesis in N171-82Q mice have not been investigated.)] TJ ET BT 26.250 148.339 Td /F1 9.8 Tf [(Transgenic N171-82Q mice express a human N-terminal truncated huntingtin cDNA encoding a 171 amino acid fragment with )] TJ ET BT 26.250 136.434 Td /F1 9.8 Tf [(82 polyglutamine repeats driven by a neuron specific mouse prion protein promoter )] TJ ET 0.267 0.267 0.267 rg BT 387.156 136.434 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 422.392 136.434 Td /F1 9.8 Tf [( . These mice have mutant )] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Huntingtin-positive \(mHtt )] TJ ET BT 135.694 128.418 Td /F1 8.7 Tf [(+)] TJ ET BT 140.755 124.530 Td /F1 9.8 Tf [( \) nuclear inclusions, neuritic aggregates, motor and cognitive deficits, hyperglycemia, weight loss )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(and reduced lifespan )] TJ ET 0.267 0.267 0.267 rg BT 119.470 112.625 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 211.627 112.625 Td /F1 9.8 Tf [( . From 11 weeks of age, weight loss, tremors and clasping are found. Cognitive )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(deficits begin around 14 weeks. By week 16, neuronal loss and mHtt )] TJ ET BT 324.308 104.608 Td /F1 8.7 Tf [(+)] TJ ET BT 329.369 100.720 Td /F1 9.8 Tf [( inclusions are detectable in striatum, cortex and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(hippocampus. Total lifespan is 5-6 months )] TJ ET 0.267 0.267 0.267 rg BT 211.578 88.815 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 303.735 88.815 Td /F1 9.8 Tf [( . The gradual symptom development allows for the study of )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(this model of disease progression and for investigation of possible pre-symptomatic therapies.)] TJ ET BT 26.250 57.506 Td /F1 9.8 Tf [(In the present study, we aimed to determine whether HD can be delayed by starting voluntary exercise in pre-symptomatic )] TJ ET BT 26.250 45.601 Td /F1 9.8 Tf [(N171-82Q mice. Surprisingly, running accelerated disease onset and exacerbated motor impairments and striatal volume )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Exercise is not beneficial and may accelerate symptom onset in )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(a mouse model of Huntingtons disease)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(December 7, 2010)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Michelle C Potter)] TJ ET 0.271 0.267 0.267 rg BT 111.319 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 116.740 663.247 Td /F1 9.8 Tf [(Chunyan Yuan)] TJ ET 0.271 0.267 0.267 rg BT 181.236 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.657 663.247 Td /F1 9.8 Tf [(Conwell Ottenritter)] TJ ET 0.271 0.267 0.267 rg BT 267.387 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 272.808 663.247 Td /F1 9.8 Tf [(Mohamed Mughal)] TJ ET 0.271 0.267 0.267 rg BT 350.837 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 356.258 663.247 Td /F1 9.8 Tf [(Henriette van Praag)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Potter MC, Yuan C, Ottenritter C, Mughal M, van Praag H. Exercise is not beneficial and may accelerate symptom onset in a )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(mouse model of Huntingtons disease. PLOS Currents Huntington Disease. 2010 Dec 7 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.RRN1201.)] TJ ET q 15.000 31.315 577.500 593.837 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Exercise benefits both general health and brain function in rodents and humans. However, it is less clear whether physical )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(activity prevents or ameliorates neurodegenerative diseases. The aim of the present study was to determine whether voluntary )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(wheel running can delay the onset or reduce the severity of Huntingtons disease \(HD\) in a mouse model. To investigate )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(whether running may delay HD symptoms lifespan, disease onset, locomotor activity, glucose levels, weight, striatal volume, )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(inclusions, cognition and hippocampal neurogenesis were studied in male N171-82Q transgenic HD mice. Running started in )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(pre-symptomatic \(441 days old\) male HD mice, did not improve function and appeared to accelerate disease onset. In )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(particular, HD runners had an earlier onset of disease symptoms \(shaking, hunched back and poor grooming\), reduced striatal )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(volume and impaired motor behavior, including a shorter latency to fall from the rotarod compared to sedentary controls. )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(Furthermore, weight loss, reduced lifespan, hyperglycemia, Morris water maze learning deficits, diminished hippocampal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions and decreased dentate gyrus volume were )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(refractory to physical activity. Taken together our research indicates that exercise is not beneficial, and may be detrimental to a )] TJ ET BT 26.250 447.524 Td /F1 9.8 Tf [(vulnerable nervous system.)] TJ ET BT 26.250 410.921 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program at the National Institute on Aging.)] TJ ET BT 26.250 361.865 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(Exercise benefits general health and brain function )] TJ ET 0.267 0.267 0.267 rg BT 247.906 341.910 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 258.749 341.910 Td /F1 9.8 Tf [( . In rodents, running increases hippocampal neurogenesis, spine density, )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(vascularization, neurotrophin levels, learning and long-term potentiation)] TJ ET 0.267 0.267 0.267 rg BT 334.594 330.006 Td /F1 9.8 Tf [( [2] [3] [4])] TJ ET 0.271 0.267 0.267 rg BT 375.251 330.006 Td /F1 9.8 Tf [( . However, it remains unclear whether )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(exercise delays or prevents neurodegenerative diseases and HD in particular. Initial research showed that environmental )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(enrichment delays symptom onset in R6/1 transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 281.466 306.196 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 292.308 306.196 Td /F1 9.8 Tf [( . An important component of enrichment is physical activity )] TJ ET 0.267 0.267 0.267 rg BT 551.327 306.196 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 562.168 306.196 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(Indeed, in R6/1 mice, running normalized rearing behavior and delayed the onset of deficits in rear-paw clasping, motor )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(coordination and spatial working memory. However, rotarod performance, ubiquitinated protein aggregates and hippocampal )] TJ ET BT 26.250 270.482 Td /F1 9.8 Tf [(BDNF protein levels were unchanged by exercise )] TJ ET 0.267 0.267 0.267 rg BT 242.456 270.482 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 266.851 270.482 Td /F1 9.8 Tf [( . In addition, running conferred some positive changes to )] TJ ET BT 26.250 258.577 Td /F1 9.8 Tf [(electrophysiological properties of medium-sized spiny neurons in the striatum of R6/2 mice)] TJ ET 0.267 0.267 0.267 rg BT 416.387 258.577 Td /F1 9.8 Tf [( [9])] TJ ET 0.271 0.267 0.267 rg BT 429.939 258.577 Td /F1 9.8 Tf [( . Thus, it is unclear whether )] TJ ET BT 26.250 246.672 Td /F1 9.8 Tf [(running enhances motor and cognitive function in HD mouse models.)] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(A biological correlate of exercise is increased hippocampal neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 340.541 227.268 Td /F1 9.8 Tf [( [4])] TJ ET 0.271 0.267 0.267 rg BT 354.094 227.268 Td /F1 9.8 Tf [( . Stimulation of endogenous dentate gyrus )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 84.779 215.363 Td /F1 9.8 Tf [( [10] [11])] TJ ET 0.271 0.267 0.267 rg BT 122.726 215.363 Td /F1 9.8 Tf [( may be a therapeutic intervention)] TJ ET 0.267 0.267 0.267 rg BT 269.591 215.363 Td /F1 9.8 Tf [( [12])] TJ ET 0.271 0.267 0.267 rg BT 288.564 215.363 Td /F1 9.8 Tf [( for HD related cognitive deficits. However, in R6/2 mice, )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(neurogenesis is reduced and refractory to exercise)] TJ ET 0.267 0.267 0.267 rg BT 245.177 203.458 Td /F1 9.8 Tf [( [13])] TJ ET 0.271 0.267 0.267 rg BT 264.150 203.458 Td /F1 9.8 Tf [( . It is unknown whether lack of an effect of running is limited to this )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(transgenic strain. R6/2 mice are mainly a model for the juvenile-onset form of HD, whereas R6/1 transgenic mice have a later )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(disease onset and longer lifespan )] TJ ET 0.267 0.267 0.267 rg BT 174.206 179.649 Td /F1 9.8 Tf [([14] [15])] TJ ET 0.271 0.267 0.267 rg BT 209.443 179.649 Td /F1 9.8 Tf [( . Interestingly, environmental enrichment enhanced neurogenesis in this mouse )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(model )] TJ ET 0.267 0.267 0.267 rg BT 55.510 167.744 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 71.773 167.744 Td /F1 9.8 Tf [( . Effects of running on cell genesis in N171-82Q mice have not been investigated.)] TJ ET BT 26.250 148.339 Td /F1 9.8 Tf [(Transgenic N171-82Q mice express a human N-terminal truncated huntingtin cDNA encoding a 171 amino acid fragment with )] TJ ET BT 26.250 136.434 Td /F1 9.8 Tf [(82 polyglutamine repeats driven by a neuron specific mouse prion protein promoter )] TJ ET 0.267 0.267 0.267 rg BT 387.156 136.434 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 422.392 136.434 Td /F1 9.8 Tf [( . These mice have mutant )] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Huntingtin-positive \(mHtt )] TJ ET BT 135.694 128.418 Td /F1 8.7 Tf [(+)] TJ ET BT 140.755 124.530 Td /F1 9.8 Tf [( \) nuclear inclusions, neuritic aggregates, motor and cognitive deficits, hyperglycemia, weight loss )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(and reduced lifespan )] TJ ET 0.267 0.267 0.267 rg BT 119.470 112.625 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 211.627 112.625 Td /F1 9.8 Tf [( . From 11 weeks of age, weight loss, tremors and clasping are found. Cognitive )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(deficits begin around 14 weeks. By week 16, neuronal loss and mHtt )] TJ ET BT 324.308 104.608 Td /F1 8.7 Tf [(+)] TJ ET BT 329.369 100.720 Td /F1 9.8 Tf [( inclusions are detectable in striatum, cortex and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(hippocampus. Total lifespan is 5-6 months )] TJ ET 0.267 0.267 0.267 rg BT 211.578 88.815 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 303.735 88.815 Td /F1 9.8 Tf [( . The gradual symptom development allows for the study of )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(this model of disease progression and for investigation of possible pre-symptomatic therapies.)] TJ ET BT 26.250 57.506 Td /F1 9.8 Tf [(In the present study, we aimed to determine whether HD can be delayed by starting voluntary exercise in pre-symptomatic )] TJ ET BT 26.250 45.601 Td /F1 9.8 Tf [(N171-82Q mice. Surprisingly, running accelerated disease onset and exacerbated motor impairments and striatal volume )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Exercise is not beneficial and may accelerate symptom onset in )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(a mouse model of Huntingtons disease)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(December 7, 2010)] TJ ET BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Michelle C Potter)] TJ ET 0.271 0.267 0.267 rg BT 111.319 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 116.740 663.247 Td /F1 9.8 Tf [(Chunyan Yuan)] TJ ET 0.271 0.267 0.267 rg BT 181.236 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 186.657 663.247 Td /F1 9.8 Tf [(Conwell Ottenritter)] TJ ET 0.271 0.267 0.267 rg BT 267.387 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 272.808 663.247 Td /F1 9.8 Tf [(Mohamed Mughal)] TJ ET 0.271 0.267 0.267 rg BT 350.837 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 356.258 663.247 Td /F1 9.8 Tf [(Henriette van Praag)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Potter MC, Yuan C, Ottenritter C, Mughal M, van Praag H. Exercise is not beneficial and may accelerate symptom onset in a )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(mouse model of Huntingtons disease. PLOS Currents Huntington Disease. 2010 Dec 7 . Edition 1. doi: )] TJ ET BT 26.250 627.533 Td /F1 9.8 Tf [(10.1371/currents.RRN1201.)] TJ ET q 15.000 31.315 577.500 593.837 re W n 0.271 0.267 0.267 rg BT 26.250 598.430 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Exercise benefits both general health and brain function in rodents and humans. However, it is less clear whether physical )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(activity prevents or ameliorates neurodegenerative diseases. The aim of the present study was to determine whether voluntary )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(wheel running can delay the onset or reduce the severity of Huntingtons disease \(HD\) in a mouse model. To investigate )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(whether running may delay HD symptoms lifespan, disease onset, locomotor activity, glucose levels, weight, striatal volume, )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(inclusions, cognition and hippocampal neurogenesis were studied in male N171-82Q transgenic HD mice. Running started in )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(pre-symptomatic \(441 days old\) male HD mice, did not improve function and appeared to accelerate disease onset. In )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(particular, HD runners had an earlier onset of disease symptoms \(shaking, hunched back and poor grooming\), reduced striatal )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(volume and impaired motor behavior, including a shorter latency to fall from the rotarod compared to sedentary controls. )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(Furthermore, weight loss, reduced lifespan, hyperglycemia, Morris water maze learning deficits, diminished hippocampal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions and decreased dentate gyrus volume were )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(refractory to physical activity. Taken together our research indicates that exercise is not beneficial, and may be detrimental to a )] TJ ET BT 26.250 447.524 Td /F1 9.8 Tf [(vulnerable nervous system.)] TJ ET BT 26.250 410.921 Td /F4 12.0 Tf [(Funding Statement)] TJ ET BT 26.250 390.967 Td /F1 9.8 Tf [(This research was supported by the Intramural Research Program at the National Institute on Aging.)] TJ ET BT 26.250 361.865 Td /F4 12.0 Tf [(Introduction)] TJ ET BT 26.250 341.910 Td /F1 9.8 Tf [(Exercise benefits general health and brain function )] TJ ET 0.267 0.267 0.267 rg BT 247.906 341.910 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 258.749 341.910 Td /F1 9.8 Tf [( . In rodents, running increases hippocampal neurogenesis, spine density, )] TJ ET BT 26.250 330.006 Td /F1 9.8 Tf [(vascularization, neurotrophin levels, learning and long-term potentiation)] TJ ET 0.267 0.267 0.267 rg BT 334.594 330.006 Td /F1 9.8 Tf [( [2] [3] [4])] TJ ET 0.271 0.267 0.267 rg BT 375.251 330.006 Td /F1 9.8 Tf [( . However, it remains unclear whether )] TJ ET BT 26.250 318.101 Td /F1 9.8 Tf [(exercise delays or prevents neurodegenerative diseases and HD in particular. Initial research showed that environmental )] TJ ET BT 26.250 306.196 Td /F1 9.8 Tf [(enrichment delays symptom onset in R6/1 transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 281.466 306.196 Td /F1 9.8 Tf [([5])] TJ ET 0.271 0.267 0.267 rg BT 292.308 306.196 Td /F1 9.8 Tf [( . An important component of enrichment is physical activity )] TJ ET 0.267 0.267 0.267 rg BT 551.327 306.196 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 562.168 306.196 Td /F1 9.8 Tf [( . )] TJ ET BT 26.250 294.291 Td /F1 9.8 Tf [(Indeed, in R6/1 mice, running normalized rearing behavior and delayed the onset of deficits in rear-paw clasping, motor )] TJ ET BT 26.250 282.387 Td /F1 9.8 Tf [(coordination and spatial working memory. However, rotarod performance, ubiquitinated protein aggregates and hippocampal )] TJ ET BT 26.250 270.482 Td /F1 9.8 Tf [(BDNF protein levels were unchanged by exercise )] TJ ET 0.267 0.267 0.267 rg BT 242.456 270.482 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 266.851 270.482 Td /F1 9.8 Tf [( . In addition, running conferred some positive changes to )] TJ ET BT 26.250 258.577 Td /F1 9.8 Tf [(electrophysiological properties of medium-sized spiny neurons in the striatum of R6/2 mice)] TJ ET 0.267 0.267 0.267 rg BT 416.387 258.577 Td /F1 9.8 Tf [( [9])] TJ ET 0.271 0.267 0.267 rg BT 429.939 258.577 Td /F1 9.8 Tf [( . Thus, it is unclear whether )] TJ ET BT 26.250 246.672 Td /F1 9.8 Tf [(running enhances motor and cognitive function in HD mouse models.)] TJ ET BT 26.250 227.268 Td /F1 9.8 Tf [(A biological correlate of exercise is increased hippocampal neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 340.541 227.268 Td /F1 9.8 Tf [( [4])] TJ ET 0.271 0.267 0.267 rg BT 354.094 227.268 Td /F1 9.8 Tf [( . Stimulation of endogenous dentate gyrus )] TJ ET BT 26.250 215.363 Td /F1 9.8 Tf [(neurogenesis)] TJ ET 0.267 0.267 0.267 rg BT 84.779 215.363 Td /F1 9.8 Tf [( [10] [11])] TJ ET 0.271 0.267 0.267 rg BT 122.726 215.363 Td /F1 9.8 Tf [( may be a therapeutic intervention)] TJ ET 0.267 0.267 0.267 rg BT 269.591 215.363 Td /F1 9.8 Tf [( [12])] TJ ET 0.271 0.267 0.267 rg BT 288.564 215.363 Td /F1 9.8 Tf [( for HD related cognitive deficits. However, in R6/2 mice, )] TJ ET BT 26.250 203.458 Td /F1 9.8 Tf [(neurogenesis is reduced and refractory to exercise)] TJ ET 0.267 0.267 0.267 rg BT 245.177 203.458 Td /F1 9.8 Tf [( [13])] TJ ET 0.271 0.267 0.267 rg BT 264.150 203.458 Td /F1 9.8 Tf [( . It is unknown whether lack of an effect of running is limited to this )] TJ ET BT 26.250 191.553 Td /F1 9.8 Tf [(transgenic strain. R6/2 mice are mainly a model for the juvenile-onset form of HD, whereas R6/1 transgenic mice have a later )] TJ ET BT 26.250 179.649 Td /F1 9.8 Tf [(disease onset and longer lifespan )] TJ ET 0.267 0.267 0.267 rg BT 174.206 179.649 Td /F1 9.8 Tf [([14] [15])] TJ ET 0.271 0.267 0.267 rg BT 209.443 179.649 Td /F1 9.8 Tf [( . Interestingly, environmental enrichment enhanced neurogenesis in this mouse )] TJ ET BT 26.250 167.744 Td /F1 9.8 Tf [(model )] TJ ET 0.267 0.267 0.267 rg BT 55.510 167.744 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 71.773 167.744 Td /F1 9.8 Tf [( . Effects of running on cell genesis in N171-82Q mice have not been investigated.)] TJ ET BT 26.250 148.339 Td /F1 9.8 Tf [(Transgenic N171-82Q mice express a human N-terminal truncated huntingtin cDNA encoding a 171 amino acid fragment with )] TJ ET BT 26.250 136.434 Td /F1 9.8 Tf [(82 polyglutamine repeats driven by a neuron specific mouse prion protein promoter )] TJ ET 0.267 0.267 0.267 rg BT 387.156 136.434 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 422.392 136.434 Td /F1 9.8 Tf [( . These mice have mutant )] TJ ET BT 26.250 124.530 Td /F1 9.8 Tf [(Huntingtin-positive \(mHtt )] TJ ET BT 135.694 128.418 Td /F1 8.7 Tf [(+)] TJ ET BT 140.755 124.530 Td /F1 9.8 Tf [( \) nuclear inclusions, neuritic aggregates, motor and cognitive deficits, hyperglycemia, weight loss )] TJ ET BT 26.250 112.625 Td /F1 9.8 Tf [(and reduced lifespan )] TJ ET 0.267 0.267 0.267 rg BT 119.470 112.625 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 211.627 112.625 Td /F1 9.8 Tf [( . From 11 weeks of age, weight loss, tremors and clasping are found. Cognitive )] TJ ET BT 26.250 100.720 Td /F1 9.8 Tf [(deficits begin around 14 weeks. By week 16, neuronal loss and mHtt )] TJ ET BT 324.308 104.608 Td /F1 8.7 Tf [(+)] TJ ET BT 329.369 100.720 Td /F1 9.8 Tf [( inclusions are detectable in striatum, cortex and )] TJ ET BT 26.250 88.815 Td /F1 9.8 Tf [(hippocampus. Total lifespan is 5-6 months )] TJ ET 0.267 0.267 0.267 rg BT 211.578 88.815 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 303.735 88.815 Td /F1 9.8 Tf [( . The gradual symptom development allows for the study of )] TJ ET BT 26.250 76.911 Td /F1 9.8 Tf [(this model of disease progression and for investigation of possible pre-symptomatic therapies.)] TJ ET BT 26.250 57.506 Td /F1 9.8 Tf [(In the present study, we aimed to determine whether HD can be delayed by starting voluntary exercise in pre-symptomatic )] TJ ET BT 26.250 45.601 Td /F1 9.8 Tf [(N171-82Q mice. 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In addition, physical activity did not improve hippocampal neurogenesis, dentate gyrus volume, weight, )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hyperglycemia, cognition, mHtt )] TJ ET BT 162.253 759.460 Td /F1 8.7 Tf [(+)] TJ ET BT 167.314 755.571 Td /F1 9.8 Tf [( cell number and lifespan. Our research indicates that in a mouse model of HD, exercise is not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(beneficial, and could be detrimental for general health and brain function.)] TJ ET BT 26.250 707.064 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 687.110 Td /F4 9.8 Tf [(Subjects)] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(WT C3H/HEJxC57BL/6J F )] TJ ET BT 143.815 665.641 Td /F1 8.7 Tf [(1)] TJ ET BT 148.634 667.705 Td /F1 9.8 Tf [( hybrid females were mated with male transgenic N171-82Q mice expressing a human N-terminal )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(truncated huntingtin with 82 polyglutamine repeats driven by a mouse prion protein promoter provided by D.R. Borchelt \(Johns )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(Hopkins University, Baltimore\) )] TJ ET 0.267 0.267 0.267 rg BT 159.523 643.896 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 194.759 643.896 Td /F1 9.8 Tf [( . These animals were housed in a temperature-controlled animal facility on a 12 hour/12 )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(hour light dark cycle with free access to food and water. The animal facility was fully accredited by the American Association for )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(the Accreditation of Laboratory Animal Care \(AAALAC\). The offspring were genotyped subsequent to weaning. In the lifespan )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(mice \(L, Fig 1A\), the number of CAG repeats was sequenced \(Table 1\) in the transgenic animals \(Laragen Inc. 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Therefore, the CAG repeat numbers determined by GM technique is smaller than the CAG repeat )] TJ ET BT 35.250 279.712 Td /F1 9.8 Tf [(numbers determined by DNA sequencing technique \(SEQ\), which are closer to the actual CAG repeat numbers. Overall this )] TJ ET BT 35.250 265.975 Td /F1 9.8 Tf [(analysis showed that CAG repeat number remained stable, had not expanded further with breeding and did not differ )] TJ ET BT 35.250 252.239 Td /F1 9.8 Tf [(between transgenic controls and runners \(p>0.59\).)] TJ ET Q BT 26.250 213.718 Td /F4 9.8 Tf [(General Experimental Procedure)] TJ ET BT 26.250 194.313 Td /F1 9.8 Tf [(Male HD heterozygotes \(N=26\) and non-transgenic controls \(N=28\) \(441 days old\) were individually housed in standard cages )] TJ ET BT 26.250 182.409 Td /F1 9.8 Tf [(with or without a running wheel \(WTS=13; WTR=15; HTS=13; HTR=13\) \(Fig 1A\). 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One hemisphere was dissected and the cortex, hippocampus and striatum were stored at -80C for future biochemical )] TJ ET BT 26.250 99.075 Td /F1 9.8 Tf [(and molecular assays. The other hemisphere was placed in cold 4% paraformaldehyde \(PFA\) in 0.1 M PBS for 3-4 days, then )] TJ ET BT 26.250 87.171 Td /F1 9.8 Tf [(transferred to 30% sucrose and processed for immunostaining as described below. The remaining animals were followed )] TJ ET BT 26.250 75.266 Td /F1 9.8 Tf [(throughout their lives for the appearance of disease symptoms and lifespan comparisons \(L mice: WTS=7; WTR=10; HTS=6; )] TJ ET BT 26.250 63.361 Td /F1 9.8 Tf [(HTR=7\). Upon development of severe symptoms resulting in immobility and inability to feed, transgenic mice were deeply )] TJ ET BT 26.250 51.456 Td /F1 9.8 Tf [(anesthetized and perfused with 4% PFA in 0.1 M PBS and then equilibrated in 30% sucrose after 3-4 days. Once all the )] TJ ET BT 26.250 39.552 Td /F1 9.8 Tf [(transgenic mice had died, the remaining WT mice were sacrificed and treated in the same manner. Sequential coronal sections )] TJ ET Q q 15.000 25.266 577.500 751.734 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(reduction. In addition, physical activity did not improve hippocampal neurogenesis, dentate gyrus volume, weight, )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hyperglycemia, cognition, mHtt )] TJ ET BT 162.253 759.460 Td /F1 8.7 Tf [(+)] TJ ET BT 167.314 755.571 Td /F1 9.8 Tf [( cell number and lifespan. Our research indicates that in a mouse model of HD, exercise is not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(beneficial, and could be detrimental for general health and brain function.)] TJ ET BT 26.250 707.064 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 687.110 Td /F4 9.8 Tf [(Subjects)] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(WT C3H/HEJxC57BL/6J F )] TJ ET BT 143.815 665.641 Td /F1 8.7 Tf [(1)] TJ ET BT 148.634 667.705 Td /F1 9.8 Tf [( hybrid females were mated with male transgenic N171-82Q mice expressing a human N-terminal )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(truncated huntingtin with 82 polyglutamine repeats driven by a mouse prion protein promoter provided by D.R. Borchelt \(Johns )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(Hopkins University, Baltimore\) )] TJ ET 0.267 0.267 0.267 rg BT 159.523 643.896 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 194.759 643.896 Td /F1 9.8 Tf [( . These animals were housed in a temperature-controlled animal facility on a 12 hour/12 )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(hour light dark cycle with free access to food and water. The animal facility was fully accredited by the American Association for )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(the Accreditation of Laboratory Animal Care \(AAALAC\). The offspring were genotyped subsequent to weaning. In the lifespan )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(mice \(L, Fig 1A\), the number of CAG repeats was sequenced \(Table 1\) in the transgenic animals \(Laragen Inc. Los Angeles, )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(CA\).)] TJ ET 0.965 0.965 0.965 rg 26.250 230.742 555.000 355.654 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 586.396 m 581.250 586.396 l 581.250 585.646 l 26.250 585.646 l f 26.250 230.742 m 581.250 230.742 l 581.250 231.492 l 26.250 231.492 l f q 184.500 0 0 225.000 35.250 351.646 cm /I3 Do Q q 35.250 241.992 537.000 103.654 re W n 0.271 0.267 0.267 rg BT 35.250 334.657 Td /F4 9.8 Tf [(Table 1.)] TJ ET BT 71.559 334.657 Td /F1 9.8 Tf [( The number of CAG repeats in the HD mice used for lifespan \(L\) analysis. The CAG repeat number was measured )] TJ ET BT 35.250 320.920 Td /F1 9.8 Tf [(by ABI Genemapper \(GM\) technique \(Laragen Inc. Los Angeles, CA\). The CAG numbers were derived from the PCR )] TJ ET BT 35.250 307.184 Td /F1 9.8 Tf [(fragment size. The DNA fragments with trinucleotide repeats such as CAG migrate faster than the DNA fragments with )] TJ ET BT 35.250 293.448 Td /F1 9.8 Tf [(random sequences. Therefore, the CAG repeat numbers determined by GM technique is smaller than the CAG repeat )] TJ ET BT 35.250 279.712 Td /F1 9.8 Tf [(numbers determined by DNA sequencing technique \(SEQ\), which are closer to the actual CAG repeat numbers. Overall this )] TJ ET BT 35.250 265.975 Td /F1 9.8 Tf [(analysis showed that CAG repeat number remained stable, had not expanded further with breeding and did not differ )] TJ ET BT 35.250 252.239 Td /F1 9.8 Tf [(between transgenic controls and runners \(p>0.59\).)] TJ ET Q BT 26.250 213.718 Td /F4 9.8 Tf [(General Experimental Procedure)] TJ ET BT 26.250 194.313 Td /F1 9.8 Tf [(Male HD heterozygotes \(N=26\) and non-transgenic controls \(N=28\) \(441 days old\) were individually housed in standard cages )] TJ ET BT 26.250 182.409 Td /F1 9.8 Tf [(with or without a running wheel \(WTS=13; WTR=15; HTS=13; HTR=13\) \(Fig 1A\). During the first 10 days of the experiment, all )] TJ ET BT 26.250 170.504 Td /F1 9.8 Tf [(mice were injected with bromodeoxyuridine \(BrdU, Sigma, St. Louis MO; 50 mg/kg\) to label dividing cells. General health and )] TJ ET BT 26.250 158.599 Td /F1 9.8 Tf [(disease symptoms, including body weight and glucose levels as well as running distance were recorded throughout the entire )] TJ ET BT 26.250 146.694 Td /F1 9.8 Tf [(experiment in all mice. A subset \(S\) of these mice \(S mice: WTS=6; WTR=5; HTS=7; HTR=6\) were tested in the Morris water )] TJ ET BT 26.250 134.790 Td /F1 9.8 Tf [(maze \(881 days old\), rotarod \(1001 days old\) and open field \(1031 days old\). On completion of behavioral testing \(1131 )] TJ ET BT 26.250 122.885 Td /F1 9.8 Tf [(days old\), these mice were deeply anesthetized with isofluorane \(Abbott Laboratories\) and perfused transcardially with 0.9% )] TJ ET BT 26.250 110.980 Td /F1 9.8 Tf [(saline. One hemisphere was dissected and the cortex, hippocampus and striatum were stored at -80C for future biochemical )] TJ ET BT 26.250 99.075 Td /F1 9.8 Tf [(and molecular assays. The other hemisphere was placed in cold 4% paraformaldehyde \(PFA\) in 0.1 M PBS for 3-4 days, then )] TJ ET BT 26.250 87.171 Td /F1 9.8 Tf [(transferred to 30% sucrose and processed for immunostaining as described below. The remaining animals were followed )] TJ ET BT 26.250 75.266 Td /F1 9.8 Tf [(throughout their lives for the appearance of disease symptoms and lifespan comparisons \(L mice: WTS=7; WTR=10; HTS=6; )] TJ ET BT 26.250 63.361 Td /F1 9.8 Tf [(HTR=7\). Upon development of severe symptoms resulting in immobility and inability to feed, transgenic mice were deeply )] TJ ET BT 26.250 51.456 Td /F1 9.8 Tf [(anesthetized and perfused with 4% PFA in 0.1 M PBS and then equilibrated in 30% sucrose after 3-4 days. Once all the )] TJ ET BT 26.250 39.552 Td /F1 9.8 Tf [(transgenic mice had died, the remaining WT mice were sacrificed and treated in the same manner. Sequential coronal sections )] TJ ET Q q 15.000 25.266 577.500 751.734 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(reduction. In addition, physical activity did not improve hippocampal neurogenesis, dentate gyrus volume, weight, )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(hyperglycemia, cognition, mHtt )] TJ ET BT 162.253 759.460 Td /F1 8.7 Tf [(+)] TJ ET BT 167.314 755.571 Td /F1 9.8 Tf [( cell number and lifespan. Our research indicates that in a mouse model of HD, exercise is not )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(beneficial, and could be detrimental for general health and brain function.)] TJ ET BT 26.250 707.064 Td /F4 12.0 Tf [(Materials and Methods)] TJ ET BT 26.250 687.110 Td /F4 9.8 Tf [(Subjects)] TJ ET BT 26.250 667.705 Td /F1 9.8 Tf [(WT C3H/HEJxC57BL/6J F )] TJ ET BT 143.815 665.641 Td /F1 8.7 Tf [(1)] TJ ET BT 148.634 667.705 Td /F1 9.8 Tf [( hybrid females were mated with male transgenic N171-82Q mice expressing a human N-terminal )] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(truncated huntingtin with 82 polyglutamine repeats driven by a mouse prion protein promoter provided by D.R. Borchelt \(Johns )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(Hopkins University, Baltimore\) )] TJ ET 0.267 0.267 0.267 rg BT 159.523 643.896 Td /F1 9.8 Tf [([17] [18])] TJ ET 0.271 0.267 0.267 rg BT 194.759 643.896 Td /F1 9.8 Tf [( . These animals were housed in a temperature-controlled animal facility on a 12 hour/12 )] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(hour light dark cycle with free access to food and water. The animal facility was fully accredited by the American Association for )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(the Accreditation of Laboratory Animal Care \(AAALAC\). The offspring were genotyped subsequent to weaning. In the lifespan )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(mice \(L, Fig 1A\), the number of CAG repeats was sequenced \(Table 1\) in the transgenic animals \(Laragen Inc. Los Angeles, )] TJ ET BT 26.250 596.277 Td /F1 9.8 Tf [(CA\).)] TJ ET 0.965 0.965 0.965 rg 26.250 230.742 555.000 355.654 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 586.396 m 581.250 586.396 l 581.250 585.646 l 26.250 585.646 l f 26.250 230.742 m 581.250 230.742 l 581.250 231.492 l 26.250 231.492 l f q 184.500 0 0 225.000 35.250 351.646 cm /I3 Do Q q 35.250 241.992 537.000 103.654 re W n 0.271 0.267 0.267 rg BT 35.250 334.657 Td /F4 9.8 Tf [(Table 1.)] TJ ET BT 71.559 334.657 Td /F1 9.8 Tf [( The number of CAG repeats in the HD mice used for lifespan \(L\) analysis. The CAG repeat number was measured )] TJ ET BT 35.250 320.920 Td /F1 9.8 Tf [(by ABI Genemapper \(GM\) technique \(Laragen Inc. Los Angeles, CA\). The CAG numbers were derived from the PCR )] TJ ET BT 35.250 307.184 Td /F1 9.8 Tf [(fragment size. The DNA fragments with trinucleotide repeats such as CAG migrate faster than the DNA fragments with )] TJ ET BT 35.250 293.448 Td /F1 9.8 Tf [(random sequences. Therefore, the CAG repeat numbers determined by GM technique is smaller than the CAG repeat )] TJ ET BT 35.250 279.712 Td /F1 9.8 Tf [(numbers determined by DNA sequencing technique \(SEQ\), which are closer to the actual CAG repeat numbers. Overall this )] TJ ET BT 35.250 265.975 Td /F1 9.8 Tf [(analysis showed that CAG repeat number remained stable, had not expanded further with breeding and did not differ )] TJ ET BT 35.250 252.239 Td /F1 9.8 Tf [(between transgenic controls and runners \(p>0.59\).)] TJ ET Q BT 26.250 213.718 Td /F4 9.8 Tf [(General Experimental Procedure)] TJ ET BT 26.250 194.313 Td /F1 9.8 Tf [(Male HD heterozygotes \(N=26\) and non-transgenic controls \(N=28\) \(441 days old\) were individually housed in standard cages )] TJ ET BT 26.250 182.409 Td /F1 9.8 Tf [(with or without a running wheel \(WTS=13; WTR=15; HTS=13; HTR=13\) \(Fig 1A\). During the first 10 days of the experiment, all )] TJ ET BT 26.250 170.504 Td /F1 9.8 Tf [(mice were injected with bromodeoxyuridine \(BrdU, Sigma, St. Louis MO; 50 mg/kg\) to label dividing cells. General health and )] TJ ET BT 26.250 158.599 Td /F1 9.8 Tf [(disease symptoms, including body weight and glucose levels as well as running distance were recorded throughout the entire )] TJ ET BT 26.250 146.694 Td /F1 9.8 Tf [(experiment in all mice. A subset \(S\) of these mice \(S mice: WTS=6; WTR=5; HTS=7; HTR=6\) were tested in the Morris water )] TJ ET BT 26.250 134.790 Td /F1 9.8 Tf [(maze \(881 days old\), rotarod \(1001 days old\) and open field \(1031 days old\). On completion of behavioral testing \(1131 )] TJ ET BT 26.250 122.885 Td /F1 9.8 Tf [(days old\), these mice were deeply anesthetized with isofluorane \(Abbott Laboratories\) and perfused transcardially with 0.9% )] TJ ET BT 26.250 110.980 Td /F1 9.8 Tf [(saline. One hemisphere was dissected and the cortex, hippocampus and striatum were stored at -80C for future biochemical )] TJ ET BT 26.250 99.075 Td /F1 9.8 Tf [(and molecular assays. The other hemisphere was placed in cold 4% paraformaldehyde \(PFA\) in 0.1 M PBS for 3-4 days, then )] TJ ET BT 26.250 87.171 Td /F1 9.8 Tf [(transferred to 30% sucrose and processed for immunostaining as described below. The remaining animals were followed )] TJ ET BT 26.250 75.266 Td /F1 9.8 Tf [(throughout their lives for the appearance of disease symptoms and lifespan comparisons \(L mice: WTS=7; WTR=10; HTS=6; )] TJ ET BT 26.250 63.361 Td /F1 9.8 Tf [(HTR=7\). Upon development of severe symptoms resulting in immobility and inability to feed, transgenic mice were deeply )] TJ ET BT 26.250 51.456 Td /F1 9.8 Tf [(anesthetized and perfused with 4% PFA in 0.1 M PBS and then equilibrated in 30% sucrose after 3-4 days. Once all the )] TJ ET BT 26.250 39.552 Td /F1 9.8 Tf [(transgenic mice had died, the remaining WT mice were sacrificed and treated in the same manner. Sequential coronal sections )] TJ ET Q q 184.500 0 0 225.000 35.250 351.646 cm /I3 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(2)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 148 0 obj << /Type /Annot /Subtype /Link /A 149 0 R /Border [0 0 0] /H /I /Rect [ 159.5228 642.9938 194.7593 652.9144 ] >> endobj 149 0 obj << /Type /Action >> endobj 150 0 obj << /Type /Annot /Subtype /Link /A 151 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 351.6457 219.7500 576.6457 ] >> endobj 151 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/table-1-plos_001.jpg) >> endobj 152 0 obj << /Type /XObject /Subtype /Image /Width 246 /Height 300 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 23579>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?؏A1Uu|7ujN2]^[nV\ey8~_ '^f tMx70D? ףC~K׼@ #?%g?a/^g2|\2:ee WG 3Y>5_ mhC~K !?%hg?I|3z3@ !?%g?_ '^a/^Fh?g$O/0D? ׯw[|Fᗇ/bkUJ53_1Lg?9+a/G0D? ׯw-x?0D? פg?@ !?%g?h@ !?%??g$O{_ '^a/^K@Vo Ҽ1s}Cs.*,@+෿L^D'L_|u|UoxPC< 1GXnKg q+ ?:J>-~ξk7zZ[k>홃2<{l08~_~_ <1 3iV~W qw+sqyݥ\-G"< o]j>]sG֞O_op1*Rր8>,j 3n5o&p`6+Rӿ:N+>!hΧuz !!9l[^v:57<=α-^iCopy2w?1.<ס|?_>%ּ?o5:> _30Ekd$[uEAVs@֝q%݅@I&6#%I^UKi_ms"Y:_a ߄^nt}&=kZg"o&w/6%c^I 8uď ^%ѭ5/>-普i:`!I.nXg2y%! +?tωlvQFDt`C#*AIa|o[seqxaF$!T IӼ3';v)xnOe6g{~2|d> ~ȟ zNx/"b&mI.'o<*P>'|{kXbkDuZh乁 F''ߵƥښã7{=Xե,nծXFٍӀX57zmNJ#w֓ntPვFG$(cIŮj>[)'7/0473B*99wb=u;JoŦjmռ;cmW?.g o%C@RO4:ޙw1kw I.fT p\ xӃX4;Ěņa#i.4  &Lqe ? 4_x'{ yb3o%vJq+ʴo烴m-uVk{k'Q Kōn-ՙ[0 xV@C3@>.G/~=6wh;H.6HҐߗ-B7o▯'.QҾ4X|;e+gEOhH{y"IwbHRvi'8F=qqN-LP* nv9۞4~~#3_=-G[\G'pKGJʐI'qaj>'<{{XmOֵn,  1Wg' GkOß&a[ݖj7pjqO$1 [T|kAfww∮>kn?mc}OV{I"30r!!Fqcuo'Լ<"u)uYQ(CApU٘P`|o|cv:.w kk=4H7sʝo9^ $z-i?8>7LT9#?1&݀X͌8\CVS״[MJ+5e$%vesSs6mVo5/KH,!/m[l(,IZ0#Iaӭ ˇ]8g_%h y|4dJ@ ?e'7ֵ}{FN2O*ꗑo5vGtO ?:=?>,+")rW~~ O˗?:7~9|scoϮj+X39i.+k97YU(75Y4jVQQeN\ʡ@`} 8rW~?d?$ȹs?_L_?lWi:NMCQ-/ɍ Mgw`YBc䐳n~ \/o.5>0]A{k 9-jתP> "lIʾ^EKm!CSB \cW#ƿ~^kMxUOBw (r0JW' .|cؗiz7wvzխn4I$PukPH)Ub>VeCSB \cLuG-摬4ׄF{6F7B3s^ ˟_s_  V5ߍx2Ÿ.uCSB{j(?йs?H߲/•˟_N|Lu6}gRJ{m6o*[D,R$|ͅ A-l#qn9"`pU ^^AhM %[eu# 'w>i|/5 ROcF1j[kKxoU @?e-*A1VfK왬7i|SEP@P CSB \c)C>X|*nmU5 ~PKx2Jo]>*+>'?¯%}@N~4xhI ?E*+>]>*+>gPW_FW_F8>UůMB9o~1h4eك<zW gs =GO4On?&]Ьkױ@M _E|s?' _E|s?'׬Q@M _E|s?')?EmGzuIFkm,-4V1yHUv"B_#?ş'%kԐI! 4eٸ U`@"9"9qFy7.hG.h^0( [EHuKIlf&%W0෇ c蕢>zq+gGI_Df1> dφڗ'4~ѧ.`0q^ Q oVſmh]XxR$͵m2 ʎk?dk 'm<5oL`xUyp:? ?|A+O=C1k6Η$Ѕ혢p0E}_(~EzkȾ??#|A ?x_iC6>̇oFp=>'}_(~EϫEX'}_(~E?|Aj-R0[<idu;>Pl1 cq;[=&Qk~mugwaë8k$UFnNO5?(Ao??o"=g"ד>o??o"gPfד>o??o"gP^7??  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FM˿ǧ5翆S_E~?ht?htY"Wu4HHÞAҿ :? :i(E{F`T𕯇tȵ]bM\hn\ eMEB(! _YxrM/]|{X}#r_|=3Ώ|=3΀?rk@ @ ܺ?4~??)~??)-?_+E|G?j}G|q&M[g iw ( endstream endobj 153 0 obj << /Type /Annot /Subtype /Link /A 154 0 R /Border [0 0 0] /H /I /Rect [ 159.5228 642.9938 194.7593 652.9144 ] >> endobj 154 0 obj << /Type /Action >> endobj 155 0 obj << /Type /Annot /Subtype /Link /A 156 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 351.6457 219.7500 576.6457 ] >> endobj 156 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/table-1-plos_001.jpg) >> endobj 157 0 obj << /Type /Annot /Subtype /Link /A 158 0 R /Border [0 0 0] /H /I /Rect [ 159.5228 642.9938 194.7593 652.9144 ] >> endobj 158 0 obj << /Type /Action >> endobj 159 0 obj << /Type /Annot /Subtype /Link /A 160 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 351.6457 219.7500 576.6457 ] >> endobj 160 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/table-1-plos_001.jpg) >> endobj 161 0 obj << /Type /Page /Parent 3 0 R /Contents 162 0 R >> endobj 162 0 obj << /Length 9844 >> stream 0.271 0.267 0.267 rg q 15.000 35.572 577.500 741.428 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(\(40 ?m\) were taken through the rostral-caudal extent of the brain and stored in phosphate-buffered glycerol at -20C until further )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(processing for immunostaining. For a timeline of the experiments see Fig 1A.)] TJ ET BT 26.250 736.167 Td /F4 9.8 Tf [(Health Assessment)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(General health assessments were performed biweekly. Mice \(L\) were checked for the presence or absence of symptoms )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(including hunched back, poor grooming, involuntary shaking, erratic behavior, hind leg clinching, and inactivity \(Table 2\). The )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(age of onset of disease symptoms was recorded as the first day any of the above mentioned symptoms were observed in each )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(mouse \(L mice\). At regular intervals, body weight was recorded and glucose levels were measured using blood glucose test )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(strips and a blood glucose meter \(Ascensia ELITE XL Blood Glucose Meter\). 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The mice were placed on the rotating rod and the latency until they fell off and the number of falls over 5 min were )] TJ ET BT 26.250 119.976 Td /F1 9.8 Tf [(recorded. This procedure was repeated 3 times consecutively and the averages were used as measures of locomotor ability.)] TJ ET BT 26.250 100.572 Td /F1 9.8 Tf [(Open field)] TJ ET Q q 15.000 35.572 577.500 741.428 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(\(40 ?m\) were taken through the rostral-caudal extent of the brain and stored in phosphate-buffered glycerol at -20C until further )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(processing for immunostaining. For a timeline of the experiments see Fig 1A.)] TJ ET BT 26.250 736.167 Td /F4 9.8 Tf [(Health Assessment)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(General health assessments were performed biweekly. 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The age of onset of disease symptoms was recorded as the first day symptoms associated with HD were )] TJ ET BT 26.250 264.619 Td /F1 9.8 Tf [(observed in each individual mouse in the lifespan group.)] TJ ET BT 26.250 245.214 Td /F4 9.8 Tf [(Motor Skills)] TJ ET BT 26.250 225.810 Td /F1 9.8 Tf [(Running wheel distance)] TJ ET BT 26.250 206.405 Td /F1 9.8 Tf [(Running distances were recorded in kilometers weekly through a mini-computer \(Sigma Sport, Batavia IL\) attached to the )] TJ ET BT 26.250 194.500 Td /F1 9.8 Tf [(running wheels. These data \(S+L mice\) are presented at the age of acquisition of the measurement over the time course of the )] TJ ET BT 26.250 182.595 Td /F1 9.8 Tf [(experiment.)] TJ ET BT 26.250 163.191 Td /F1 9.8 Tf [(Rotarod tests)] TJ ET BT 26.250 143.786 Td /F1 9.8 Tf [(An accelerating paradigm from 3 to 30 rpm was used for testing on the rotarod \(S mice\), with a maximum duration of 5 min per )] TJ ET BT 26.250 131.881 Td /F1 9.8 Tf [(trial. The mice were placed on the rotating rod and the latency until they fell off and the number of falls over 5 min were )] TJ ET BT 26.250 119.976 Td /F1 9.8 Tf [(recorded. This procedure was repeated 3 times consecutively and the averages were used as measures of locomotor ability.)] TJ ET BT 26.250 100.572 Td /F1 9.8 Tf [(Open field)] TJ ET Q q 15.000 35.572 577.500 741.428 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(\(40 ?m\) were taken through the rostral-caudal extent of the brain and stored in phosphate-buffered glycerol at -20C until further )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(processing for immunostaining. For a timeline of the experiments see Fig 1A.)] TJ ET BT 26.250 736.167 Td /F4 9.8 Tf [(Health Assessment)] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(General health assessments were performed biweekly. Mice \(L\) were checked for the presence or absence of symptoms )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(including hunched back, poor grooming, involuntary shaking, erratic behavior, hind leg clinching, and inactivity \(Table 2\). The )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(age of onset of disease symptoms was recorded as the first day any of the above mentioned symptoms were observed in each )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(mouse \(L mice\). At regular intervals, body weight was recorded and glucose levels were measured using blood glucose test )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(strips and a blood glucose meter \(Ascensia ELITE XL Blood Glucose Meter\). Weights and glucose measurements \(S+L mice\) in )] TJ ET BT 26.250 657.238 Td /F1 9.8 Tf [(the study are presented at the age of acquisition of the measurement over the time course of the experiment.)] TJ ET q 450.000 0 0 330.000 26.250 317.357 cm /I9 Do Q BT 26.250 300.333 Td /F4 9.8 Tf [(Table 2.)] TJ ET BT 62.559 300.333 Td /F1 9.8 Tf [( The timing of the appearance of characteristic HD symptoms throughout the study following bi-weekly monitoring by )] TJ ET BT 26.250 288.429 Td /F1 9.8 Tf [(the investigators. S = Involuntary shaking; C = Hind leg clinching; H = Hunched back; G = Poor grooming; I = Inactivity; B = )] TJ ET BT 26.250 276.524 Td /F1 9.8 Tf [(Erratic behavior. 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Ìh66 `ޒD2uU8$OL0L]"@l&XWM+` ^;6=uyeŬBf6Cd6?:TD/eP s񧿵{K>3wLӐ7s{v lqdǚUW>|dMoǶ7;|G?}u]9O3c[fH}UhrmZO޽ugWIo]5ś `T͊APJsr& sf-0kf{!M/1+ӳy{]܏u%ȁәi+L3V Ìϯb`W9+g(.'B{L>>v}-l}xiwk2-񧯇=?yvG $g1eд_nߪzNtl_CO=xGՉL)%wrfCo_EDסA}|#?,̸Uij)szЮCFy f״xHQ'M P)oƃ F']G*\i{TSW63&-f+uM13-C,z8 2]|piw-^مG,j&Cd^<Ϋ.qNH9`ŵ3-Q 6ˌA3`c=^&LBtrM5LXWy]yB]ix t%N`XW`l!c$$|Ch*p; I٘Ub@9<.KfAuRڠJhqxȖgV<&ts,ΐf-03xZ |cqiQ&*&raQ]#dKm3rrxgN $ F Es'G+~2wxTs3%hH0.kGW-0fجؕlFѽ4x>,b^' ')?jYkR, C=fDCTKa6D:f.@jN_1p7zgb3f<]cEw)@W GyA]HWr.:뗮8}3wq0 ؃Ȭ<=G= dypG2;0{-Mc83fy-1b3H{aښ쾾<󈄧=^ .?@'H^O^!-5 g[tP`G'bE0_`7% ɋyࠚ }æͩxeei!i$zgw9i:o@ hcU!r% tebYfa @eu.e'rteձОWz[yn>*ٿ8=d)x0Q=Ot׮]^ziccĉ+FT!;v3fLCCC͛'O\Ue-z{{l2u cǎݻmo{[BtvvvvvT.{zz+b߾}C \^{/nll۷?.ߵiӦSsٶm۔)S*_D?a„ʅ7n\B8p@DFY{8pE]T;w5jԀ*۶mǎkoo޶ . º.ϫ=IӴ7sa]Xօua]XkS2 endstream endobj 169 0 obj << /Type /Page /Parent 3 0 R /Annots [ 171 0 R 173 0 R 175 0 R 177 0 R 179 0 R 181 0 R ] /Contents 170 0 R >> endobj 170 0 obj << /Length 31204 >> stream 0.271 0.267 0.267 rg q 15.000 23.429 577.500 753.571 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Animals from the 4 groups \(S mice\) were tested in an open field arena \(27.3 x 27.3 cm, height 20.3 cm\) \(Med Associates Inc., )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Georgia, VT\). Each arena had a black floor and walls where x-y movements are monitored by two sets of pulsed-modulated )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(infrared photobeams. Animals were placed in the center of the arena at the beginning of the testing paradigm and were left )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(undisturbed for 30 min. The total distance traveled in the open field over the 30 min was recorded and analyzed.)] TJ ET BT 26.250 712.357 Td /F4 9.8 Tf [(Cognition)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(Morris water maze)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Mice \(S mice\) were trained in the Morris water maze \(pool diameter 1.4 m\) for 8 consecutive days with 4 trials per day beginning )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(at a different starting point every trial, as described previously [21] . Each trial was 1 min long with a 10 sec inter-trial interval. )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(Once the mice found the platform, they were given a 15 sec rest on the platform. If the mouse was unable to find the platform in )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1 min, it was manually placed on the platform for 15 sec. The latency to reach the platform and swim speed were recorded semi-)] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(automatically by a video tracking system \(Anymaze, Stoelting Inc.\). A 60 sec probe trial was performed 24 hours after the last )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(training session. For this trial, the platform was removed and the mouse was allowed to swim for 60 sec. The time spent in each )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(quadrant and the number of platform crossings were recorded.)] TJ ET BT 26.250 582.714 Td /F4 9.8 Tf [(Histological Analysis)] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Immunohistochemistry for BrdU and immunofluorescent double labeling for BrdU and NeuN were performed on separate free-)] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(floating one-in-six series of 40?m coronal sections \(240?m apart\) that were pretreated for BrdU immunohistochemistry by )] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(denaturing DNA, as described previously [21] . The primary antibodies used were BrdU anti-rat \(1:200; Accurate, Harlan Sera-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(Lab\) and mouse anti-NeuN \(1:100; Millipore\). To visualize BrdU-labeled cells for counting total number of BrdU )] TJ ET BT 506.340 531.484 Td /F1 8.7 Tf [(+)] TJ ET BT 511.401 527.595 Td /F1 9.8 Tf [( cells, the )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(peroxidase method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-rat secondary )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. For double-labeling )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(experiments to determine the percentage of BrdU )] TJ ET BT 242.476 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 247.537 491.881 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 280.590 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 285.651 491.881 Td /F1 9.8 Tf [( cells, the fluorescent secondary antibodies used were donkey anti-)] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(rat Alexa Fluor 488 \(1:250; Invitrogen\), and donkey anti-mouse Cy3 \(1:250; Jackson ImmunoResearch, West Grove, PA\). In )] TJ ET BT 26.250 468.072 Td /F1 9.8 Tf [(addition, morphological assessment of the cells was carried out using doublecortin \(DCX\) staining. Specifically, a 1:12 series of )] TJ ET BT 26.250 456.167 Td /F1 9.8 Tf [(sections were labeled with DCX \(1:250; Santa Cruz, CA\) and the fluorescent secondary antibody used was donkey anti-goat )] TJ ET BT 26.250 444.262 Td /F1 9.8 Tf [(Cy5 \(1:250; Jackson ImmunoResearch, West Grove, PA\). Complexity of dendritic branching of DCX-labeled immature neurons )] TJ ET BT 26.250 432.357 Td /F1 9.8 Tf [(was assessed by an investigator blinded to the group identity.)] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 416.841 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 412.953 Td /F1 9.8 Tf [( cell counts were performed through a 20X objective \(Olympus BX51\) throughout the entire GCL and hilus of the DG by a )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(blinded investigator, as described )] TJ ET 0.267 0.267 0.267 rg BT 173.650 401.048 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 189.913 401.048 Td /F1 9.8 Tf [( . An adjacent one-in-six series of sections were stained with DAPI \(4-6-diaminodino-2-)] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(phenylindole, 1 ?l/10 ml Tris-buffered saline \(TBS\) for 10 min\) to estimate GCL total volume. The GCL area was traced with a )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(20X objective using stereology software \(StereoInvestigator, MicroBrightfield\). The GCL volume was determined by the sum of )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(the traced areas from the one-in-six series of sections multiplied by the distance between sections \(240?m\). The number of )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(BrdU-labeled cells was matched to GCL volume and multiplied by the reference volume to estimate total number and density of )] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 345.412 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 341.524 Td /F1 9.8 Tf [( cells in the GCL.)] TJ ET BT 26.250 322.119 Td /F1 9.8 Tf [(To investigate the phenotype of these newly born cells an additional one-in-six series of sections were double-labeled with BrdU )] TJ ET BT 26.250 310.215 Td /F1 9.8 Tf [(and NeuN as described above and visualized by confocal microscopy \(Fluoview, Olympus\). At least 50 BrdU )] TJ ET BT 496.590 314.103 Td /F1 8.7 Tf [(+)] TJ ET BT 501.651 310.215 Td /F1 9.8 Tf [( cells per animal )] TJ ET BT 26.250 298.310 Td /F1 9.8 Tf [(were analyzed for the co-expression of BrdU and NeuN. The percent of total BrdU )] TJ ET BT 382.281 302.198 Td /F1 8.7 Tf [(+)] TJ ET BT 387.342 298.310 Td /F1 9.8 Tf [( cells co-labeling with NeuN were )] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(determined \(% BrdU )] TJ ET BT 117.276 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 122.337 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 155.390 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 160.451 286.405 Td /F1 9.8 Tf [( cells\). Based on this percentage, the total number of BrdU )] TJ ET BT 416.242 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 421.304 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 454.356 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 459.418 286.405 Td /F1 9.8 Tf [( cell numbers could be )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(calculated from the total number of BrdU )] TJ ET BT 203.993 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 209.054 274.500 Td /F1 9.8 Tf [( cells. Striatal volume was measured in the same tissue used to perform the BrdU )] TJ ET BT 563.437 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(cell counts. Briefly, the average of the total area of striatal tissue from 3-4 sections prior to the anterior commissure was used for )] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(striatal volume. The percent change from control mice \(WTS\) was calculated and used for statistical analysis.)] TJ ET BT 26.250 231.286 Td /F1 9.8 Tf [(Immunohistochemistry for mHtt was performed on separate free-floating one-in-twelve series of 40?m coronal sections \(480?m )] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(apart\) The primary antibody used was mHtt anti-mouse \(1:100 Millipore, CA\) To visualize mHtt-labeled cells, the peroxidase )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-mouse secondary )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. The optical fractionator )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(method \(sampling grid = 7575?m\) \(Stereoinvestigator, Microbrightfield, VT\) was used to quantify the number of cells with mHtt )] TJ ET BT 26.250 175.651 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 171.762 Td /F1 9.8 Tf [( inclusions in 2 representative sections by a blinded investigator with a 40X oil objective \(Olympus BX51\). The estimated )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(number of mHtt )] TJ ET BT 96.148 163.746 Td /F1 8.7 Tf [(+)] TJ ET BT 101.209 159.858 Td /F1 9.8 Tf [( cells was matched to the traced GCL area and multiplied by the reference volume to estimate the number of )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(mHtt )] TJ ET BT 49.543 151.841 Td /F1 8.7 Tf [(+)] TJ ET BT 54.604 147.953 Td /F1 9.8 Tf [( cells.)] TJ ET BT 26.250 128.548 Td /F4 9.8 Tf [(Statistical Analysis)] TJ ET BT 26.250 109.143 Td /F1 9.8 Tf [(For weights, glucose and running distance, a mixed effects statistical model was used to estimate the longitudinal trajectories )] TJ ET BT 26.250 97.239 Td /F1 9.8 Tf [(while accounting for the within-subject correlations)] TJ ET 0.267 0.267 0.267 rg BT 243.538 97.239 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 262.512 97.239 Td /F1 9.8 Tf [( . Weights, glucose and running distance were the dependent variables )] TJ ET BT 26.250 85.334 Td /F1 9.8 Tf [(and the predictors included group and time. All the analyses were conducted in R \(version 2.9.0\). All other statistical analysis )] TJ ET BT 26.250 73.429 Td /F1 9.8 Tf [(was carried out using Statview \(Abacus Corporation\) unless otherwise stated. For the Morris water maze, latency and swim )] TJ ET BT 26.250 61.524 Td /F1 9.8 Tf [(speed, a two way ANOVA \(Genotype x Exercise\) with repeated measures \(Time\) was performed followed by a one-way ANOVA )] TJ ET BT 26.250 49.620 Td /F1 9.8 Tf [(and Fishers post-hoc tests for individual days. A power analysis was performed for comparing four groups simultaneously and )] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(the statistical power obtained was 0.80 \(SAS\). For histological, rotarod, open field and Morris water maze probe trial data, a two )] TJ ET Q q 15.000 23.429 577.500 753.571 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Animals from the 4 groups \(S mice\) were tested in an open field arena \(27.3 x 27.3 cm, height 20.3 cm\) \(Med Associates Inc., )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Georgia, VT\). Each arena had a black floor and walls where x-y movements are monitored by two sets of pulsed-modulated )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(infrared photobeams. Animals were placed in the center of the arena at the beginning of the testing paradigm and were left )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(undisturbed for 30 min. The total distance traveled in the open field over the 30 min was recorded and analyzed.)] TJ ET BT 26.250 712.357 Td /F4 9.8 Tf [(Cognition)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(Morris water maze)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Mice \(S mice\) were trained in the Morris water maze \(pool diameter 1.4 m\) for 8 consecutive days with 4 trials per day beginning )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(at a different starting point every trial, as described previously [21] . Each trial was 1 min long with a 10 sec inter-trial interval. )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(Once the mice found the platform, they were given a 15 sec rest on the platform. If the mouse was unable to find the platform in )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1 min, it was manually placed on the platform for 15 sec. The latency to reach the platform and swim speed were recorded semi-)] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(automatically by a video tracking system \(Anymaze, Stoelting Inc.\). A 60 sec probe trial was performed 24 hours after the last )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(training session. For this trial, the platform was removed and the mouse was allowed to swim for 60 sec. The time spent in each )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(quadrant and the number of platform crossings were recorded.)] TJ ET BT 26.250 582.714 Td /F4 9.8 Tf [(Histological Analysis)] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Immunohistochemistry for BrdU and immunofluorescent double labeling for BrdU and NeuN were performed on separate free-)] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(floating one-in-six series of 40?m coronal sections \(240?m apart\) that were pretreated for BrdU immunohistochemistry by )] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(denaturing DNA, as described previously [21] . The primary antibodies used were BrdU anti-rat \(1:200; Accurate, Harlan Sera-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(Lab\) and mouse anti-NeuN \(1:100; Millipore\). To visualize BrdU-labeled cells for counting total number of BrdU )] TJ ET BT 506.340 531.484 Td /F1 8.7 Tf [(+)] TJ ET BT 511.401 527.595 Td /F1 9.8 Tf [( cells, the )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(peroxidase method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-rat secondary )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. For double-labeling )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(experiments to determine the percentage of BrdU )] TJ ET BT 242.476 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 247.537 491.881 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 280.590 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 285.651 491.881 Td /F1 9.8 Tf [( cells, the fluorescent secondary antibodies used were donkey anti-)] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(rat Alexa Fluor 488 \(1:250; Invitrogen\), and donkey anti-mouse Cy3 \(1:250; Jackson ImmunoResearch, West Grove, PA\). In )] TJ ET BT 26.250 468.072 Td /F1 9.8 Tf [(addition, morphological assessment of the cells was carried out using doublecortin \(DCX\) staining. Specifically, a 1:12 series of )] TJ ET BT 26.250 456.167 Td /F1 9.8 Tf [(sections were labeled with DCX \(1:250; Santa Cruz, CA\) and the fluorescent secondary antibody used was donkey anti-goat )] TJ ET BT 26.250 444.262 Td /F1 9.8 Tf [(Cy5 \(1:250; Jackson ImmunoResearch, West Grove, PA\). Complexity of dendritic branching of DCX-labeled immature neurons )] TJ ET BT 26.250 432.357 Td /F1 9.8 Tf [(was assessed by an investigator blinded to the group identity.)] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 416.841 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 412.953 Td /F1 9.8 Tf [( cell counts were performed through a 20X objective \(Olympus BX51\) throughout the entire GCL and hilus of the DG by a )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(blinded investigator, as described )] TJ ET 0.267 0.267 0.267 rg BT 173.650 401.048 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 189.913 401.048 Td /F1 9.8 Tf [( . An adjacent one-in-six series of sections were stained with DAPI \(4-6-diaminodino-2-)] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(phenylindole, 1 ?l/10 ml Tris-buffered saline \(TBS\) for 10 min\) to estimate GCL total volume. The GCL area was traced with a )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(20X objective using stereology software \(StereoInvestigator, MicroBrightfield\). The GCL volume was determined by the sum of )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(the traced areas from the one-in-six series of sections multiplied by the distance between sections \(240?m\). The number of )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(BrdU-labeled cells was matched to GCL volume and multiplied by the reference volume to estimate total number and density of )] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 345.412 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 341.524 Td /F1 9.8 Tf [( cells in the GCL.)] TJ ET BT 26.250 322.119 Td /F1 9.8 Tf [(To investigate the phenotype of these newly born cells an additional one-in-six series of sections were double-labeled with BrdU )] TJ ET BT 26.250 310.215 Td /F1 9.8 Tf [(and NeuN as described above and visualized by confocal microscopy \(Fluoview, Olympus\). At least 50 BrdU )] TJ ET BT 496.590 314.103 Td /F1 8.7 Tf [(+)] TJ ET BT 501.651 310.215 Td /F1 9.8 Tf [( cells per animal )] TJ ET BT 26.250 298.310 Td /F1 9.8 Tf [(were analyzed for the co-expression of BrdU and NeuN. The percent of total BrdU )] TJ ET BT 382.281 302.198 Td /F1 8.7 Tf [(+)] TJ ET BT 387.342 298.310 Td /F1 9.8 Tf [( cells co-labeling with NeuN were )] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(determined \(% BrdU )] TJ ET BT 117.276 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 122.337 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 155.390 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 160.451 286.405 Td /F1 9.8 Tf [( cells\). Based on this percentage, the total number of BrdU )] TJ ET BT 416.242 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 421.304 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 454.356 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 459.418 286.405 Td /F1 9.8 Tf [( cell numbers could be )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(calculated from the total number of BrdU )] TJ ET BT 203.993 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 209.054 274.500 Td /F1 9.8 Tf [( cells. Striatal volume was measured in the same tissue used to perform the BrdU )] TJ ET BT 563.437 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(cell counts. Briefly, the average of the total area of striatal tissue from 3-4 sections prior to the anterior commissure was used for )] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(striatal volume. The percent change from control mice \(WTS\) was calculated and used for statistical analysis.)] TJ ET BT 26.250 231.286 Td /F1 9.8 Tf [(Immunohistochemistry for mHtt was performed on separate free-floating one-in-twelve series of 40?m coronal sections \(480?m )] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(apart\) The primary antibody used was mHtt anti-mouse \(1:100 Millipore, CA\) To visualize mHtt-labeled cells, the peroxidase )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-mouse secondary )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. The optical fractionator )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(method \(sampling grid = 7575?m\) \(Stereoinvestigator, Microbrightfield, VT\) was used to quantify the number of cells with mHtt )] TJ ET BT 26.250 175.651 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 171.762 Td /F1 9.8 Tf [( inclusions in 2 representative sections by a blinded investigator with a 40X oil objective \(Olympus BX51\). The estimated )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(number of mHtt )] TJ ET BT 96.148 163.746 Td /F1 8.7 Tf [(+)] TJ ET BT 101.209 159.858 Td /F1 9.8 Tf [( cells was matched to the traced GCL area and multiplied by the reference volume to estimate the number of )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(mHtt )] TJ ET BT 49.543 151.841 Td /F1 8.7 Tf [(+)] TJ ET BT 54.604 147.953 Td /F1 9.8 Tf [( cells.)] TJ ET BT 26.250 128.548 Td /F4 9.8 Tf [(Statistical Analysis)] TJ ET BT 26.250 109.143 Td /F1 9.8 Tf [(For weights, glucose and running distance, a mixed effects statistical model was used to estimate the longitudinal trajectories )] TJ ET BT 26.250 97.239 Td /F1 9.8 Tf [(while accounting for the within-subject correlations)] TJ ET 0.267 0.267 0.267 rg BT 243.538 97.239 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 262.512 97.239 Td /F1 9.8 Tf [( . Weights, glucose and running distance were the dependent variables )] TJ ET BT 26.250 85.334 Td /F1 9.8 Tf [(and the predictors included group and time. All the analyses were conducted in R \(version 2.9.0\). All other statistical analysis )] TJ ET BT 26.250 73.429 Td /F1 9.8 Tf [(was carried out using Statview \(Abacus Corporation\) unless otherwise stated. For the Morris water maze, latency and swim )] TJ ET BT 26.250 61.524 Td /F1 9.8 Tf [(speed, a two way ANOVA \(Genotype x Exercise\) with repeated measures \(Time\) was performed followed by a one-way ANOVA )] TJ ET BT 26.250 49.620 Td /F1 9.8 Tf [(and Fishers post-hoc tests for individual days. A power analysis was performed for comparing four groups simultaneously and )] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(the statistical power obtained was 0.80 \(SAS\). For histological, rotarod, open field and Morris water maze probe trial data, a two )] TJ ET Q q 15.000 23.429 577.500 753.571 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(Animals from the 4 groups \(S mice\) were tested in an open field arena \(27.3 x 27.3 cm, height 20.3 cm\) \(Med Associates Inc., )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(Georgia, VT\). Each arena had a black floor and walls where x-y movements are monitored by two sets of pulsed-modulated )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(infrared photobeams. Animals were placed in the center of the arena at the beginning of the testing paradigm and were left )] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(undisturbed for 30 min. The total distance traveled in the open field over the 30 min was recorded and analyzed.)] TJ ET BT 26.250 712.357 Td /F4 9.8 Tf [(Cognition)] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(Morris water maze)] TJ ET BT 26.250 673.548 Td /F1 9.8 Tf [(Mice \(S mice\) were trained in the Morris water maze \(pool diameter 1.4 m\) for 8 consecutive days with 4 trials per day beginning )] TJ ET BT 26.250 661.643 Td /F1 9.8 Tf [(at a different starting point every trial, as described previously [21] . Each trial was 1 min long with a 10 sec inter-trial interval. )] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(Once the mice found the platform, they were given a 15 sec rest on the platform. If the mouse was unable to find the platform in )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(1 min, it was manually placed on the platform for 15 sec. The latency to reach the platform and swim speed were recorded semi-)] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(automatically by a video tracking system \(Anymaze, Stoelting Inc.\). A 60 sec probe trial was performed 24 hours after the last )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(training session. For this trial, the platform was removed and the mouse was allowed to swim for 60 sec. The time spent in each )] TJ ET BT 26.250 602.119 Td /F1 9.8 Tf [(quadrant and the number of platform crossings were recorded.)] TJ ET BT 26.250 582.714 Td /F4 9.8 Tf [(Histological Analysis)] TJ ET BT 26.250 563.310 Td /F1 9.8 Tf [(Immunohistochemistry for BrdU and immunofluorescent double labeling for BrdU and NeuN were performed on separate free-)] TJ ET BT 26.250 551.405 Td /F1 9.8 Tf [(floating one-in-six series of 40?m coronal sections \(240?m apart\) that were pretreated for BrdU immunohistochemistry by )] TJ ET BT 26.250 539.500 Td /F1 9.8 Tf [(denaturing DNA, as described previously [21] . The primary antibodies used were BrdU anti-rat \(1:200; Accurate, Harlan Sera-)] TJ ET BT 26.250 527.595 Td /F1 9.8 Tf [(Lab\) and mouse anti-NeuN \(1:100; Millipore\). To visualize BrdU-labeled cells for counting total number of BrdU )] TJ ET BT 506.340 531.484 Td /F1 8.7 Tf [(+)] TJ ET BT 511.401 527.595 Td /F1 9.8 Tf [( cells, the )] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(peroxidase method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-rat secondary )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. For double-labeling )] TJ ET BT 26.250 491.881 Td /F1 9.8 Tf [(experiments to determine the percentage of BrdU )] TJ ET BT 242.476 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 247.537 491.881 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 280.590 495.769 Td /F1 8.7 Tf [(+)] TJ ET BT 285.651 491.881 Td /F1 9.8 Tf [( cells, the fluorescent secondary antibodies used were donkey anti-)] TJ ET BT 26.250 479.976 Td /F1 9.8 Tf [(rat Alexa Fluor 488 \(1:250; Invitrogen\), and donkey anti-mouse Cy3 \(1:250; Jackson ImmunoResearch, West Grove, PA\). In )] TJ ET BT 26.250 468.072 Td /F1 9.8 Tf [(addition, morphological assessment of the cells was carried out using doublecortin \(DCX\) staining. Specifically, a 1:12 series of )] TJ ET BT 26.250 456.167 Td /F1 9.8 Tf [(sections were labeled with DCX \(1:250; Santa Cruz, CA\) and the fluorescent secondary antibody used was donkey anti-goat )] TJ ET BT 26.250 444.262 Td /F1 9.8 Tf [(Cy5 \(1:250; Jackson ImmunoResearch, West Grove, PA\). Complexity of dendritic branching of DCX-labeled immature neurons )] TJ ET BT 26.250 432.357 Td /F1 9.8 Tf [(was assessed by an investigator blinded to the group identity.)] TJ ET BT 26.250 412.953 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 416.841 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 412.953 Td /F1 9.8 Tf [( cell counts were performed through a 20X objective \(Olympus BX51\) throughout the entire GCL and hilus of the DG by a )] TJ ET BT 26.250 401.048 Td /F1 9.8 Tf [(blinded investigator, as described )] TJ ET 0.267 0.267 0.267 rg BT 173.650 401.048 Td /F1 9.8 Tf [([21])] TJ ET 0.271 0.267 0.267 rg BT 189.913 401.048 Td /F1 9.8 Tf [( . An adjacent one-in-six series of sections were stained with DAPI \(4-6-diaminodino-2-)] TJ ET BT 26.250 389.143 Td /F1 9.8 Tf [(phenylindole, 1 ?l/10 ml Tris-buffered saline \(TBS\) for 10 min\) to estimate GCL total volume. The GCL area was traced with a )] TJ ET BT 26.250 377.238 Td /F1 9.8 Tf [(20X objective using stereology software \(StereoInvestigator, MicroBrightfield\). The GCL volume was determined by the sum of )] TJ ET BT 26.250 365.334 Td /F1 9.8 Tf [(the traced areas from the one-in-six series of sections multiplied by the distance between sections \(240?m\). The number of )] TJ ET BT 26.250 353.429 Td /F1 9.8 Tf [(BrdU-labeled cells was matched to GCL volume and multiplied by the reference volume to estimate total number and density of )] TJ ET BT 26.250 341.524 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 345.412 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 341.524 Td /F1 9.8 Tf [( cells in the GCL.)] TJ ET BT 26.250 322.119 Td /F1 9.8 Tf [(To investigate the phenotype of these newly born cells an additional one-in-six series of sections were double-labeled with BrdU )] TJ ET BT 26.250 310.215 Td /F1 9.8 Tf [(and NeuN as described above and visualized by confocal microscopy \(Fluoview, Olympus\). At least 50 BrdU )] TJ ET BT 496.590 314.103 Td /F1 8.7 Tf [(+)] TJ ET BT 501.651 310.215 Td /F1 9.8 Tf [( cells per animal )] TJ ET BT 26.250 298.310 Td /F1 9.8 Tf [(were analyzed for the co-expression of BrdU and NeuN. The percent of total BrdU )] TJ ET BT 382.281 302.198 Td /F1 8.7 Tf [(+)] TJ ET BT 387.342 298.310 Td /F1 9.8 Tf [( cells co-labeling with NeuN were )] TJ ET BT 26.250 286.405 Td /F1 9.8 Tf [(determined \(% BrdU )] TJ ET BT 117.276 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 122.337 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 155.390 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 160.451 286.405 Td /F1 9.8 Tf [( cells\). Based on this percentage, the total number of BrdU )] TJ ET BT 416.242 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 421.304 286.405 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 454.356 290.293 Td /F1 8.7 Tf [(+)] TJ ET BT 459.418 286.405 Td /F1 9.8 Tf [( cell numbers could be )] TJ ET BT 26.250 274.500 Td /F1 9.8 Tf [(calculated from the total number of BrdU )] TJ ET BT 203.993 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 209.054 274.500 Td /F1 9.8 Tf [( cells. Striatal volume was measured in the same tissue used to perform the BrdU )] TJ ET BT 563.437 278.389 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 262.596 Td /F1 9.8 Tf [(cell counts. Briefly, the average of the total area of striatal tissue from 3-4 sections prior to the anterior commissure was used for )] TJ ET BT 26.250 250.691 Td /F1 9.8 Tf [(striatal volume. The percent change from control mice \(WTS\) was calculated and used for statistical analysis.)] TJ ET BT 26.250 231.286 Td /F1 9.8 Tf [(Immunohistochemistry for mHtt was performed on separate free-floating one-in-twelve series of 40?m coronal sections \(480?m )] TJ ET BT 26.250 219.381 Td /F1 9.8 Tf [(apart\) The primary antibody used was mHtt anti-mouse \(1:100 Millipore, CA\) To visualize mHtt-labeled cells, the peroxidase )] TJ ET BT 26.250 207.477 Td /F1 9.8 Tf [(method was used \(ABC system \(Vector Laboratories, Burlingame, CA\) with a biotinylated donkey anti-mouse secondary )] TJ ET BT 26.250 195.572 Td /F1 9.8 Tf [(antibody \(Jackson Immunoresearch West Grove, PA\) and diaminobenzadine \(DAB\) as a chromogen. The optical fractionator )] TJ ET BT 26.250 183.667 Td /F1 9.8 Tf [(method \(sampling grid = 7575?m\) \(Stereoinvestigator, Microbrightfield, VT\) was used to quantify the number of cells with mHtt )] TJ ET BT 26.250 175.651 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 171.762 Td /F1 9.8 Tf [( inclusions in 2 representative sections by a blinded investigator with a 40X oil objective \(Olympus BX51\). The estimated )] TJ ET BT 26.250 159.858 Td /F1 9.8 Tf [(number of mHtt )] TJ ET BT 96.148 163.746 Td /F1 8.7 Tf [(+)] TJ ET BT 101.209 159.858 Td /F1 9.8 Tf [( cells was matched to the traced GCL area and multiplied by the reference volume to estimate the number of )] TJ ET BT 26.250 147.953 Td /F1 9.8 Tf [(mHtt )] TJ ET BT 49.543 151.841 Td /F1 8.7 Tf [(+)] TJ ET BT 54.604 147.953 Td /F1 9.8 Tf [( cells.)] TJ ET BT 26.250 128.548 Td /F4 9.8 Tf [(Statistical Analysis)] TJ ET BT 26.250 109.143 Td /F1 9.8 Tf [(For weights, glucose and running distance, a mixed effects statistical model was used to estimate the longitudinal trajectories )] TJ ET BT 26.250 97.239 Td /F1 9.8 Tf [(while accounting for the within-subject correlations)] TJ ET 0.267 0.267 0.267 rg BT 243.538 97.239 Td /F1 9.8 Tf [( [22])] TJ ET 0.271 0.267 0.267 rg BT 262.512 97.239 Td /F1 9.8 Tf [( . Weights, glucose and running distance were the dependent variables )] TJ ET BT 26.250 85.334 Td /F1 9.8 Tf [(and the predictors included group and time. All the analyses were conducted in R \(version 2.9.0\). All other statistical analysis )] TJ ET BT 26.250 73.429 Td /F1 9.8 Tf [(was carried out using Statview \(Abacus Corporation\) unless otherwise stated. For the Morris water maze, latency and swim )] TJ ET BT 26.250 61.524 Td /F1 9.8 Tf [(speed, a two way ANOVA \(Genotype x Exercise\) with repeated measures \(Time\) was performed followed by a one-way ANOVA )] TJ ET BT 26.250 49.620 Td /F1 9.8 Tf [(and Fishers post-hoc tests for individual days. A power analysis was performed for comparing four groups simultaneously and )] TJ ET BT 26.250 37.715 Td /F1 9.8 Tf [(the statistical power obtained was 0.80 \(SAS\). For histological, rotarod, open field and Morris water maze probe trial data, a two )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(4)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 171 0 obj << /Type /Annot /Subtype /Link /A 172 0 R /Border [0 0 0] /H /I /Rect [ 173.6505 400.1461 189.9135 410.0667 ] >> endobj 172 0 obj << /Type /Action >> endobj 173 0 obj << /Type /Annot /Subtype /Link /A 174 0 R /Border [0 0 0] /H /I /Rect [ 243.5385 96.3368 262.5120 106.2574 ] >> endobj 174 0 obj << /Type /Action >> endobj 175 0 obj << /Type /Annot /Subtype /Link /A 176 0 R /Border [0 0 0] /H /I /Rect [ 173.6505 400.1461 189.9135 410.0667 ] >> endobj 176 0 obj << /Type /Action >> endobj 177 0 obj << /Type /Annot /Subtype /Link /A 178 0 R /Border [0 0 0] /H /I /Rect [ 243.5385 96.3368 262.5120 106.2574 ] >> endobj 178 0 obj << /Type /Action >> endobj 179 0 obj << /Type /Annot /Subtype /Link /A 180 0 R /Border [0 0 0] /H /I /Rect [ 173.6505 400.1461 189.9135 410.0667 ] >> endobj 180 0 obj << /Type /Action >> endobj 181 0 obj << /Type /Annot /Subtype /Link /A 182 0 R /Border [0 0 0] /H /I /Rect [ 243.5385 96.3368 262.5120 106.2574 ] >> endobj 182 0 obj << /Type /Action >> endobj 183 0 obj << /Type /Page /Parent 3 0 R /Annots [ 185 0 R 188 0 R 190 0 R 192 0 R 194 0 R 196 0 R 198 0 R 200 0 R 202 0 R 204 0 R 206 0 R 208 0 R ] /Contents 184 0 R >> endobj 184 0 obj << /Length 20398 >> stream 0.271 0.267 0.267 rg q 15.000 31.030 577.500 745.970 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(way ANOVA \(Genotype x Exercise\) was performed followed by Fishers post-hoc tests. Since the HD mice did not cross the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(platform zone during the probe trial an unpaired students t-test was performed to compare the WTR and WTS groups. For )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(striatal volume measurements, a two way ANOVA \(Genotype x Exercise\) was performed followed by post-hoc t-tests. For mHtt )] TJ ET BT 575.136 747.555 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(cell number and disease onset data, unpaired students t-tests were carried out.)] TJ ET BT 26.250 695.159 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 675.205 Td /F4 9.8 Tf [(Running accelerates the age of onset and increases the severity of HD symptoms)] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(The age of onset of disease was recorded as the first day symptoms associated with HD were observed in bi-weekly )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(assessments in the L mice \(Fig 1A,B\). It was observed that running significantly accelerated onset of disease symptoms \(t )] TJ ET BT 554.047 641.831 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(=2.44: p<0.03\). HTR mice presented with symptoms such as hunched back, poor grooming and involuntary shaking an average )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(of 16 days \(2.17 days\) sooner than sedentary \(HTS\) controls \(Fig 1B & Table 2\). Although running accelerated disease onset, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(it did not influence lifespan in HD mice \(t )] TJ ET BT 202.900 606.117 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 218.310 608.181 Td /F1 9.8 Tf [( =0.20: p<0.84; Fig 1C\). All HD mice had died by 26 weeks of age \(Fig 1A,E\).)] TJ ET 0.965 0.965 0.965 rg 26.250 270.910 555.000 327.390 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 598.300 m 581.250 598.300 l 581.250 597.550 l 26.250 597.550 l f 26.250 270.910 m 581.250 270.910 l 581.250 271.660 l 26.250 271.660 l f q 225.000 0 0 183.000 35.250 405.550 cm /I10 Do Q q 35.250 282.160 537.000 117.390 re W n 0.271 0.267 0.267 rg BT 35.250 388.561 Td /F4 9.8 Tf [(Figure 1.)] TJ ET BT 75.888 388.561 Td /F1 9.8 Tf [( Running accelerated the onset of characteristic HD disease symptoms but did not affect hyperglycemia, weight )] TJ ET BT 35.250 374.825 Td /F1 9.8 Tf [(loss or lifespan. \(A\) Timeline of experiment in weeks of age in the subset \(S\) and lifespan \(L\) mice \(WT, N=28; HD, N=26, at )] TJ ET BT 35.250 361.089 Td /F1 9.8 Tf [(the beginning of the study\). Behavioral testing was carried out from week 12 to 15 \(S mice: WTS=6; WTR=5; HTS=7; )] TJ ET BT 35.250 347.353 Td /F1 9.8 Tf [(HTR=6\). Mice \(S\) were sacrificed \(SAC\) at approximately 16.2 weeks of age. Survival analysis \(L mice: HTS=6; HTR=7\) )] TJ ET BT 35.250 333.616 Td /F1 9.8 Tf [(indicated that HD mice died between 11 and 26 weeks of age. WT controls \(L mice: WTS=7; WTR=10\) were sacrificed at )] TJ ET BT 35.250 319.880 Td /F1 9.8 Tf [(29 weeks. Abbreviations: MWM =Morris water maze; OF= Open field; S=Subset; L= Lifespan group; SAC = sacrificed. \(B\) )] TJ ET BT 35.250 306.144 Td /F1 9.8 Tf [(Onset of disease symptoms \(L mice\) such as hunched back, poor grooming and involuntary shaking occurred earlier in HD )] TJ ET BT 35.250 292.408 Td /F1 9.8 Tf [(runners; * p)] TJ ET Q BT 26.250 253.887 Td /F1 9.8 Tf [(HD mice display progressive weight loss or failure to continue to gain weight over their lifetime)] TJ ET 0.267 0.267 0.267 rg BT 431.558 253.887 Td /F1 9.8 Tf [( [15] [17] [18] [19] [20] )] TJ ET 0.271 0.267 0.267 rg BT 529.135 253.887 Td /F1 9.8 Tf [(. Weight )] TJ ET BT 26.250 241.982 Td /F1 9.8 Tf [(measurements were taken for every mouse \(WTS=13; WTR=15; HTS=13; HTR=13\) up to week 11, after which time mice were )] TJ ET BT 26.250 230.077 Td /F1 9.8 Tf [(progressively lost from the study \(Fig 1E\). Therefore, a mixed effects statistical model was used to estimate the longitudinal )] TJ ET BT 26.250 218.172 Td /F1 9.8 Tf [(trajectories while accounting for the within-subject correlations. There were significant differences in time-related change for )] TJ ET BT 26.250 206.268 Td /F1 9.8 Tf [(WTR vs HTR \(F )] TJ ET BT 98.283 204.203 Td /F1 8.7 Tf [(\(2,44.1\))] TJ ET BT 128.148 206.268 Td /F1 9.8 Tf [( = 20.36, p<0.0001\) and WTS vs HTS \(F )] TJ ET BT 305.901 204.203 Td /F1 8.7 Tf [(\(2,52.1\))] TJ ET BT 335.766 206.268 Td /F1 9.8 Tf [( = 4.54, p<0.01\) \(Fig 1D\). The differences for WTR vs )] TJ ET BT 26.250 194.363 Td /F1 9.8 Tf [(WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 174.958 Td /F1 9.8 Tf [(Both HD patients and mouse models of the disease appear to show deficient glucose metabolism )] TJ ET 0.267 0.267 0.267 rg BT 448.406 174.958 Td /F1 9.8 Tf [([18] [23] [24] [25])] TJ ET 0.271 0.267 0.267 rg BT 521.589 174.958 Td /F1 9.8 Tf [( . In our )] TJ ET BT 26.250 163.053 Td /F1 9.8 Tf [(study, similar statistical analysis was performed as described above for weights. There were significant differences in time-)] TJ ET BT 26.250 151.149 Td /F1 9.8 Tf [(related change for WTR vs HTR \(F )] TJ ET BT 179.578 149.084 Td /F1 8.7 Tf [(\(2,82.5\))] TJ ET BT 209.444 151.149 Td /F1 9.8 Tf [( = 9.07, p<0.0003\) and WTS and HTS \(F )] TJ ET BT 388.288 149.084 Td /F1 8.7 Tf [(\(2,79.2\))] TJ ET BT 418.153 151.149 Td /F1 9.8 Tf [( = 3.04, p<0.05\) \(Fig 1F\). The )] TJ ET BT 26.250 139.244 Td /F1 9.8 Tf [(differences for WTR vs WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 119.839 Td /F4 9.8 Tf [(Running increases the severity of motor deficits)] TJ ET BT 26.250 100.434 Td /F1 9.8 Tf [(Deficits in locomotor activity are a hallmark of HD )] TJ ET 0.267 0.267 0.267 rg BT 241.345 100.434 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 333.502 100.434 Td /F1 9.8 Tf [( . We investigated the effect of running on rotarod )] TJ ET BT 26.250 88.530 Td /F1 9.8 Tf [(performance \(1001 days old\) and open field behavior \(1031 days old\) \(S mice\). In addition, running distance \(Fig 1A\) and )] TJ ET BT 26.250 76.625 Td /F1 9.8 Tf [(striatal volume were measured in both groups \(S and L mice\).)] TJ ET BT 26.250 57.220 Td /F1 9.8 Tf [(The latency to the first fall from the rotarod and the number of falls over 5 min was recorded in three consecutive trials and the )] TJ ET BT 26.250 45.315 Td /F1 9.8 Tf [(average of these three trials was calculated \(Fig 2 A,D\). There was a significant main effect of genotype in the latency to first fall )] TJ ET Q q 15.000 31.030 577.500 745.970 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(way ANOVA \(Genotype x Exercise\) was performed followed by Fishers post-hoc tests. Since the HD mice did not cross the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(platform zone during the probe trial an unpaired students t-test was performed to compare the WTR and WTS groups. For )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(striatal volume measurements, a two way ANOVA \(Genotype x Exercise\) was performed followed by post-hoc t-tests. For mHtt )] TJ ET BT 575.136 747.555 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(cell number and disease onset data, unpaired students t-tests were carried out.)] TJ ET BT 26.250 695.159 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 675.205 Td /F4 9.8 Tf [(Running accelerates the age of onset and increases the severity of HD symptoms)] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(The age of onset of disease was recorded as the first day symptoms associated with HD were observed in bi-weekly )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(assessments in the L mice \(Fig 1A,B\). It was observed that running significantly accelerated onset of disease symptoms \(t )] TJ ET BT 554.047 641.831 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(=2.44: p<0.03\). HTR mice presented with symptoms such as hunched back, poor grooming and involuntary shaking an average )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(of 16 days \(2.17 days\) sooner than sedentary \(HTS\) controls \(Fig 1B & Table 2\). Although running accelerated disease onset, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(it did not influence lifespan in HD mice \(t )] TJ ET BT 202.900 606.117 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 218.310 608.181 Td /F1 9.8 Tf [( =0.20: p<0.84; Fig 1C\). All HD mice had died by 26 weeks of age \(Fig 1A,E\).)] TJ ET 0.965 0.965 0.965 rg 26.250 270.910 555.000 327.390 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 598.300 m 581.250 598.300 l 581.250 597.550 l 26.250 597.550 l f 26.250 270.910 m 581.250 270.910 l 581.250 271.660 l 26.250 271.660 l f q 225.000 0 0 183.000 35.250 405.550 cm /I10 Do Q q 35.250 282.160 537.000 117.390 re W n 0.271 0.267 0.267 rg BT 35.250 388.561 Td /F4 9.8 Tf [(Figure 1.)] TJ ET BT 75.888 388.561 Td /F1 9.8 Tf [( Running accelerated the onset of characteristic HD disease symptoms but did not affect hyperglycemia, weight )] TJ ET BT 35.250 374.825 Td /F1 9.8 Tf [(loss or lifespan. \(A\) Timeline of experiment in weeks of age in the subset \(S\) and lifespan \(L\) mice \(WT, N=28; HD, N=26, at )] TJ ET BT 35.250 361.089 Td /F1 9.8 Tf [(the beginning of the study\). Behavioral testing was carried out from week 12 to 15 \(S mice: WTS=6; WTR=5; HTS=7; )] TJ ET BT 35.250 347.353 Td /F1 9.8 Tf [(HTR=6\). Mice \(S\) were sacrificed \(SAC\) at approximately 16.2 weeks of age. Survival analysis \(L mice: HTS=6; HTR=7\) )] TJ ET BT 35.250 333.616 Td /F1 9.8 Tf [(indicated that HD mice died between 11 and 26 weeks of age. WT controls \(L mice: WTS=7; WTR=10\) were sacrificed at )] TJ ET BT 35.250 319.880 Td /F1 9.8 Tf [(29 weeks. Abbreviations: MWM =Morris water maze; OF= Open field; S=Subset; L= Lifespan group; SAC = sacrificed. \(B\) )] TJ ET BT 35.250 306.144 Td /F1 9.8 Tf [(Onset of disease symptoms \(L mice\) such as hunched back, poor grooming and involuntary shaking occurred earlier in HD )] TJ ET BT 35.250 292.408 Td /F1 9.8 Tf [(runners; * p)] TJ ET Q BT 26.250 253.887 Td /F1 9.8 Tf [(HD mice display progressive weight loss or failure to continue to gain weight over their lifetime)] TJ ET 0.267 0.267 0.267 rg BT 431.558 253.887 Td /F1 9.8 Tf [( [15] [17] [18] [19] [20] )] TJ ET 0.271 0.267 0.267 rg BT 529.135 253.887 Td /F1 9.8 Tf [(. Weight )] TJ ET BT 26.250 241.982 Td /F1 9.8 Tf [(measurements were taken for every mouse \(WTS=13; WTR=15; HTS=13; HTR=13\) up to week 11, after which time mice were )] TJ ET BT 26.250 230.077 Td /F1 9.8 Tf [(progressively lost from the study \(Fig 1E\). Therefore, a mixed effects statistical model was used to estimate the longitudinal )] TJ ET BT 26.250 218.172 Td /F1 9.8 Tf [(trajectories while accounting for the within-subject correlations. There were significant differences in time-related change for )] TJ ET BT 26.250 206.268 Td /F1 9.8 Tf [(WTR vs HTR \(F )] TJ ET BT 98.283 204.203 Td /F1 8.7 Tf [(\(2,44.1\))] TJ ET BT 128.148 206.268 Td /F1 9.8 Tf [( = 20.36, p<0.0001\) and WTS vs HTS \(F )] TJ ET BT 305.901 204.203 Td /F1 8.7 Tf [(\(2,52.1\))] TJ ET BT 335.766 206.268 Td /F1 9.8 Tf [( = 4.54, p<0.01\) \(Fig 1D\). The differences for WTR vs )] TJ ET BT 26.250 194.363 Td /F1 9.8 Tf [(WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 174.958 Td /F1 9.8 Tf [(Both HD patients and mouse models of the disease appear to show deficient glucose metabolism )] TJ ET 0.267 0.267 0.267 rg BT 448.406 174.958 Td /F1 9.8 Tf [([18] [23] [24] [25])] TJ ET 0.271 0.267 0.267 rg BT 521.589 174.958 Td /F1 9.8 Tf [( . In our )] TJ ET BT 26.250 163.053 Td /F1 9.8 Tf [(study, similar statistical analysis was performed as described above for weights. There were significant differences in time-)] TJ ET BT 26.250 151.149 Td /F1 9.8 Tf [(related change for WTR vs HTR \(F )] TJ ET BT 179.578 149.084 Td /F1 8.7 Tf [(\(2,82.5\))] TJ ET BT 209.444 151.149 Td /F1 9.8 Tf [( = 9.07, p<0.0003\) and WTS and HTS \(F )] TJ ET BT 388.288 149.084 Td /F1 8.7 Tf [(\(2,79.2\))] TJ ET BT 418.153 151.149 Td /F1 9.8 Tf [( = 3.04, p<0.05\) \(Fig 1F\). The )] TJ ET BT 26.250 139.244 Td /F1 9.8 Tf [(differences for WTR vs WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 119.839 Td /F4 9.8 Tf [(Running increases the severity of motor deficits)] TJ ET BT 26.250 100.434 Td /F1 9.8 Tf [(Deficits in locomotor activity are a hallmark of HD )] TJ ET 0.267 0.267 0.267 rg BT 241.345 100.434 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 333.502 100.434 Td /F1 9.8 Tf [( . We investigated the effect of running on rotarod )] TJ ET BT 26.250 88.530 Td /F1 9.8 Tf [(performance \(1001 days old\) and open field behavior \(1031 days old\) \(S mice\). In addition, running distance \(Fig 1A\) and )] TJ ET BT 26.250 76.625 Td /F1 9.8 Tf [(striatal volume were measured in both groups \(S and L mice\).)] TJ ET BT 26.250 57.220 Td /F1 9.8 Tf [(The latency to the first fall from the rotarod and the number of falls over 5 min was recorded in three consecutive trials and the )] TJ ET BT 26.250 45.315 Td /F1 9.8 Tf [(average of these three trials was calculated \(Fig 2 A,D\). There was a significant main effect of genotype in the latency to first fall )] TJ ET Q q 15.000 31.030 577.500 745.970 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(way ANOVA \(Genotype x Exercise\) was performed followed by Fishers post-hoc tests. Since the HD mice did not cross the )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(platform zone during the probe trial an unpaired students t-test was performed to compare the WTR and WTS groups. For )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(striatal volume measurements, a two way ANOVA \(Genotype x Exercise\) was performed followed by post-hoc t-tests. For mHtt )] TJ ET BT 575.136 747.555 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 731.762 Td /F1 9.8 Tf [(cell number and disease onset data, unpaired students t-tests were carried out.)] TJ ET BT 26.250 695.159 Td /F4 12.0 Tf [(Results)] TJ ET BT 26.250 675.205 Td /F4 9.8 Tf [(Running accelerates the age of onset and increases the severity of HD symptoms)] TJ ET BT 26.250 655.800 Td /F1 9.8 Tf [(The age of onset of disease was recorded as the first day symptoms associated with HD were observed in bi-weekly )] TJ ET BT 26.250 643.896 Td /F1 9.8 Tf [(assessments in the L mice \(Fig 1A,B\). It was observed that running significantly accelerated onset of disease symptoms \(t )] TJ ET BT 554.047 641.831 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 26.250 631.991 Td /F1 9.8 Tf [(=2.44: p<0.03\). HTR mice presented with symptoms such as hunched back, poor grooming and involuntary shaking an average )] TJ ET BT 26.250 620.086 Td /F1 9.8 Tf [(of 16 days \(2.17 days\) sooner than sedentary \(HTS\) controls \(Fig 1B & Table 2\). Although running accelerated disease onset, )] TJ ET BT 26.250 608.181 Td /F1 9.8 Tf [(it did not influence lifespan in HD mice \(t )] TJ ET BT 202.900 606.117 Td /F1 8.7 Tf [(\(11\))] TJ ET BT 218.310 608.181 Td /F1 9.8 Tf [( =0.20: p<0.84; Fig 1C\). All HD mice had died by 26 weeks of age \(Fig 1A,E\).)] TJ ET 0.965 0.965 0.965 rg 26.250 270.910 555.000 327.390 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 598.300 m 581.250 598.300 l 581.250 597.550 l 26.250 597.550 l f 26.250 270.910 m 581.250 270.910 l 581.250 271.660 l 26.250 271.660 l f q 225.000 0 0 183.000 35.250 405.550 cm /I10 Do Q q 35.250 282.160 537.000 117.390 re W n 0.271 0.267 0.267 rg BT 35.250 388.561 Td /F4 9.8 Tf [(Figure 1.)] TJ ET BT 75.888 388.561 Td /F1 9.8 Tf [( Running accelerated the onset of characteristic HD disease symptoms but did not affect hyperglycemia, weight )] TJ ET BT 35.250 374.825 Td /F1 9.8 Tf [(loss or lifespan. \(A\) Timeline of experiment in weeks of age in the subset \(S\) and lifespan \(L\) mice \(WT, N=28; HD, N=26, at )] TJ ET BT 35.250 361.089 Td /F1 9.8 Tf [(the beginning of the study\). Behavioral testing was carried out from week 12 to 15 \(S mice: WTS=6; WTR=5; HTS=7; )] TJ ET BT 35.250 347.353 Td /F1 9.8 Tf [(HTR=6\). Mice \(S\) were sacrificed \(SAC\) at approximately 16.2 weeks of age. Survival analysis \(L mice: HTS=6; HTR=7\) )] TJ ET BT 35.250 333.616 Td /F1 9.8 Tf [(indicated that HD mice died between 11 and 26 weeks of age. WT controls \(L mice: WTS=7; WTR=10\) were sacrificed at )] TJ ET BT 35.250 319.880 Td /F1 9.8 Tf [(29 weeks. Abbreviations: MWM =Morris water maze; OF= Open field; S=Subset; L= Lifespan group; SAC = sacrificed. \(B\) )] TJ ET BT 35.250 306.144 Td /F1 9.8 Tf [(Onset of disease symptoms \(L mice\) such as hunched back, poor grooming and involuntary shaking occurred earlier in HD )] TJ ET BT 35.250 292.408 Td /F1 9.8 Tf [(runners; * p)] TJ ET Q BT 26.250 253.887 Td /F1 9.8 Tf [(HD mice display progressive weight loss or failure to continue to gain weight over their lifetime)] TJ ET 0.267 0.267 0.267 rg BT 431.558 253.887 Td /F1 9.8 Tf [( [15] [17] [18] [19] [20] )] TJ ET 0.271 0.267 0.267 rg BT 529.135 253.887 Td /F1 9.8 Tf [(. Weight )] TJ ET BT 26.250 241.982 Td /F1 9.8 Tf [(measurements were taken for every mouse \(WTS=13; WTR=15; HTS=13; HTR=13\) up to week 11, after which time mice were )] TJ ET BT 26.250 230.077 Td /F1 9.8 Tf [(progressively lost from the study \(Fig 1E\). Therefore, a mixed effects statistical model was used to estimate the longitudinal )] TJ ET BT 26.250 218.172 Td /F1 9.8 Tf [(trajectories while accounting for the within-subject correlations. There were significant differences in time-related change for )] TJ ET BT 26.250 206.268 Td /F1 9.8 Tf [(WTR vs HTR \(F )] TJ ET BT 98.283 204.203 Td /F1 8.7 Tf [(\(2,44.1\))] TJ ET BT 128.148 206.268 Td /F1 9.8 Tf [( = 20.36, p<0.0001\) and WTS vs HTS \(F )] TJ ET BT 305.901 204.203 Td /F1 8.7 Tf [(\(2,52.1\))] TJ ET BT 335.766 206.268 Td /F1 9.8 Tf [( = 4.54, p<0.01\) \(Fig 1D\). The differences for WTR vs )] TJ ET BT 26.250 194.363 Td /F1 9.8 Tf [(WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 174.958 Td /F1 9.8 Tf [(Both HD patients and mouse models of the disease appear to show deficient glucose metabolism )] TJ ET 0.267 0.267 0.267 rg BT 448.406 174.958 Td /F1 9.8 Tf [([18] [23] [24] [25])] TJ ET 0.271 0.267 0.267 rg BT 521.589 174.958 Td /F1 9.8 Tf [( . In our )] TJ ET BT 26.250 163.053 Td /F1 9.8 Tf [(study, similar statistical analysis was performed as described above for weights. There were significant differences in time-)] TJ ET BT 26.250 151.149 Td /F1 9.8 Tf [(related change for WTR vs HTR \(F )] TJ ET BT 179.578 149.084 Td /F1 8.7 Tf [(\(2,82.5\))] TJ ET BT 209.444 151.149 Td /F1 9.8 Tf [( = 9.07, p<0.0003\) and WTS and HTS \(F )] TJ ET BT 388.288 149.084 Td /F1 8.7 Tf [(\(2,79.2\))] TJ ET BT 418.153 151.149 Td /F1 9.8 Tf [( = 3.04, p<0.05\) \(Fig 1F\). The )] TJ ET BT 26.250 139.244 Td /F1 9.8 Tf [(differences for WTR vs WTS and HTR vs HTS were not statistically different.)] TJ ET BT 26.250 119.839 Td /F4 9.8 Tf [(Running increases the severity of motor deficits)] TJ ET BT 26.250 100.434 Td /F1 9.8 Tf [(Deficits in locomotor activity are a hallmark of HD )] TJ ET 0.267 0.267 0.267 rg BT 241.345 100.434 Td /F1 9.8 Tf [([15] [17] [18] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 333.502 100.434 Td /F1 9.8 Tf [( . We investigated the effect of running on rotarod )] TJ ET BT 26.250 88.530 Td /F1 9.8 Tf [(performance \(1001 days old\) and open field behavior \(1031 days old\) \(S mice\). In addition, running distance \(Fig 1A\) and )] TJ ET BT 26.250 76.625 Td /F1 9.8 Tf [(striatal volume were measured in both groups \(S and L mice\).)] TJ ET BT 26.250 57.220 Td /F1 9.8 Tf [(The latency to the first fall from the rotarod and the number of falls over 5 min was recorded in three consecutive trials and the )] TJ ET BT 26.250 45.315 Td /F1 9.8 Tf [(average of these three trials was calculated \(Fig 2 A,D\). There was a significant main effect of genotype in the latency to first fall )] TJ ET Q q 225.000 0 0 183.000 35.250 405.550 cm /I10 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 185 0 obj << /Type /Annot /Subtype /Link /A 186 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 405.5505 260.2500 588.5505 ] >> endobj 186 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-1-plos-legend.jpg) >> endobj 187 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 244 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 20666>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?R'hI_WM~kfJkOVE c8j~uᚿj_,omoeCcgǘX̣ s&T{-%hh撊^h/4sHh@ Q@ ~tPE%-P%RQ@ %P/4dPE%-f@ Q@ E'E/4sGI@ 'GG@|GPmk:ׇaԴk.=&.-UR!wgblh>?FqG&OͣHq驪tmcU^Y\ec-ۚþn+L1^KA)}˹Uʆ+W18DPY5 ¿3iHV<+Q΢>Ov$WhP!(bO^3;Kuky5e,)"#11Nou+C6U?^? +iI)}nMP#L>sqLx\?Q?Я uoÿCgbc o23 k|?Dc?@{7ph^{9hsͤɾ+"NF7 u 0Љ,§G'LҸ_բԮ#sȐ#"8N#w,ǽ{B=y'1# G1# @?Уph^I u'?CmQ u'?CmP(\?W| ?| ?;ӿu"u5ܗ6 {4KÖU#QkRh[i]Rt*#:Rsl>+֏/ ͔k>lma136q#X'yυg? ·=vM] y^QEfCjX$ZZoi mQ"My}DyYQT`>r[;c&ojַO$R*\Qf;Y LLBaA>hIJ|25 ּDmmTƉ|vYco2 It+`G)[K'MLuZx n#KK '$`( gN.zM1XQfTu?vVrr?7?}Cg}=ޓnj^FIqG,#k?34CRN[jZei41f |aPkmGq1Vvi#q]6_nb7gz' gUWaK)wƉO R6 dʼnڎlymy?c* $ d6EejKZuc[EӤ aM$2Lpp㙣ynC)oO\]>֊Fn4JRMoQe[>{M+ w? |{y:Dy&gvb,I$Ԛ-a߁*u²wemhl-4O<+!?k{G} >_#6E_#6EfxLyz}Ok4؉5anbLTl1fdϖ=]B;V~zƉ| +flL-xdʥÁّM:b4˖m@-U0# h6" 7<@qzgZOO='ŷ6>lȵY2$Eb%< /O$lq|4m^9w{Oⶕ|*<>IHkG-Q,t1S@l(\?W8O)ke5%D2bn8\d( ]+/Vo >]_QPu &nlѰª5(Л_MyoY_.o-=to2I#E1phʏʹ3oul|M^^Lvh&n( )??"'suS~$; OԻ 6@=Dc~DnSWNj7ԖhЅS(`s:t4ìxjD oH7'dnSm ̅O#??k9^!†L0!L4iX` c]B184,ڦb ĞHnTWxWR*;mK_K$8Ļb,J =yMծ)!'mFWxڣ?E9tb;fAo$w[#\ٵC89:S$ _Z\{"FPMPyh݇^)Iw g:QQ~4{<7q$<2yVE8#jŮM$#m`uQڀ>P?Qixlg\3[2HaL6p0NV@Fk͖c WbC$l 4-;5Lfq {$R)GGX 8x>6AWmemgė˘r1><9ilwv9,$54:gK~GmRPXWwd`JߥiQXhx .M i^T\l Kn84ǫ-~2!1k: 55$ t#PKfuK. u a̪y1KqkV࿊^'_?\\O}ˎh. )vCv_jװxK!nd,@‚@RҀ2.'Sޟ:]=ݾb!9fMBҟ\G~,rJf]5-t@tgДYN_ @7sa{\DkVh7oYC)9`,G?% kʶ/ fPY F##wvǡ_&x #I0%Z1{ gG4X\k:W/,Rϛ'6xz5?_ $ v;@ھ.~)oz{aGFhh*_5/@k>Zϴ_P_}}X+}NQ0j;" (E(QEQEQE%y|Fl m&'E"u< \,WHt-E}ڊ!Tȸ `Eд@5YZrV^̷p@N$˻R'aјlfm;Lnt=Rĥ?UI$!2W3M!q? 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Specific comparisons showed that the HTR mice )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(fell off the rotarod sooner than the other three groups \(p<0.03; Fig 2A\) and had more total falls than the two WT groups \(p<0.02; )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Fig 2D\).)] TJ ET 0.965 0.965 0.965 rg 26.250 571.313 555.000 162.473 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 733.786 m 581.250 733.786 l 581.250 733.036 l 26.250 733.036 l f 26.250 571.313 m 581.250 571.313 l 581.250 572.063 l 26.250 572.063 l f q 225.000 0 0 100.500 35.250 623.536 cm /I11 Do Q q 35.250 582.563 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 606.547 Td /F4 9.8 Tf [(Figure 2.)] TJ ET BT 75.888 606.547 Td /F1 9.8 Tf [( Exercise exacerbated locomotor deficits in HD mice and reduced striatal volume. \(A,D\) The latency to fall off an )] TJ ET BT 35.250 592.810 Td /F1 9.8 Tf [(accelerating rotarod was shorter in HTR mice than in all other groups \(A\); * p0.16\). Data represents mean SEM.)] TJ ET Q BT 26.250 554.289 Td /F1 9.8 Tf [(Analysis of distance traveled in the open field over 30 min only revealed a significant main effect of genotype \(F )] TJ ET BT 508.563 552.225 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 531.200 554.289 Td /F1 9.8 Tf [( =4.39, )] TJ ET BT 26.250 542.385 Td /F1 9.8 Tf [(p<0.049; Fig 2B\). Overall, HD mice had reduced open field activity as compared to WT controls. Posthoc tests showed that the )] TJ ET BT 26.250 530.480 Td /F1 9.8 Tf [(HTR covered significantly less distance in the open field than WT running mice \(WTR\) \(p<0.03: Fig 2B\).)] TJ ET BT 26.250 511.075 Td /F1 9.8 Tf [(Voluntary running distance in the home cage was monitored in WTR and HTR groups and data were analyzed as described for )] TJ ET BT 26.250 499.170 Td /F1 9.8 Tf [(weights and glucose above. There was no significant difference between the groups in running distance over the duration of the )] TJ ET BT 26.250 487.266 Td /F1 9.8 Tf [(experiment \(F )] TJ ET BT 89.099 485.201 Td /F1 8.7 Tf [(\(2,275\))] TJ ET BT 116.555 487.266 Td /F1 9.8 Tf [( = 1.83, p < 0.16; Fig 2E\).)] TJ ET BT 26.250 467.861 Td /F1 9.8 Tf [(Striatal volume was measured in both S and L groups. Analysis of the percent change in volume in the HD mice compared to )] TJ ET BT 26.250 455.956 Td /F1 9.8 Tf [(WT control mice showed no difference between the groups in the S mice \(Fig 2C\), but did reveal a significant main effect of )] TJ ET BT 26.250 444.051 Td /F1 9.8 Tf [(genotype for the L group \(F )] TJ ET BT 147.111 441.987 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 169.748 444.051 Td /F1 9.8 Tf [( =6.24, p<0.02\); Fig 2F\). Posthoc tests showed that HTR mice \(L\) had significantly diminished )] TJ ET BT 26.250 432.147 Td /F1 9.8 Tf [(striatal volume compared to HTS mice \(p<0.046: Fig 2F\), and both groups differed significantly from WTS mice \(p<0.006: Fig )] TJ ET BT 26.250 420.242 Td /F1 9.8 Tf [(2F\).)] TJ ET BT 26.250 400.837 Td /F4 9.8 Tf [(Running fails to rescue cognitive impairment)] TJ ET BT 26.250 381.432 Td /F1 9.8 Tf [(Morris water maze )] TJ ET 0.267 0.267 0.267 rg BT 109.135 381.432 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 125.398 381.432 Td /F1 9.8 Tf [( performance was tested around the time when cognitive abnormalities appear \(881 days old; S mice; )] TJ ET BT 26.250 369.528 Td /F1 9.8 Tf [(Fig 1A\) )] TJ ET 0.267 0.267 0.267 rg BT 60.385 369.528 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 76.648 369.528 Td /F1 9.8 Tf [( . Mice were trained over 8 days with 4 daily consecutive trials. A two-way ANOVA with repeated measures \(Days\) )] TJ ET BT 26.250 357.623 Td /F1 9.8 Tf [(revealed a significant difference in latency to the platform, with main effects of genotype \(F )] TJ ET BT 418.600 355.559 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 441.237 357.623 Td /F1 9.8 Tf [( =74.08, p<0.0001\) and )] TJ ET BT 26.250 345.718 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 343.654 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 99.812 345.718 Td /F1 9.8 Tf [( = 4.88, p<0.04\), \(Fig 3A\). There was no interaction between genotype and exercise \(p>0.39\). WT mice )] TJ ET BT 26.250 333.813 Td /F1 9.8 Tf [(performed better than the transgenic animals \(p<0.0002\). Furthermore, WTR had a greater rate of learning on this task than all )] TJ ET BT 26.250 321.909 Td /F1 9.8 Tf [(other groups \(p<0.048\). Learning curve comparison revealed a significant decrease in latency from day 1 to day 8 in the WT )] TJ ET BT 26.250 310.004 Td /F1 9.8 Tf [(mice \(F )] TJ ET BT 61.457 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 79.276 310.004 Td /F1 9.8 Tf [( =5.36, p<0.0001\) but not in the transgenic mice \(F )] TJ ET BT 300.942 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 318.761 310.004 Td /F1 9.8 Tf [( =0.64, p>0.72\). Swim speed analysis showed main effects )] TJ ET BT 26.250 298.099 Td /F1 9.8 Tf [(of genotype \(F )] TJ ET BT 91.829 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 114.466 298.099 Td /F1 9.8 Tf [( = 28.25, p<0.0001\) and exercise \(F )] TJ ET BT 272.182 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 294.819 298.099 Td /F1 9.8 Tf [( =5.04, p<0.04\), and no interaction \(p>0.29\), \(Fig 3B\). Overall )] TJ ET BT 26.250 286.194 Td /F1 9.8 Tf [(transgenic mice swam slower than the WT mice \(p<0.04\). However, the HTR mice swam faster than the HTS mice \(p<0.02\). )] TJ ET BT 26.250 274.290 Td /F1 9.8 Tf [(There was no difference in swim speed between WT sedentary mice \(WTS\) and WTR \(p>0.44\), suggesting enhanced WTR )] TJ ET BT 26.250 262.385 Td /F1 9.8 Tf [(performance is not due to improved motor skills.)] TJ ET 0.965 0.965 0.965 rg 26.250 53.795 555.000 198.709 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 252.504 m 581.250 252.504 l 581.250 251.754 l 26.250 251.754 l f q 225.000 0 0 134.250 35.250 108.504 cm /I12 Do Q q 35.250 53.795 537.000 48.709 re W n Q Q q 15.000 53.795 577.500 723.205 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(\(F )] TJ ET BT 38.165 765.412 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 60.802 767.476 Td /F1 9.8 Tf [( = 4.56, p<0.05\) and for the number of falls \(F )] TJ ET BT 260.248 765.412 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 282.885 767.476 Td /F1 9.8 Tf [( = 5.99, p<0.02\). Specific comparisons showed that the HTR mice )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(fell off the rotarod sooner than the other three groups \(p<0.03; Fig 2A\) and had more total falls than the two WT groups \(p<0.02; )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Fig 2D\).)] TJ ET 0.965 0.965 0.965 rg 26.250 571.313 555.000 162.473 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 733.786 m 581.250 733.786 l 581.250 733.036 l 26.250 733.036 l f 26.250 571.313 m 581.250 571.313 l 581.250 572.063 l 26.250 572.063 l f q 225.000 0 0 100.500 35.250 623.536 cm /I11 Do Q q 35.250 582.563 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 606.547 Td /F4 9.8 Tf [(Figure 2.)] TJ ET BT 75.888 606.547 Td /F1 9.8 Tf [( Exercise exacerbated locomotor deficits in HD mice and reduced striatal volume. \(A,D\) The latency to fall off an )] TJ ET BT 35.250 592.810 Td /F1 9.8 Tf [(accelerating rotarod was shorter in HTR mice than in all other groups \(A\); * p0.16\). Data represents mean SEM.)] TJ ET Q BT 26.250 554.289 Td /F1 9.8 Tf [(Analysis of distance traveled in the open field over 30 min only revealed a significant main effect of genotype \(F )] TJ ET BT 508.563 552.225 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 531.200 554.289 Td /F1 9.8 Tf [( =4.39, )] TJ ET BT 26.250 542.385 Td /F1 9.8 Tf [(p<0.049; Fig 2B\). Overall, HD mice had reduced open field activity as compared to WT controls. Posthoc tests showed that the )] TJ ET BT 26.250 530.480 Td /F1 9.8 Tf [(HTR covered significantly less distance in the open field than WT running mice \(WTR\) \(p<0.03: Fig 2B\).)] TJ ET BT 26.250 511.075 Td /F1 9.8 Tf [(Voluntary running distance in the home cage was monitored in WTR and HTR groups and data were analyzed as described for )] TJ ET BT 26.250 499.170 Td /F1 9.8 Tf [(weights and glucose above. There was no significant difference between the groups in running distance over the duration of the )] TJ ET BT 26.250 487.266 Td /F1 9.8 Tf [(experiment \(F )] TJ ET BT 89.099 485.201 Td /F1 8.7 Tf [(\(2,275\))] TJ ET BT 116.555 487.266 Td /F1 9.8 Tf [( = 1.83, p < 0.16; Fig 2E\).)] TJ ET BT 26.250 467.861 Td /F1 9.8 Tf [(Striatal volume was measured in both S and L groups. Analysis of the percent change in volume in the HD mice compared to )] TJ ET BT 26.250 455.956 Td /F1 9.8 Tf [(WT control mice showed no difference between the groups in the S mice \(Fig 2C\), but did reveal a significant main effect of )] TJ ET BT 26.250 444.051 Td /F1 9.8 Tf [(genotype for the L group \(F )] TJ ET BT 147.111 441.987 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 169.748 444.051 Td /F1 9.8 Tf [( =6.24, p<0.02\); Fig 2F\). Posthoc tests showed that HTR mice \(L\) had significantly diminished )] TJ ET BT 26.250 432.147 Td /F1 9.8 Tf [(striatal volume compared to HTS mice \(p<0.046: Fig 2F\), and both groups differed significantly from WTS mice \(p<0.006: Fig )] TJ ET BT 26.250 420.242 Td /F1 9.8 Tf [(2F\).)] TJ ET BT 26.250 400.837 Td /F4 9.8 Tf [(Running fails to rescue cognitive impairment)] TJ ET BT 26.250 381.432 Td /F1 9.8 Tf [(Morris water maze )] TJ ET 0.267 0.267 0.267 rg BT 109.135 381.432 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 125.398 381.432 Td /F1 9.8 Tf [( performance was tested around the time when cognitive abnormalities appear \(881 days old; S mice; )] TJ ET BT 26.250 369.528 Td /F1 9.8 Tf [(Fig 1A\) )] TJ ET 0.267 0.267 0.267 rg BT 60.385 369.528 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 76.648 369.528 Td /F1 9.8 Tf [( . Mice were trained over 8 days with 4 daily consecutive trials. A two-way ANOVA with repeated measures \(Days\) )] TJ ET BT 26.250 357.623 Td /F1 9.8 Tf [(revealed a significant difference in latency to the platform, with main effects of genotype \(F )] TJ ET BT 418.600 355.559 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 441.237 357.623 Td /F1 9.8 Tf [( =74.08, p<0.0001\) and )] TJ ET BT 26.250 345.718 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 343.654 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 99.812 345.718 Td /F1 9.8 Tf [( = 4.88, p<0.04\), \(Fig 3A\). There was no interaction between genotype and exercise \(p>0.39\). WT mice )] TJ ET BT 26.250 333.813 Td /F1 9.8 Tf [(performed better than the transgenic animals \(p<0.0002\). Furthermore, WTR had a greater rate of learning on this task than all )] TJ ET BT 26.250 321.909 Td /F1 9.8 Tf [(other groups \(p<0.048\). Learning curve comparison revealed a significant decrease in latency from day 1 to day 8 in the WT )] TJ ET BT 26.250 310.004 Td /F1 9.8 Tf [(mice \(F )] TJ ET BT 61.457 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 79.276 310.004 Td /F1 9.8 Tf [( =5.36, p<0.0001\) but not in the transgenic mice \(F )] TJ ET BT 300.942 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 318.761 310.004 Td /F1 9.8 Tf [( =0.64, p>0.72\). Swim speed analysis showed main effects )] TJ ET BT 26.250 298.099 Td /F1 9.8 Tf [(of genotype \(F )] TJ ET BT 91.829 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 114.466 298.099 Td /F1 9.8 Tf [( = 28.25, p<0.0001\) and exercise \(F )] TJ ET BT 272.182 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 294.819 298.099 Td /F1 9.8 Tf [( =5.04, p<0.04\), and no interaction \(p>0.29\), \(Fig 3B\). Overall )] TJ ET BT 26.250 286.194 Td /F1 9.8 Tf [(transgenic mice swam slower than the WT mice \(p<0.04\). However, the HTR mice swam faster than the HTS mice \(p<0.02\). )] TJ ET BT 26.250 274.290 Td /F1 9.8 Tf [(There was no difference in swim speed between WT sedentary mice \(WTS\) and WTR \(p>0.44\), suggesting enhanced WTR )] TJ ET BT 26.250 262.385 Td /F1 9.8 Tf [(performance is not due to improved motor skills.)] TJ ET 0.965 0.965 0.965 rg 26.250 53.795 555.000 198.709 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 252.504 m 581.250 252.504 l 581.250 251.754 l 26.250 251.754 l f q 225.000 0 0 134.250 35.250 108.504 cm /I12 Do Q q 35.250 53.795 537.000 48.709 re W n Q Q q 15.000 53.795 577.500 723.205 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(\(F )] TJ ET BT 38.165 765.412 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 60.802 767.476 Td /F1 9.8 Tf [( = 4.56, p<0.05\) and for the number of falls \(F )] TJ ET BT 260.248 765.412 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 282.885 767.476 Td /F1 9.8 Tf [( = 5.99, p<0.02\). Specific comparisons showed that the HTR mice )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(fell off the rotarod sooner than the other three groups \(p<0.03; Fig 2A\) and had more total falls than the two WT groups \(p<0.02; )] TJ ET BT 26.250 743.667 Td /F1 9.8 Tf [(Fig 2D\).)] TJ ET 0.965 0.965 0.965 rg 26.250 571.313 555.000 162.473 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 733.786 m 581.250 733.786 l 581.250 733.036 l 26.250 733.036 l f 26.250 571.313 m 581.250 571.313 l 581.250 572.063 l 26.250 572.063 l f q 225.000 0 0 100.500 35.250 623.536 cm /I11 Do Q q 35.250 582.563 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 606.547 Td /F4 9.8 Tf [(Figure 2.)] TJ ET BT 75.888 606.547 Td /F1 9.8 Tf [( Exercise exacerbated locomotor deficits in HD mice and reduced striatal volume. \(A,D\) The latency to fall off an )] TJ ET BT 35.250 592.810 Td /F1 9.8 Tf [(accelerating rotarod was shorter in HTR mice than in all other groups \(A\); * p0.16\). Data represents mean SEM.)] TJ ET Q BT 26.250 554.289 Td /F1 9.8 Tf [(Analysis of distance traveled in the open field over 30 min only revealed a significant main effect of genotype \(F )] TJ ET BT 508.563 552.225 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 531.200 554.289 Td /F1 9.8 Tf [( =4.39, )] TJ ET BT 26.250 542.385 Td /F1 9.8 Tf [(p<0.049; Fig 2B\). Overall, HD mice had reduced open field activity as compared to WT controls. Posthoc tests showed that the )] TJ ET BT 26.250 530.480 Td /F1 9.8 Tf [(HTR covered significantly less distance in the open field than WT running mice \(WTR\) \(p<0.03: Fig 2B\).)] TJ ET BT 26.250 511.075 Td /F1 9.8 Tf [(Voluntary running distance in the home cage was monitored in WTR and HTR groups and data were analyzed as described for )] TJ ET BT 26.250 499.170 Td /F1 9.8 Tf [(weights and glucose above. There was no significant difference between the groups in running distance over the duration of the )] TJ ET BT 26.250 487.266 Td /F1 9.8 Tf [(experiment \(F )] TJ ET BT 89.099 485.201 Td /F1 8.7 Tf [(\(2,275\))] TJ ET BT 116.555 487.266 Td /F1 9.8 Tf [( = 1.83, p < 0.16; Fig 2E\).)] TJ ET BT 26.250 467.861 Td /F1 9.8 Tf [(Striatal volume was measured in both S and L groups. Analysis of the percent change in volume in the HD mice compared to )] TJ ET BT 26.250 455.956 Td /F1 9.8 Tf [(WT control mice showed no difference between the groups in the S mice \(Fig 2C\), but did reveal a significant main effect of )] TJ ET BT 26.250 444.051 Td /F1 9.8 Tf [(genotype for the L group \(F )] TJ ET BT 147.111 441.987 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 169.748 444.051 Td /F1 9.8 Tf [( =6.24, p<0.02\); Fig 2F\). Posthoc tests showed that HTR mice \(L\) had significantly diminished )] TJ ET BT 26.250 432.147 Td /F1 9.8 Tf [(striatal volume compared to HTS mice \(p<0.046: Fig 2F\), and both groups differed significantly from WTS mice \(p<0.006: Fig )] TJ ET BT 26.250 420.242 Td /F1 9.8 Tf [(2F\).)] TJ ET BT 26.250 400.837 Td /F4 9.8 Tf [(Running fails to rescue cognitive impairment)] TJ ET BT 26.250 381.432 Td /F1 9.8 Tf [(Morris water maze )] TJ ET 0.267 0.267 0.267 rg BT 109.135 381.432 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 125.398 381.432 Td /F1 9.8 Tf [( performance was tested around the time when cognitive abnormalities appear \(881 days old; S mice; )] TJ ET BT 26.250 369.528 Td /F1 9.8 Tf [(Fig 1A\) )] TJ ET 0.267 0.267 0.267 rg BT 60.385 369.528 Td /F1 9.8 Tf [([19])] TJ ET 0.271 0.267 0.267 rg BT 76.648 369.528 Td /F1 9.8 Tf [( . Mice were trained over 8 days with 4 daily consecutive trials. A two-way ANOVA with repeated measures \(Days\) )] TJ ET BT 26.250 357.623 Td /F1 9.8 Tf [(revealed a significant difference in latency to the platform, with main effects of genotype \(F )] TJ ET BT 418.600 355.559 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 441.237 357.623 Td /F1 9.8 Tf [( =74.08, p<0.0001\) and )] TJ ET BT 26.250 345.718 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 343.654 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 99.812 345.718 Td /F1 9.8 Tf [( = 4.88, p<0.04\), \(Fig 3A\). There was no interaction between genotype and exercise \(p>0.39\). WT mice )] TJ ET BT 26.250 333.813 Td /F1 9.8 Tf [(performed better than the transgenic animals \(p<0.0002\). Furthermore, WTR had a greater rate of learning on this task than all )] TJ ET BT 26.250 321.909 Td /F1 9.8 Tf [(other groups \(p<0.048\). Learning curve comparison revealed a significant decrease in latency from day 1 to day 8 in the WT )] TJ ET BT 26.250 310.004 Td /F1 9.8 Tf [(mice \(F )] TJ ET BT 61.457 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 79.276 310.004 Td /F1 9.8 Tf [( =5.36, p<0.0001\) but not in the transgenic mice \(F )] TJ ET BT 300.942 307.940 Td /F1 8.7 Tf [(\(1,7\))] TJ ET BT 318.761 310.004 Td /F1 9.8 Tf [( =0.64, p>0.72\). Swim speed analysis showed main effects )] TJ ET BT 26.250 298.099 Td /F1 9.8 Tf [(of genotype \(F )] TJ ET BT 91.829 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 114.466 298.099 Td /F1 9.8 Tf [( = 28.25, p<0.0001\) and exercise \(F )] TJ ET BT 272.182 296.035 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 294.819 298.099 Td /F1 9.8 Tf [( =5.04, p<0.04\), and no interaction \(p>0.29\), \(Fig 3B\). Overall )] TJ ET BT 26.250 286.194 Td /F1 9.8 Tf [(transgenic mice swam slower than the WT mice \(p<0.04\). However, the HTR mice swam faster than the HTS mice \(p<0.02\). )] TJ ET BT 26.250 274.290 Td /F1 9.8 Tf [(There was no difference in swim speed between WT sedentary mice \(WTS\) and WTR \(p>0.44\), suggesting enhanced WTR )] TJ ET BT 26.250 262.385 Td /F1 9.8 Tf [(performance is not due to improved motor skills.)] TJ ET 0.965 0.965 0.965 rg 26.250 53.795 555.000 198.709 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 252.504 m 581.250 252.504 l 581.250 251.754 l 26.250 251.754 l f q 225.000 0 0 134.250 35.250 108.504 cm /I12 Do Q q 35.250 53.795 537.000 48.709 re W n Q Q q 225.000 0 0 100.500 35.250 623.536 cm /I11 Do Q q 225.000 0 0 134.250 35.250 108.504 cm /I12 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 212 0 obj << /Type /Annot /Subtype /Link /A 213 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 623.5358 260.2500 724.0358 ] >> endobj 213 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-2-plos.jpg) >> endobj 214 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 134 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 11473>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?Q/ i'ƅQ g=yxK|Y6բh{bdU6&'$Ozג|W↯q\|5%gFI6C@!C9 N½GQ)|j+ 4tRE%f( )JĻϊ:]J[yg j`ǰNy} )Jz젰|w%޳5ZP6N 6*,(-RPRRERPHzW+'k}㯴E=navL-ټ!{zE_'~-C7mϾ] 2#N08#O|S>7WKS-ƨ[ZY X(MĶh(.T[?n=nsjҠzRqEQGG@䟵G‹qZsSiV?kX:-J-^^QO]i? /u}J}>;}EҪ ͸y㯎6t'Ӗ}̱Jpȹ13wKS}ƞ*s|É 8$c llC{¾ ZDFz&ϰœy¾/sivm$ᦶfk%e$ ?dxĺviϦzxIX`=Ҁ>+V_>&5µ^DhzId`pqr;~y mu4 䕶($w (U FG,lt򡽂g5ρd>g x2c Ntk\7,w`޿~0K:;u<5[ԡnt.Wukw<ILי~:]HJek/wxFUͻmk払p3d+o\TxştxY1nk,-Or!QU|Œ18vqxWg@h x];ñq^|E d2b|W7k yɐxKv=+OۿQ׶b_9?_~+w_'?s8IxWN۟GU|cE;Yʀ$)3@k3ѼYfzc#VPIW\3}kSE[đDhU¾fៈ0j^GS̵|Wlpyf^Դ=IdkBɐaUPG h*dm?&nb2xnn0rp^W>x:^>M9.u C  n88+gj>ZM$q18`Aǵ0 њ($fᏈ~]êiz/ f Ǵ"/m]q nf@W-9-rԫma8<DlTM\mD) Ht!|++OA ^E[6- 1؀H뼸|7XtGȲǝq0APAP.1]f/ ,Tlo3ji3p*#4]ijĞyK?szgeA7 xVD)wDv|ޘ=~џk1oOa͓G# <ͦ3iaslfm̹ ?P(]灏n"iS`4։f uG%ԛNo PYR>$J$rB!Os`2H8_:?Y-l4Xυ 76ʓU I:`gRo[I짂{x`-Ĉu0F5xºoWu{dAs*7"w|Qu > լ OJ"cOXhN s^{-X.\3qUU§FOKiI0< l g>p?xפ3Fh('K[yf8Իtd5^CGQʆEXl嵕 D&RESX 9뎚xR "nE*H}7rZZ O:k,kIYq*( 5i:yalId E8%ki@9WЌBqT> \~ץ_,# tGNbn&n77k/WYm!.4c84(FecC᷈>i:Լ3AaC7zĤDF2 F1!Q^57F o%'x{h v {1ݏzm_kio,gYA*H<8=A2G\/s&b"}a_k0yUzpki@GH1l)h)?Җc\Qڨk6[@E3z@kX[kZc4W*`x# 3؃^m|^BFkOpIaܪ!s]+xkQ[u:P y'TlFp:U߇.׼[H$9qhu[xVUڳDYrw7V꤃@VP11E-̍$N6 *}Fx/hZ賳ִ뻶 COx3Vsy-"/+c|hp;Ec|*?>u~j moZIHaQqO׏Acx/5R}֥C|#ڎF0FQ^@)_Ju6T#dWp#*pGҀ<y3▛ev>w=@.atیP&*9* EXo>0[޽4ֺ|)рT7TP#Cjzcݡ$ `o2ݤyc]GK?xMĚ!cVMͳb[9MvM z(,_"?V{}d0wT_ \ [fbλb4j0ʲ=APR:,X`S 6x\D~F4,m8-- (`$hUQ1S@+/? >e'$2 ue_3o>%%㽎GH)dq9rzxgjh;Ei쯣W,# d My?h>++4pIoI!kg%_3 s'Qxk.xw@:fL1H#Vg`w!1׎|f~8xkY$ MGcb\ r0#^k?e7YeM 2lQV $Wy>ɐxKv1ր/r-f 6^M$'~p sX?>?v4?u,-zKKJcF/՘wuοOmF@?V_:W./WwqWϦ?"&]AN~RA rxwNA?G 1F(5rFH#*^h_o|)|1b~SO$v'z-M?`%ZMU3Y J!Ѐ=@͟/:^#mnQ)֞XO9V,8iv5R@%>^̜oݴw5f(3x#Unm|;^qlu3_s9?e P=wR[ڼ{mWmCQו2|$<{wzō@֖L+d,@g%PVzi!H±)˖HW nञ'ƿN|A=ZO"Kxܺ,lT1 @5_i75kQkhbUx36t51. o7Hʯ0k7JsWwL|j?fy`'z\oƯ#~< vtKEteҘTlqɤٗPmI>#M4gR0|az䞗~>|{4I-lu(%|"{Ec?2c*X OXgjdFf26 WUNmE6V$q ݻ9=sց lkmXoa{'_34`C HZ~ ɞ` Z.fF)!/ #0OaE1H:χO]ys^_3 F*p WEYgvX|G{2(RI^<{mw8r0GKhMΐa>aQ,nR}N@( +S#/݋P,zϿz>熵00/\Z  |#YdӼSġmo+ e«A)E# q Ɩ%TáKH`AU= @Z^OY3m[y{{XzX:W/ⴼ櫥4ȖȒ!h|dr3[ Λ{ŖF9UKlu+m,H$q}\xu+ zEsrV13eTH'`rCt b(oڮ&Up!pT d"Ծ5_^9ѭMִ`X XYqݿfF7ٯs!džnkڭŃKg A1y,0;@8# Wok^ ?x5xY5IAIVb2K| OZW7k Ÿ2 nRgs:{h6*4nF^/?;)s;g+q+;/;όg-?}]d?rxWNA"?GiyP^/燼-v˖<"] e _ɏ$gnNIi_Dj;dv1(@b' |;amfK++X5%:(;F2eVq򞬾'喧mR)\Z֢Ӥ-*)V$Įp௃S GŦsUx@ª) .b??e>[jO6ڍ6'^9f7i6;G q* |/6Lѵjm*;>ZDų4{ aNI&34}?W6ڂgR& |rPfO46*[F 9wXQE&+ȥA2^qzkuumo5DA~o*0[ife ŏ_^lEmIOIfOt* [۵sss%R36=WqEcڊ(1K(4J1Ecv((i( ( ( ( Z((hJ PQE-%PEPKE endstream endobj 215 0 obj << /Type /Annot /Subtype /Link /A 216 0 R /Border [0 0 0] /H /I /Rect [ 109.1347 380.5306 125.3978 390.4512 ] >> endobj 216 0 obj << /Type /Action >> endobj 217 0 obj << /Type /Annot /Subtype /Link /A 218 0 R /Border [0 0 0] /H /I /Rect [ 60.3847 368.6258 76.6478 378.5464 ] >> endobj 218 0 obj << /Type /Action >> endobj 219 0 obj << /Type /Annot /Subtype /Link /A 220 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 108.5040 260.2500 242.7540 ] >> endobj 220 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-3-plos.jpg) >> endobj 221 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 179 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 16140>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?RҊJ~:o~9#ӥ!ë4a-^[ 9=^ A|-pG>yh6[&|HN eH%g4-SRQ$lQ8 8ee>ڴ((? ? 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(ր(Kފ((\t_Z1EwQEPhQERQE(PR(Q@ AQ@:EP@Q@((Q@ endstream endobj 222 0 obj << /Type /Annot /Subtype /Link /A 223 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 623.5358 260.2500 724.0358 ] >> endobj 223 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-2-plos.jpg) >> endobj 224 0 obj << /Type /Annot /Subtype /Link /A 225 0 R /Border [0 0 0] /H /I /Rect [ 109.1347 380.5306 125.3978 390.4512 ] >> endobj 225 0 obj << /Type /Action >> endobj 226 0 obj << /Type /Annot /Subtype /Link /A 227 0 R /Border [0 0 0] /H /I /Rect [ 60.3847 368.6258 76.6478 378.5464 ] >> endobj 227 0 obj << /Type /Action >> endobj 228 0 obj << /Type /Annot /Subtype /Link /A 229 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 108.5040 260.2500 242.7540 ] >> endobj 229 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-3-plos.jpg) >> endobj 230 0 obj << /Type /Annot /Subtype /Link /A 231 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 623.5358 260.2500 724.0358 ] >> endobj 231 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-2-plos.jpg) >> endobj 232 0 obj << /Type /Annot /Subtype /Link /A 233 0 R /Border [0 0 0] /H /I /Rect [ 109.1347 380.5306 125.3978 390.4512 ] >> endobj 233 0 obj << /Type /Action >> endobj 234 0 obj << /Type /Annot /Subtype /Link /A 235 0 R /Border [0 0 0] /H /I /Rect [ 60.3847 368.6258 76.6478 378.5464 ] >> endobj 235 0 obj << /Type /Action >> endobj 236 0 obj << /Type /Annot /Subtype /Link /A 237 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 108.5040 260.2500 242.7540 ] >> endobj 237 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-3-plos.jpg) >> endobj 238 0 obj << /Type /Page /Parent 3 0 R /Annots [ 240 0 R 242 0 R 244 0 R 247 0 R 250 0 R 252 0 R 254 0 R 256 0 R 258 0 R 260 0 R 262 0 R 264 0 R ] /Contents 239 0 R >> endobj 239 0 obj << /Length 23301 >> stream q 15.000 -36.205 577.500 813.205 re W n 0.965 0.965 0.965 rg 26.250 717.041 555.000 59.959 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 717.041 m 581.250 717.041 l 581.250 717.791 l 26.250 717.791 l f q 35.250 728.291 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Figure 3.)] TJ ET BT 75.888 766.011 Td /F1 9.8 Tf [( Running did not rescue the spatial learning deficit in the Morris water maze. \(A\) Latency to reach the platform in )] TJ ET BT 35.250 752.275 Td /F1 9.8 Tf [(the Morris water maze over 8 test days \(data represents the average of 4 trials per day\) was reduced in WT but not HD )] TJ ET BT 35.250 738.538 Td /F1 9.8 Tf [(mice; p0.06\) . HD mice did not cross the platform zone during the probe trial. Data represents mean SEM.)] TJ ET Q BT 26.250 700.017 Td /F1 9.8 Tf [(A probe trial was performed 24 hr after the last training session. For time spent in the target quadrant there was a significant )] TJ ET BT 26.250 688.113 Td /F1 9.8 Tf [(genotype x exercise interaction \(F )] TJ ET BT 175.269 686.048 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 197.906 688.113 Td /F1 9.8 Tf [( = 4.53, p<0.05\). Specific comparisons showed that only the WTR group spent more )] TJ ET BT 26.250 676.208 Td /F1 9.8 Tf [(time in the target quadrant compared to the three other groups \(p<0.05\) \(Fig 3C\). HD mice did not cross the platform zone )] TJ ET BT 26.250 664.303 Td /F1 9.8 Tf [(during the probe trial. There was no significant difference in the number of platform crossings between WTR and WTS mice )] TJ ET BT 26.250 652.398 Td /F1 9.8 Tf [(\(p>0.06\) \(Fig 3D\).)] TJ ET BT 26.250 632.994 Td /F4 9.8 Tf [(Running does not reverse decreased neurogenesis or diminish mHtt inclusions)] TJ ET BT 26.250 613.589 Td /F1 9.8 Tf [(Neurogenesis is decreased in mouse HD models)] TJ ET 0.267 0.267 0.267 rg BT 237.571 613.589 Td /F1 9.8 Tf [( [13] [16] [27] [28] [29])] TJ ET 0.271 0.267 0.267 rg BT 332.439 613.589 Td /F1 9.8 Tf [( . Data for all mice tested \(S and L mice; Fig 1A\) did not )] TJ ET BT 26.250 601.684 Td /F1 9.8 Tf [(differ and was therefore combined \(WTS=13; WTR=15; HTS=9-12; HTR=10-12\). There was a significant main effect of )] TJ ET BT 26.250 589.779 Td /F1 9.8 Tf [(genotype on BrdU )] TJ ET BT 107.546 593.668 Td /F1 8.7 Tf [(+)] TJ ET BT 112.607 589.779 Td /F1 9.8 Tf [( cell number \(F )] TJ ET BT 180.330 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 202.968 589.779 Td /F1 9.8 Tf [( = 41.14, p<0.0001\) and density F )] TJ ET BT 352.026 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 374.663 589.779 Td /F1 9.8 Tf [( = 33.52, p<0.0001\). HD mice had reduced )] TJ ET BT 26.250 577.875 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 577.875 Td /F1 9.8 Tf [( cell number and density compared to WT animals \(p<0.002\). WTR had more BrdU )] TJ ET BT 416.836 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 421.897 577.875 Td /F1 9.8 Tf [( cells than all the other groups )] TJ ET BT 26.250 565.970 Td /F1 9.8 Tf [(\(p<0.03\) confirming that running enhances new cell survival under standard conditions, whereas there was no effect of exercise )] TJ ET BT 26.250 554.065 Td /F1 9.8 Tf [(in HD mice \(p>0.93\) \(Fig 4A,B\). To identify the percentage of surviving BrdU )] TJ ET BT 357.604 557.953 Td /F1 8.7 Tf [(+)] TJ ET BT 362.665 554.065 Td /F1 9.8 Tf [( cells that become neurons, double labeling for )] TJ ET BT 26.250 542.160 Td /F1 9.8 Tf [(BrdU and NeuN was performed. Significant main effects of genotype \(F )] TJ ET BT 336.212 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 358.850 542.160 Td /F1 9.8 Tf [( = 303.37, p<0.0001\) and exercise \(F )] TJ ET BT 521.987 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 544.624 542.160 Td /F1 9.8 Tf [( = 7.89, )] TJ ET BT 26.250 530.256 Td /F1 9.8 Tf [(p<0.008\) and no interaction of genotype and exercise \(p>0.72\) were observed. The percentage of double-labeled BrdU )] TJ ET BT 541.654 534.144 Td /F1 8.7 Tf [(+)] TJ ET BT 546.716 530.256 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 26.250 522.239 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 518.351 Td /F1 9.8 Tf [( cells was significantly higher in HTR than HTS mice \(p<0.05; Fig 4C\). However, the total number of new neurons did not differ )] TJ ET BT 26.250 506.446 Td /F1 9.8 Tf [(between the HTR and HTS groups \(p>0.88; Fig 4D\). Furthermore, analysis of granule cell layer \(GCL\) volume revealed a main )] TJ ET BT 26.250 494.541 Td /F1 9.8 Tf [(effect of genotype \(F )] TJ ET BT 118.388 492.477 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 141.025 494.541 Td /F1 9.8 Tf [( =18.29, p<0.0001; Fig 4E\), suggesting that reduced neurogenesis in HD mice may have translated )] TJ ET BT 26.250 482.637 Td /F1 9.8 Tf [(to a significant volume reduction. Alternatively, this volume reduction could be explained by neuronal atrophy leading to )] TJ ET BT 26.250 470.732 Td /F1 9.8 Tf [(reductions in hippocampal volume )] TJ ET 0.267 0.267 0.267 rg BT 176.351 470.732 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 192.614 470.732 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 302.878 555.000 157.973 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 460.851 m 581.250 460.851 l 581.250 460.101 l 26.250 460.101 l f 26.250 302.878 m 581.250 302.878 l 581.250 303.628 l 26.250 303.628 l f q 225.000 0 0 96.000 35.250 355.101 cm /I13 Do Q q 35.250 314.128 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 338.112 Td /F4 9.8 Tf [(Figure 4.)] TJ ET BT 75.888 338.112 Td /F1 9.8 Tf [( Exercise failed to rescue the neurogenic deficit and decreased GCL volume in HD mice. \(A\) The number of )] TJ ET BT 35.250 324.376 Td /F1 9.8 Tf [(BrdU+ cells was significantly increased in WTR as compared to all other groups; ** p)] TJ ET Q BT 26.250 285.855 Td /F1 9.8 Tf [(An interesting observation was made pertaining to the location of BrdU )] TJ ET BT 333.521 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 338.583 285.855 Td /F1 9.8 Tf [( cells. There was a higher percentage of hilar BrdU )] TJ ET BT 560.756 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 273.950 Td /F1 9.8 Tf [(cells in HD compared to WT mice \(F )] TJ ET BT 185.526 271.886 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 208.163 273.950 Td /F1 9.8 Tf [( =242.56, p<0.0001\). There was also a significant interaction between genotype and )] TJ ET BT 26.250 262.045 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 259.981 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 99.812 262.045 Td /F1 9.8 Tf [( =4.82, p<0.03\). Specific comparisons showed that HTR had a significantly lower percentage of hilar BrdU )] TJ ET BT 558.803 265.933 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 250.140 Td /F1 9.8 Tf [(cells than HTS \(p<0.0007; Fig 4F\). Together with the increase in percentage BrdU )] TJ ET BT 382.554 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 387.615 250.140 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 420.668 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 425.729 250.140 Td /F1 9.8 Tf [( cells, this suggests a possible )] TJ ET BT 26.250 238.236 Td /F1 9.8 Tf [(modest beneficial effect of exercise on neurogenesis in HTR mice. However, doublecortin \(DCX\) staining revealed that the )] TJ ET BT 26.250 226.331 Td /F1 9.8 Tf [(immature neurons in both HD groups appear to have less dendritic branching and dendrites that do not extend into the )] TJ ET BT 26.250 214.426 Td /F1 9.8 Tf [(molecular layer as compared to WT mice \(Fig 5\).)] TJ ET 0.965 0.965 0.965 rg 26.250 -36.205 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 204.545 m 581.250 204.545 l 581.250 203.795 l 26.250 203.795 l f q 126.750 0 0 225.000 35.250 -30.205 cm /I14 Do Q q 35.250 -36.205 537.000 0.000 re W n Q Q q 15.000 -36.205 577.500 813.205 re W n 0.965 0.965 0.965 rg 26.250 717.041 555.000 59.959 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 717.041 m 581.250 717.041 l 581.250 717.791 l 26.250 717.791 l f q 35.250 728.291 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Figure 3.)] TJ ET BT 75.888 766.011 Td /F1 9.8 Tf [( Running did not rescue the spatial learning deficit in the Morris water maze. \(A\) Latency to reach the platform in )] TJ ET BT 35.250 752.275 Td /F1 9.8 Tf [(the Morris water maze over 8 test days \(data represents the average of 4 trials per day\) was reduced in WT but not HD )] TJ ET BT 35.250 738.538 Td /F1 9.8 Tf [(mice; p0.06\) . HD mice did not cross the platform zone during the probe trial. Data represents mean SEM.)] TJ ET Q BT 26.250 700.017 Td /F1 9.8 Tf [(A probe trial was performed 24 hr after the last training session. For time spent in the target quadrant there was a significant )] TJ ET BT 26.250 688.113 Td /F1 9.8 Tf [(genotype x exercise interaction \(F )] TJ ET BT 175.269 686.048 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 197.906 688.113 Td /F1 9.8 Tf [( = 4.53, p<0.05\). Specific comparisons showed that only the WTR group spent more )] TJ ET BT 26.250 676.208 Td /F1 9.8 Tf [(time in the target quadrant compared to the three other groups \(p<0.05\) \(Fig 3C\). HD mice did not cross the platform zone )] TJ ET BT 26.250 664.303 Td /F1 9.8 Tf [(during the probe trial. There was no significant difference in the number of platform crossings between WTR and WTS mice )] TJ ET BT 26.250 652.398 Td /F1 9.8 Tf [(\(p>0.06\) \(Fig 3D\).)] TJ ET BT 26.250 632.994 Td /F4 9.8 Tf [(Running does not reverse decreased neurogenesis or diminish mHtt inclusions)] TJ ET BT 26.250 613.589 Td /F1 9.8 Tf [(Neurogenesis is decreased in mouse HD models)] TJ ET 0.267 0.267 0.267 rg BT 237.571 613.589 Td /F1 9.8 Tf [( [13] [16] [27] [28] [29])] TJ ET 0.271 0.267 0.267 rg BT 332.439 613.589 Td /F1 9.8 Tf [( . Data for all mice tested \(S and L mice; Fig 1A\) did not )] TJ ET BT 26.250 601.684 Td /F1 9.8 Tf [(differ and was therefore combined \(WTS=13; WTR=15; HTS=9-12; HTR=10-12\). There was a significant main effect of )] TJ ET BT 26.250 589.779 Td /F1 9.8 Tf [(genotype on BrdU )] TJ ET BT 107.546 593.668 Td /F1 8.7 Tf [(+)] TJ ET BT 112.607 589.779 Td /F1 9.8 Tf [( cell number \(F )] TJ ET BT 180.330 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 202.968 589.779 Td /F1 9.8 Tf [( = 41.14, p<0.0001\) and density F )] TJ ET BT 352.026 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 374.663 589.779 Td /F1 9.8 Tf [( = 33.52, p<0.0001\). HD mice had reduced )] TJ ET BT 26.250 577.875 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 577.875 Td /F1 9.8 Tf [( cell number and density compared to WT animals \(p<0.002\). WTR had more BrdU )] TJ ET BT 416.836 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 421.897 577.875 Td /F1 9.8 Tf [( cells than all the other groups )] TJ ET BT 26.250 565.970 Td /F1 9.8 Tf [(\(p<0.03\) confirming that running enhances new cell survival under standard conditions, whereas there was no effect of exercise )] TJ ET BT 26.250 554.065 Td /F1 9.8 Tf [(in HD mice \(p>0.93\) \(Fig 4A,B\). To identify the percentage of surviving BrdU )] TJ ET BT 357.604 557.953 Td /F1 8.7 Tf [(+)] TJ ET BT 362.665 554.065 Td /F1 9.8 Tf [( cells that become neurons, double labeling for )] TJ ET BT 26.250 542.160 Td /F1 9.8 Tf [(BrdU and NeuN was performed. Significant main effects of genotype \(F )] TJ ET BT 336.212 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 358.850 542.160 Td /F1 9.8 Tf [( = 303.37, p<0.0001\) and exercise \(F )] TJ ET BT 521.987 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 544.624 542.160 Td /F1 9.8 Tf [( = 7.89, )] TJ ET BT 26.250 530.256 Td /F1 9.8 Tf [(p<0.008\) and no interaction of genotype and exercise \(p>0.72\) were observed. The percentage of double-labeled BrdU )] TJ ET BT 541.654 534.144 Td /F1 8.7 Tf [(+)] TJ ET BT 546.716 530.256 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 26.250 522.239 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 518.351 Td /F1 9.8 Tf [( cells was significantly higher in HTR than HTS mice \(p<0.05; Fig 4C\). However, the total number of new neurons did not differ )] TJ ET BT 26.250 506.446 Td /F1 9.8 Tf [(between the HTR and HTS groups \(p>0.88; Fig 4D\). Furthermore, analysis of granule cell layer \(GCL\) volume revealed a main )] TJ ET BT 26.250 494.541 Td /F1 9.8 Tf [(effect of genotype \(F )] TJ ET BT 118.388 492.477 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 141.025 494.541 Td /F1 9.8 Tf [( =18.29, p<0.0001; Fig 4E\), suggesting that reduced neurogenesis in HD mice may have translated )] TJ ET BT 26.250 482.637 Td /F1 9.8 Tf [(to a significant volume reduction. Alternatively, this volume reduction could be explained by neuronal atrophy leading to )] TJ ET BT 26.250 470.732 Td /F1 9.8 Tf [(reductions in hippocampal volume )] TJ ET 0.267 0.267 0.267 rg BT 176.351 470.732 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 192.614 470.732 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 302.878 555.000 157.973 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 460.851 m 581.250 460.851 l 581.250 460.101 l 26.250 460.101 l f 26.250 302.878 m 581.250 302.878 l 581.250 303.628 l 26.250 303.628 l f q 225.000 0 0 96.000 35.250 355.101 cm /I13 Do Q q 35.250 314.128 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 338.112 Td /F4 9.8 Tf [(Figure 4.)] TJ ET BT 75.888 338.112 Td /F1 9.8 Tf [( Exercise failed to rescue the neurogenic deficit and decreased GCL volume in HD mice. \(A\) The number of )] TJ ET BT 35.250 324.376 Td /F1 9.8 Tf [(BrdU+ cells was significantly increased in WTR as compared to all other groups; ** p)] TJ ET Q BT 26.250 285.855 Td /F1 9.8 Tf [(An interesting observation was made pertaining to the location of BrdU )] TJ ET BT 333.521 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 338.583 285.855 Td /F1 9.8 Tf [( cells. There was a higher percentage of hilar BrdU )] TJ ET BT 560.756 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 273.950 Td /F1 9.8 Tf [(cells in HD compared to WT mice \(F )] TJ ET BT 185.526 271.886 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 208.163 273.950 Td /F1 9.8 Tf [( =242.56, p<0.0001\). There was also a significant interaction between genotype and )] TJ ET BT 26.250 262.045 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 259.981 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 99.812 262.045 Td /F1 9.8 Tf [( =4.82, p<0.03\). Specific comparisons showed that HTR had a significantly lower percentage of hilar BrdU )] TJ ET BT 558.803 265.933 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 250.140 Td /F1 9.8 Tf [(cells than HTS \(p<0.0007; Fig 4F\). Together with the increase in percentage BrdU )] TJ ET BT 382.554 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 387.615 250.140 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 420.668 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 425.729 250.140 Td /F1 9.8 Tf [( cells, this suggests a possible )] TJ ET BT 26.250 238.236 Td /F1 9.8 Tf [(modest beneficial effect of exercise on neurogenesis in HTR mice. However, doublecortin \(DCX\) staining revealed that the )] TJ ET BT 26.250 226.331 Td /F1 9.8 Tf [(immature neurons in both HD groups appear to have less dendritic branching and dendrites that do not extend into the )] TJ ET BT 26.250 214.426 Td /F1 9.8 Tf [(molecular layer as compared to WT mice \(Fig 5\).)] TJ ET 0.965 0.965 0.965 rg 26.250 -36.205 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 204.545 m 581.250 204.545 l 581.250 203.795 l 26.250 203.795 l f q 126.750 0 0 225.000 35.250 -30.205 cm /I14 Do Q q 35.250 -36.205 537.000 0.000 re W n Q Q q 15.000 -36.205 577.500 813.205 re W n 0.965 0.965 0.965 rg 26.250 717.041 555.000 59.959 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 717.041 m 581.250 717.041 l 581.250 717.791 l 26.250 717.791 l f q 35.250 728.291 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Figure 3.)] TJ ET BT 75.888 766.011 Td /F1 9.8 Tf [( Running did not rescue the spatial learning deficit in the Morris water maze. \(A\) Latency to reach the platform in )] TJ ET BT 35.250 752.275 Td /F1 9.8 Tf [(the Morris water maze over 8 test days \(data represents the average of 4 trials per day\) was reduced in WT but not HD )] TJ ET BT 35.250 738.538 Td /F1 9.8 Tf [(mice; p0.06\) . HD mice did not cross the platform zone during the probe trial. Data represents mean SEM.)] TJ ET Q BT 26.250 700.017 Td /F1 9.8 Tf [(A probe trial was performed 24 hr after the last training session. For time spent in the target quadrant there was a significant )] TJ ET BT 26.250 688.113 Td /F1 9.8 Tf [(genotype x exercise interaction \(F )] TJ ET BT 175.269 686.048 Td /F1 8.7 Tf [(\(1,20\))] TJ ET BT 197.906 688.113 Td /F1 9.8 Tf [( = 4.53, p<0.05\). Specific comparisons showed that only the WTR group spent more )] TJ ET BT 26.250 676.208 Td /F1 9.8 Tf [(time in the target quadrant compared to the three other groups \(p<0.05\) \(Fig 3C\). HD mice did not cross the platform zone )] TJ ET BT 26.250 664.303 Td /F1 9.8 Tf [(during the probe trial. There was no significant difference in the number of platform crossings between WTR and WTS mice )] TJ ET BT 26.250 652.398 Td /F1 9.8 Tf [(\(p>0.06\) \(Fig 3D\).)] TJ ET BT 26.250 632.994 Td /F4 9.8 Tf [(Running does not reverse decreased neurogenesis or diminish mHtt inclusions)] TJ ET BT 26.250 613.589 Td /F1 9.8 Tf [(Neurogenesis is decreased in mouse HD models)] TJ ET 0.267 0.267 0.267 rg BT 237.571 613.589 Td /F1 9.8 Tf [( [13] [16] [27] [28] [29])] TJ ET 0.271 0.267 0.267 rg BT 332.439 613.589 Td /F1 9.8 Tf [( . Data for all mice tested \(S and L mice; Fig 1A\) did not )] TJ ET BT 26.250 601.684 Td /F1 9.8 Tf [(differ and was therefore combined \(WTS=13; WTR=15; HTS=9-12; HTR=10-12\). There was a significant main effect of )] TJ ET BT 26.250 589.779 Td /F1 9.8 Tf [(genotype on BrdU )] TJ ET BT 107.546 593.668 Td /F1 8.7 Tf [(+)] TJ ET BT 112.607 589.779 Td /F1 9.8 Tf [( cell number \(F )] TJ ET BT 180.330 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 202.968 589.779 Td /F1 9.8 Tf [( = 41.14, p<0.0001\) and density F )] TJ ET BT 352.026 587.715 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 374.663 589.779 Td /F1 9.8 Tf [( = 33.52, p<0.0001\). HD mice had reduced )] TJ ET BT 26.250 577.875 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 577.875 Td /F1 9.8 Tf [( cell number and density compared to WT animals \(p<0.002\). WTR had more BrdU )] TJ ET BT 416.836 581.763 Td /F1 8.7 Tf [(+)] TJ ET BT 421.897 577.875 Td /F1 9.8 Tf [( cells than all the other groups )] TJ ET BT 26.250 565.970 Td /F1 9.8 Tf [(\(p<0.03\) confirming that running enhances new cell survival under standard conditions, whereas there was no effect of exercise )] TJ ET BT 26.250 554.065 Td /F1 9.8 Tf [(in HD mice \(p>0.93\) \(Fig 4A,B\). To identify the percentage of surviving BrdU )] TJ ET BT 357.604 557.953 Td /F1 8.7 Tf [(+)] TJ ET BT 362.665 554.065 Td /F1 9.8 Tf [( cells that become neurons, double labeling for )] TJ ET BT 26.250 542.160 Td /F1 9.8 Tf [(BrdU and NeuN was performed. Significant main effects of genotype \(F )] TJ ET BT 336.212 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 358.850 542.160 Td /F1 9.8 Tf [( = 303.37, p<0.0001\) and exercise \(F )] TJ ET BT 521.987 540.096 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 544.624 542.160 Td /F1 9.8 Tf [( = 7.89, )] TJ ET BT 26.250 530.256 Td /F1 9.8 Tf [(p<0.008\) and no interaction of genotype and exercise \(p>0.72\) were observed. The percentage of double-labeled BrdU )] TJ ET BT 541.654 534.144 Td /F1 8.7 Tf [(+)] TJ ET BT 546.716 530.256 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 26.250 522.239 Td /F1 8.7 Tf [(+)] TJ ET BT 31.311 518.351 Td /F1 9.8 Tf [( cells was significantly higher in HTR than HTS mice \(p<0.05; Fig 4C\). However, the total number of new neurons did not differ )] TJ ET BT 26.250 506.446 Td /F1 9.8 Tf [(between the HTR and HTS groups \(p>0.88; Fig 4D\). Furthermore, analysis of granule cell layer \(GCL\) volume revealed a main )] TJ ET BT 26.250 494.541 Td /F1 9.8 Tf [(effect of genotype \(F )] TJ ET BT 118.388 492.477 Td /F1 8.7 Tf [(\(1,48\))] TJ ET BT 141.025 494.541 Td /F1 9.8 Tf [( =18.29, p<0.0001; Fig 4E\), suggesting that reduced neurogenesis in HD mice may have translated )] TJ ET BT 26.250 482.637 Td /F1 9.8 Tf [(to a significant volume reduction. Alternatively, this volume reduction could be explained by neuronal atrophy leading to )] TJ ET BT 26.250 470.732 Td /F1 9.8 Tf [(reductions in hippocampal volume )] TJ ET 0.267 0.267 0.267 rg BT 176.351 470.732 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 192.614 470.732 Td /F1 9.8 Tf [( .)] TJ ET 0.965 0.965 0.965 rg 26.250 302.878 555.000 157.973 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 460.851 m 581.250 460.851 l 581.250 460.101 l 26.250 460.101 l f 26.250 302.878 m 581.250 302.878 l 581.250 303.628 l 26.250 303.628 l f q 225.000 0 0 96.000 35.250 355.101 cm /I13 Do Q q 35.250 314.128 537.000 34.973 re W n 0.271 0.267 0.267 rg BT 35.250 338.112 Td /F4 9.8 Tf [(Figure 4.)] TJ ET BT 75.888 338.112 Td /F1 9.8 Tf [( Exercise failed to rescue the neurogenic deficit and decreased GCL volume in HD mice. \(A\) The number of )] TJ ET BT 35.250 324.376 Td /F1 9.8 Tf [(BrdU+ cells was significantly increased in WTR as compared to all other groups; ** p)] TJ ET Q BT 26.250 285.855 Td /F1 9.8 Tf [(An interesting observation was made pertaining to the location of BrdU )] TJ ET BT 333.521 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 338.583 285.855 Td /F1 9.8 Tf [( cells. There was a higher percentage of hilar BrdU )] TJ ET BT 560.756 289.743 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 273.950 Td /F1 9.8 Tf [(cells in HD compared to WT mice \(F )] TJ ET BT 185.526 271.886 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 208.163 273.950 Td /F1 9.8 Tf [( =242.56, p<0.0001\). There was also a significant interaction between genotype and )] TJ ET BT 26.250 262.045 Td /F1 9.8 Tf [(exercise \(F )] TJ ET BT 77.174 259.981 Td /F1 8.7 Tf [(\(1,43\))] TJ ET BT 99.812 262.045 Td /F1 9.8 Tf [( =4.82, p<0.03\). Specific comparisons showed that HTR had a significantly lower percentage of hilar BrdU )] TJ ET BT 558.803 265.933 Td /F1 8.7 Tf [(+)] TJ ET BT 26.250 250.140 Td /F1 9.8 Tf [(cells than HTS \(p<0.0007; Fig 4F\). Together with the increase in percentage BrdU )] TJ ET BT 382.554 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 387.615 250.140 Td /F1 9.8 Tf [( /NeuN )] TJ ET BT 420.668 254.029 Td /F1 8.7 Tf [(+)] TJ ET BT 425.729 250.140 Td /F1 9.8 Tf [( cells, this suggests a possible )] TJ ET BT 26.250 238.236 Td /F1 9.8 Tf [(modest beneficial effect of exercise on neurogenesis in HTR mice. However, doublecortin \(DCX\) staining revealed that the )] TJ ET BT 26.250 226.331 Td /F1 9.8 Tf [(immature neurons in both HD groups appear to have less dendritic branching and dendrites that do not extend into the )] TJ ET BT 26.250 214.426 Td /F1 9.8 Tf [(molecular layer as compared to WT mice \(Fig 5\).)] TJ ET 0.965 0.965 0.965 rg 26.250 -36.205 555.000 240.750 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 204.545 m 581.250 204.545 l 581.250 203.795 l 26.250 203.795 l f q 126.750 0 0 225.000 35.250 -30.205 cm /I14 Do Q q 35.250 -36.205 537.000 0.000 re W n Q Q q 225.000 0 0 96.000 35.250 355.101 cm /I13 Do Q q 126.750 0 0 225.000 35.250 -30.205 cm /I14 Do Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(7)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 240 0 obj << /Type /Annot /Subtype /Link /A 241 0 R /Border [0 0 0] /H /I /Rect [ 237.5715 612.6871 332.4390 622.6077 ] >> endobj 241 0 obj << /Type /Action >> endobj 242 0 obj << /Type /Annot /Subtype /Link /A 243 0 R /Border [0 0 0] /H /I /Rect [ 176.3512 469.8301 192.6142 479.7507 ] >> endobj 243 0 obj << /Type /Action >> endobj 244 0 obj << /Type /Annot /Subtype /Link /A 245 0 R /Border [0 0 0] /H /I /Rect [ 35.2500 355.1010 260.2500 451.1010 ] >> endobj 245 0 obj << /Type /Action /S /URI /URI (https://currents.plos.org/hd/files/2010/12/figure-4-plos.jpg) >> endobj 246 0 obj << /Type /XObject /Subtype /Image /Width 300 /Height 128 /ColorSpace /DeviceRGB /Filter /DCTDecode /BitsPerComponent 8 /Length 11281>> stream JFIF;CREATOR: gd-jpeg v1.0 (using IJG JPEG v62), quality = 90 C     C   ," }!1AQa"q2#BR$3br %&'()*456789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz w!1AQaq"2B #3Rbr $4%&'()*56789:CDEFGHIJSTUVWXYZcdefghijstuvwxyz ?Q=)jii4$D"B>_'w< xA KfEThVXmw*#'w-;@K^^1X 3oP* J\ 8 xv[KNLAo#[̪<))w,רIE{Gz(J)(i(ny3Ɵ|x@ݬQUƜ 9smw79^?|Rͦf\L NIXI,6Tlpxmty(Ϲ%fb܏%v<j)i)(@Q@ E-%-%y$%ԴٞyӭCeae20|+0RszC|޷&I%bUIT ld9߆}FAw4vѫ[O+0@`,d+vsP0QGJ1@Q((+#>,|K,6Et9f8P5f9>W|~|\4G`_;(fVV\agtIдK:6?i|^QF \nxa-v-Wz|R[f%:x 3gݍIg/~W5]&++hin$(31$s~'GX5vmEIc9PDːT>:]%b]2v]hEZkzu0\]2Z?zk% rPHq+;JΎ]6baBIBO=+O7PCŬH* [YZ$|c=@M}>zc</3V5ldn5sSY}{'4KMHͧ)#oa`0#nG/i0mӚ#4 FpgySR {7Ai"iYaK퍬WQ5vYG$wImRm2?pH"GX <:W ]I;"gv2Iǩ>>!}Gэ_f~A~*RMz_Uѿ+ "ηaW?oExLwkzvz (w;v@ފM_iFkѼ:s_A' x#M}܉l4gmŇ{@U%xh-B:ǂ[xuR6WGc!rŲB6ͧ׶ nbYPO_k6?4[)5eY"4\f#Bh%#?:gk>ݭU+рݩ|'ӼiM{~MYn|r~0WPWWlj_ {oCk F-NnobokQ$N=|%@7&K#SIc3{Wm'I'?Ǯ'rܲڊ+ü'[й񕟆5=&W3j}TNS >X*8=h\o+Dk[L5l[ZvUMn!s]r.a}ŔF[)g}(H'4s|2$]xBK#,VQmu2 &GxM Ɠ'eeY7闻TȒH 7+Y8ݸF.5 [kɚ;IcFY` *8URq+uxX#<#+i I`Oɸ(`SG枏 /g1?-g5|)_u_b~4Zjzv䜯9\|]wR xǺEڜ^d-M @b~h|&8ugeiۏDhnaKԼ;};7S]E[_OF pے1cտŸ ZjWGy `ͺF<_@:+K^ 7E6vfWJ;rX'R;Owvnm H^ lGmh2{#>G i7VPjɨNRG99q^kKZE֗]gu溍@3[zeRhN( S2 ~"Wddx/:W?+|M%I|4q̶[o}N3޽o>Bma&,#cC ȶyw6z[A4iXe@Qy];: e_{H-dףxLtOZfw66Zv"*"Iz~ {>s[ tlKn# R:q] Z)(kεMƺϊu]iVYw3 CQE~eE*|[Ӯ%[za#fMXrFr >juJt-n w&9a -Nl xBݯZfR1^4t_4V$cEp2<k߭> x&KM6 X%In" ]=롓Zl] KDIbI'$`w4rUzZҡk%Ɩ|'udoq62g"QAm* z޷i-iܬ#~^Tzo~{[F=Ke H8!d燴Tz2{S}]F6oos3iљMS"*.8 f}/яgm-ZTGPexnTDf13/)g_ˡ }FK[*cw<i3q.9&Kx%%`ebF)y%z+t;iڍ^X 9W@5?:ͅ΂ivjH.L Ԥn}#.Oݷ+|-mc1[qo3J@ E tσ$[miq)DSrzh1@ IKE%/j޾.vFAlr8i׏W< K&k&t3fw XRXn,Ez}Q@b;F)(hEfL{ڼៃΒũʩoo%J ½Kp?D|/Vq!I+4A"&ox/V6t\`#,<2ŔR9GB eN~gh_xeW/$r9 |Ɨ"u?—8M;+eMN2O1T>WiߎsP|,=F]HZxHXտҭ T9VX,I ]˧gW.x,7;YPy8o|J|? 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In addition, total lifespan, progressive weight loss, )] TJ ET BT 26.250 304.725 Td /F1 9.8 Tf [(hyperglycemia, reduced neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions, decreased GCL )] TJ ET BT 26.250 292.821 Td /F1 9.8 Tf [(volume and impaired cognitive performance were not changed by exercise. Our findings differ from previous investigations with )] TJ ET BT 26.250 280.916 Td /F1 9.8 Tf [(R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 72.845 280.916 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 97.240 280.916 Td /F1 9.8 Tf [( . While it could be considered that our results are model-specific, this is unlikely. Previous work in R6/2 mice )] TJ ET BT 26.250 269.011 Td /F1 9.8 Tf [(showed that exercise did not increase neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 253.318 269.011 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 269.581 269.011 Td /F1 9.8 Tf [( , similar to our findings in the N171-82Q mice. In addition, treatment )] TJ ET BT 26.250 257.106 Td /F1 9.8 Tf [(with the antidepressant sertraline improved symptoms and neurogenesis in both the R6/1 and N171-82Q models )] TJ ET 0.267 0.267 0.267 rg BT 514.510 257.106 Td /F1 9.8 Tf [([32] [33])] TJ ET 0.271 0.267 0.267 rg BT 549.747 257.106 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 245.202 Td /F1 9.8 Tf [(indicating similar efficacy of this type of intervention in both models. Furthermore, in the studies where some benefit of exercise )] TJ ET BT 26.250 233.297 Td /F1 9.8 Tf [(was reported in R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 142.207 233.297 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 166.601 233.297 Td /F1 9.8 Tf [( , the animals were group-housed, making it unclear how much and whether individual mice )] TJ ET BT 26.250 221.392 Td /F1 9.8 Tf [(ran. In our study, the mice were singly housed to obtain accurate running distance measures and because recent research )] TJ ET BT 26.250 209.487 Td /F1 9.8 Tf [(indicated that stress and neurogenesis levels were not influenced by housing )] TJ ET 0.267 0.267 0.267 rg BT 360.626 209.487 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 376.889 209.487 Td /F1 9.8 Tf [( . Moreover it is reported that R6/1 running )] TJ ET BT 26.250 197.583 Td /F1 9.8 Tf [(mice travel less distance in the open field than sedentary transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 344.890 197.583 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 355.732 197.583 Td /F1 9.8 Tf [( . This was interpreted as a lack of interest in the )] TJ ET BT 26.250 185.678 Td /F1 9.8 Tf [(open field arena )] TJ ET 0.267 0.267 0.267 rg BT 98.878 185.678 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 109.720 185.678 Td /F1 9.8 Tf [( rather than as an emerging motor deficit. Finally, a statistical power analysis was carried out which further )] TJ ET BT 26.250 173.773 Td /F1 9.8 Tf [(supports the validity of our data.)] TJ ET BT 26.250 154.368 Td /F1 9.8 Tf [(Although we show that exercise had a negative impact on multiple HD symptoms, other interventions such as dietary restriction )] TJ ET BT 26.250 142.464 Td /F1 9.8 Tf [(and environmental enrichment do appear to delay HD symptoms and increase survival rates in HD mouse models )] TJ ET 0.267 0.267 0.267 rg BT 519.346 142.464 Td /F1 9.8 Tf [([5] [18] [35] )] TJ ET BT 26.250 130.559 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 42.513 130.559 Td /F1 9.8 Tf [( . In particular, environmental enrichment may have a superior outcome compared to running. Possibly, non-strenuous )] TJ ET BT 26.250 118.654 Td /F1 9.8 Tf [(elements of enrichment, such as increased social interaction and nesting materials may mediate the benefits. Voluntary wheel )] TJ ET BT 26.250 106.749 Td /F1 9.8 Tf [(running can be considered as a controllable voluntary stressor )] TJ ET 0.267 0.267 0.267 rg BT 297.202 106.749 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 313.465 106.749 Td /F1 9.8 Tf [( . Applying physical exercise to a mouse genetically )] TJ ET BT 26.250 94.845 Td /F1 9.8 Tf [(predisposed to develop HD may have caused unwelcome stress to an already vulnerable system )] TJ ET 0.267 0.267 0.267 rg BT 446.758 94.845 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 463.021 94.845 Td /F1 9.8 Tf [( . Further impairments in )] TJ ET BT 26.250 82.940 Td /F1 9.8 Tf [(the minimal spatial learning and neurogenesis levels may not be possible, but the exacerbation of motor symptoms and )] TJ ET BT 26.250 71.035 Td /F1 9.8 Tf [(acceleration of disease onset may have resulted. Indeed, stress may hasten the appearance of certain neurodegenerative )] TJ ET BT 26.250 59.130 Td /F1 9.8 Tf [(diseases or other pathologies )] TJ ET 0.267 0.267 0.267 rg BT 156.315 59.130 Td /F1 9.8 Tf [([39] [40] [41] [42])] TJ ET 0.271 0.267 0.267 rg BT 229.498 59.130 Td /F1 9.8 Tf [( . It has been shown that exercise may have detrimental effects following stroke )] TJ ET 0.267 0.267 0.267 rg BT 26.250 47.226 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 42.513 47.226 Td /F1 9.8 Tf [( . Moreover, the energetic demands of exercise in this metabolically-challenged transgenic mouse )] TJ ET 0.267 0.267 0.267 rg BT 466.267 47.226 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 482.530 47.226 Td /F1 9.8 Tf [( may further the )] TJ ET Q q 15.000 32.940 577.500 744.060 re W n 0.965 0.965 0.965 rg 26.250 717.041 555.000 59.959 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 717.041 m 581.250 717.041 l 581.250 717.791 l 26.250 717.791 l f q 35.250 728.291 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Figure 5.)] TJ ET BT 75.888 766.011 Td /F1 9.8 Tf [( Morphology of Doublecortin \(DCX\) expressing immature neurons in the dentate gyrus of WT and HD mice. )] TJ ET BT 35.250 752.275 Td /F1 9.8 Tf [(Dendritic branching complexity of DCX-labeled \(red\) immature neurons was reduced in the transgenic mice, \(A\) WTS, \(B\) )] TJ ET BT 35.250 738.538 Td /F1 9.8 Tf [(WTR, \(C\) HTS and \(D\) HTR. Granular cell layer neurons were labeled with DAPI \(blue\). Scale bar = 20?m.)] TJ ET Q BT 26.250 700.017 Td /F1 9.8 Tf [(To further investigate the effects of physical activity in this disease model, cells with mHtt )] TJ ET BT 411.521 703.906 Td /F1 8.7 Tf [(+)] TJ ET BT 416.583 700.017 Td /F1 9.8 Tf [( inclusion bodies were quantified in )] TJ ET BT 26.250 688.113 Td /F1 9.8 Tf [(the granule cell layer in the mice \(S\) who were sacrificed at an average of 1131 days old )] TJ ET 0.267 0.267 0.267 rg BT 415.070 688.113 Td /F1 9.8 Tf [([15] [20] [31])] TJ ET 0.271 0.267 0.267 rg BT 469.280 688.113 Td /F1 9.8 Tf [( . Running had no effect )] TJ ET BT 26.250 676.208 Td /F1 9.8 Tf [(on the number of cells with mHtt )] TJ ET BT 168.220 680.096 Td /F1 8.7 Tf [(+)] TJ ET BT 173.281 676.208 Td /F1 9.8 Tf [( inclusion bodies in the dentate gyrus of the hippocampus \(Fig 6\).)] TJ ET 0.965 0.965 0.965 rg 26.250 376.868 555.000 289.459 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 666.327 m 581.250 666.327 l 581.250 665.577 l 26.250 665.577 l f 26.250 376.868 m 581.250 376.868 l 581.250 377.618 l 26.250 377.618 l f q 225.000 0 0 213.750 35.250 442.827 cm /I15 Do Q q 35.250 388.118 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 425.838 Td /F4 9.8 Tf [(Figure 6.)] TJ ET BT 75.888 425.838 Td /F1 9.8 Tf [( Running does not alter the number of DG cells with mHtt+ inclusions. \(A\) The number of cells with mHtt+ )] TJ ET BT 35.250 412.102 Td /F1 9.8 Tf [(inclusions \(mHtt+/mm3\) does not differ between HTR and HTS mice. Data represents mean SEM \(HTS=7; HTR=6\). )] TJ ET BT 35.250 398.365 Td /F1 9.8 Tf [(Representative photomicrograph showing hippocampal mHtt+ staining in HTR \(B\) WTS \(C\) HTS \(D\). Scale bar = 10m.)] TJ ET Q BT 26.250 359.844 Td /F4 9.8 Tf [(Discussion)] TJ ET BT 26.250 340.440 Td /F1 9.8 Tf [(It is assumed that exercise can delay, prevent or ameliorate neurodegenerative disease [1] largely because of its profound )] TJ ET BT 26.250 328.535 Td /F1 9.8 Tf [(benefits under standard conditions )] TJ ET 0.267 0.267 0.267 rg BT 177.999 328.535 Td /F1 9.8 Tf [([1] [4])] TJ ET 0.271 0.267 0.267 rg BT 202.393 328.535 Td /F1 9.8 Tf [( . However, the present study shows that exercise impaired motor performance and )] TJ ET BT 26.250 316.630 Td /F1 9.8 Tf [(reduced striatal volume and age of disease onset in a HD mouse model. In addition, total lifespan, progressive weight loss, )] TJ ET BT 26.250 304.725 Td /F1 9.8 Tf [(hyperglycemia, reduced neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions, decreased GCL )] TJ ET BT 26.250 292.821 Td /F1 9.8 Tf [(volume and impaired cognitive performance were not changed by exercise. Our findings differ from previous investigations with )] TJ ET BT 26.250 280.916 Td /F1 9.8 Tf [(R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 72.845 280.916 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 97.240 280.916 Td /F1 9.8 Tf [( . While it could be considered that our results are model-specific, this is unlikely. Previous work in R6/2 mice )] TJ ET BT 26.250 269.011 Td /F1 9.8 Tf [(showed that exercise did not increase neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 253.318 269.011 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 269.581 269.011 Td /F1 9.8 Tf [( , similar to our findings in the N171-82Q mice. In addition, treatment )] TJ ET BT 26.250 257.106 Td /F1 9.8 Tf [(with the antidepressant sertraline improved symptoms and neurogenesis in both the R6/1 and N171-82Q models )] TJ ET 0.267 0.267 0.267 rg BT 514.510 257.106 Td /F1 9.8 Tf [([32] [33])] TJ ET 0.271 0.267 0.267 rg BT 549.747 257.106 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 245.202 Td /F1 9.8 Tf [(indicating similar efficacy of this type of intervention in both models. Furthermore, in the studies where some benefit of exercise )] TJ ET BT 26.250 233.297 Td /F1 9.8 Tf [(was reported in R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 142.207 233.297 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 166.601 233.297 Td /F1 9.8 Tf [( , the animals were group-housed, making it unclear how much and whether individual mice )] TJ ET BT 26.250 221.392 Td /F1 9.8 Tf [(ran. In our study, the mice were singly housed to obtain accurate running distance measures and because recent research )] TJ ET BT 26.250 209.487 Td /F1 9.8 Tf [(indicated that stress and neurogenesis levels were not influenced by housing )] TJ ET 0.267 0.267 0.267 rg BT 360.626 209.487 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 376.889 209.487 Td /F1 9.8 Tf [( . Moreover it is reported that R6/1 running )] TJ ET BT 26.250 197.583 Td /F1 9.8 Tf [(mice travel less distance in the open field than sedentary transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 344.890 197.583 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 355.732 197.583 Td /F1 9.8 Tf [( . This was interpreted as a lack of interest in the )] TJ ET BT 26.250 185.678 Td /F1 9.8 Tf [(open field arena )] TJ ET 0.267 0.267 0.267 rg BT 98.878 185.678 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 109.720 185.678 Td /F1 9.8 Tf [( rather than as an emerging motor deficit. Finally, a statistical power analysis was carried out which further )] TJ ET BT 26.250 173.773 Td /F1 9.8 Tf [(supports the validity of our data.)] TJ ET BT 26.250 154.368 Td /F1 9.8 Tf [(Although we show that exercise had a negative impact on multiple HD symptoms, other interventions such as dietary restriction )] TJ ET BT 26.250 142.464 Td /F1 9.8 Tf [(and environmental enrichment do appear to delay HD symptoms and increase survival rates in HD mouse models )] TJ ET 0.267 0.267 0.267 rg BT 519.346 142.464 Td /F1 9.8 Tf [([5] [18] [35] )] TJ ET BT 26.250 130.559 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 42.513 130.559 Td /F1 9.8 Tf [( . In particular, environmental enrichment may have a superior outcome compared to running. Possibly, non-strenuous )] TJ ET BT 26.250 118.654 Td /F1 9.8 Tf [(elements of enrichment, such as increased social interaction and nesting materials may mediate the benefits. Voluntary wheel )] TJ ET BT 26.250 106.749 Td /F1 9.8 Tf [(running can be considered as a controllable voluntary stressor )] TJ ET 0.267 0.267 0.267 rg BT 297.202 106.749 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 313.465 106.749 Td /F1 9.8 Tf [( . Applying physical exercise to a mouse genetically )] TJ ET BT 26.250 94.845 Td /F1 9.8 Tf [(predisposed to develop HD may have caused unwelcome stress to an already vulnerable system )] TJ ET 0.267 0.267 0.267 rg BT 446.758 94.845 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 463.021 94.845 Td /F1 9.8 Tf [( . Further impairments in )] TJ ET BT 26.250 82.940 Td /F1 9.8 Tf [(the minimal spatial learning and neurogenesis levels may not be possible, but the exacerbation of motor symptoms and )] TJ ET BT 26.250 71.035 Td /F1 9.8 Tf [(acceleration of disease onset may have resulted. Indeed, stress may hasten the appearance of certain neurodegenerative )] TJ ET BT 26.250 59.130 Td /F1 9.8 Tf [(diseases or other pathologies )] TJ ET 0.267 0.267 0.267 rg BT 156.315 59.130 Td /F1 9.8 Tf [([39] [40] [41] [42])] TJ ET 0.271 0.267 0.267 rg BT 229.498 59.130 Td /F1 9.8 Tf [( . It has been shown that exercise may have detrimental effects following stroke )] TJ ET 0.267 0.267 0.267 rg BT 26.250 47.226 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 42.513 47.226 Td /F1 9.8 Tf [( . Moreover, the energetic demands of exercise in this metabolically-challenged transgenic mouse )] TJ ET 0.267 0.267 0.267 rg BT 466.267 47.226 Td /F1 9.8 Tf [([18])] TJ ET 0.271 0.267 0.267 rg BT 482.530 47.226 Td /F1 9.8 Tf [( may further the )] TJ ET Q q 15.000 32.940 577.500 744.060 re W n 0.965 0.965 0.965 rg 26.250 717.041 555.000 59.959 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 717.041 m 581.250 717.041 l 581.250 717.791 l 26.250 717.791 l f q 35.250 728.291 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 766.011 Td /F4 9.8 Tf [(Figure 5.)] TJ ET BT 75.888 766.011 Td /F1 9.8 Tf [( Morphology of Doublecortin \(DCX\) expressing immature neurons in the dentate gyrus of WT and HD mice. )] TJ ET BT 35.250 752.275 Td /F1 9.8 Tf [(Dendritic branching complexity of DCX-labeled \(red\) immature neurons was reduced in the transgenic mice, \(A\) WTS, \(B\) )] TJ ET BT 35.250 738.538 Td /F1 9.8 Tf [(WTR, \(C\) HTS and \(D\) HTR. Granular cell layer neurons were labeled with DAPI \(blue\). Scale bar = 20?m.)] TJ ET Q BT 26.250 700.017 Td /F1 9.8 Tf [(To further investigate the effects of physical activity in this disease model, cells with mHtt )] TJ ET BT 411.521 703.906 Td /F1 8.7 Tf [(+)] TJ ET BT 416.583 700.017 Td /F1 9.8 Tf [( inclusion bodies were quantified in )] TJ ET BT 26.250 688.113 Td /F1 9.8 Tf [(the granule cell layer in the mice \(S\) who were sacrificed at an average of 1131 days old )] TJ ET 0.267 0.267 0.267 rg BT 415.070 688.113 Td /F1 9.8 Tf [([15] [20] [31])] TJ ET 0.271 0.267 0.267 rg BT 469.280 688.113 Td /F1 9.8 Tf [( . Running had no effect )] TJ ET BT 26.250 676.208 Td /F1 9.8 Tf [(on the number of cells with mHtt )] TJ ET BT 168.220 680.096 Td /F1 8.7 Tf [(+)] TJ ET BT 173.281 676.208 Td /F1 9.8 Tf [( inclusion bodies in the dentate gyrus of the hippocampus \(Fig 6\).)] TJ ET 0.965 0.965 0.965 rg 26.250 376.868 555.000 289.459 re f 0.267 0.267 0.267 rg 0.267 0.267 0.267 RG 26.250 666.327 m 581.250 666.327 l 581.250 665.577 l 26.250 665.577 l f 26.250 376.868 m 581.250 376.868 l 581.250 377.618 l 26.250 377.618 l f q 225.000 0 0 213.750 35.250 442.827 cm /I15 Do Q q 35.250 388.118 537.000 48.709 re W n 0.271 0.267 0.267 rg BT 35.250 425.838 Td /F4 9.8 Tf [(Figure 6.)] TJ ET BT 75.888 425.838 Td /F1 9.8 Tf [( Running does not alter the number of DG cells with mHtt+ inclusions. \(A\) The number of cells with mHtt+ )] TJ ET BT 35.250 412.102 Td /F1 9.8 Tf [(inclusions \(mHtt+/mm3\) does not differ between HTR and HTS mice. Data represents mean SEM \(HTS=7; HTR=6\). )] TJ ET BT 35.250 398.365 Td /F1 9.8 Tf [(Representative photomicrograph showing hippocampal mHtt+ staining in HTR \(B\) WTS \(C\) HTS \(D\). Scale bar = 10m.)] TJ ET Q BT 26.250 359.844 Td /F4 9.8 Tf [(Discussion)] TJ ET BT 26.250 340.440 Td /F1 9.8 Tf [(It is assumed that exercise can delay, prevent or ameliorate neurodegenerative disease [1] largely because of its profound )] TJ ET BT 26.250 328.535 Td /F1 9.8 Tf [(benefits under standard conditions )] TJ ET 0.267 0.267 0.267 rg BT 177.999 328.535 Td /F1 9.8 Tf [([1] [4])] TJ ET 0.271 0.267 0.267 rg BT 202.393 328.535 Td /F1 9.8 Tf [( . However, the present study shows that exercise impaired motor performance and )] TJ ET BT 26.250 316.630 Td /F1 9.8 Tf [(reduced striatal volume and age of disease onset in a HD mouse model. In addition, total lifespan, progressive weight loss, )] TJ ET BT 26.250 304.725 Td /F1 9.8 Tf [(hyperglycemia, reduced neurogenesis, deficits in immature neuronal morphology, intranuclear inclusions, decreased GCL )] TJ ET BT 26.250 292.821 Td /F1 9.8 Tf [(volume and impaired cognitive performance were not changed by exercise. Our findings differ from previous investigations with )] TJ ET BT 26.250 280.916 Td /F1 9.8 Tf [(R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 72.845 280.916 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 97.240 280.916 Td /F1 9.8 Tf [( . While it could be considered that our results are model-specific, this is unlikely. Previous work in R6/2 mice )] TJ ET BT 26.250 269.011 Td /F1 9.8 Tf [(showed that exercise did not increase neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 253.318 269.011 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 269.581 269.011 Td /F1 9.8 Tf [( , similar to our findings in the N171-82Q mice. In addition, treatment )] TJ ET BT 26.250 257.106 Td /F1 9.8 Tf [(with the antidepressant sertraline improved symptoms and neurogenesis in both the R6/1 and N171-82Q models )] TJ ET 0.267 0.267 0.267 rg BT 514.510 257.106 Td /F1 9.8 Tf [([32] [33])] TJ ET 0.271 0.267 0.267 rg BT 549.747 257.106 Td /F1 9.8 Tf [( , )] TJ ET BT 26.250 245.202 Td /F1 9.8 Tf [(indicating similar efficacy of this type of intervention in both models. Furthermore, in the studies where some benefit of exercise )] TJ ET BT 26.250 233.297 Td /F1 9.8 Tf [(was reported in R6/1 mice )] TJ ET 0.267 0.267 0.267 rg BT 142.207 233.297 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 166.601 233.297 Td /F1 9.8 Tf [( , the animals were group-housed, making it unclear how much and whether individual mice )] TJ ET BT 26.250 221.392 Td /F1 9.8 Tf [(ran. In our study, the mice were singly housed to obtain accurate running distance measures and because recent research )] TJ ET BT 26.250 209.487 Td /F1 9.8 Tf [(indicated that stress and neurogenesis levels were not influenced by housing )] TJ ET 0.267 0.267 0.267 rg BT 360.626 209.487 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 376.889 209.487 Td /F1 9.8 Tf [( . Moreover it is reported that R6/1 running )] TJ ET BT 26.250 197.583 Td /F1 9.8 Tf [(mice travel less distance in the open field than sedentary transgenic mice )] TJ ET 0.267 0.267 0.267 rg BT 344.890 197.583 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 355.732 197.583 Td /F1 9.8 Tf [( . This was interpreted as a lack of interest in the )] TJ ET BT 26.250 185.678 Td /F1 9.8 Tf [(open field arena )] TJ ET 0.267 0.267 0.267 rg BT 98.878 185.678 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 109.720 185.678 Td /F1 9.8 Tf [( rather than as an emerging motor deficit. Finally, a statistical power analysis was carried out which further )] TJ ET BT 26.250 173.773 Td /F1 9.8 Tf [(supports the validity of our data.)] TJ ET BT 26.250 154.368 Td /F1 9.8 Tf [(Although we show that exercise had a negative impact on multiple HD symptoms, other interventions such as dietary restriction )] TJ ET BT 26.250 142.464 Td /F1 9.8 Tf [(and environmental enrichment do appear to delay HD symptoms and increase survival rates in HD mouse models )] TJ ET 0.267 0.267 0.267 rg BT 519.346 142.464 Td /F1 9.8 Tf [([5] [18] [35] )] TJ ET BT 26.250 130.559 Td /F1 9.8 Tf [([36])] TJ ET 0.271 0.267 0.267 rg BT 42.513 130.559 Td /F1 9.8 Tf [( . In particular, environmental enrichment may have a superior outcome compared to running. Possibly, non-strenuous )] TJ ET BT 26.250 118.654 Td /F1 9.8 Tf [(elements of enrichment, such as increased social interaction and nesting materials may mediate the benefits. Voluntary wheel )] TJ ET BT 26.250 106.749 Td /F1 9.8 Tf [(running can be considered as a controllable voluntary stressor )] TJ ET 0.267 0.267 0.267 rg BT 297.202 106.749 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 313.465 106.749 Td /F1 9.8 Tf [( . Applying physical exercise to a mouse genetically )] TJ ET BT 26.250 94.845 Td /F1 9.8 Tf [(predisposed to develop HD may have caused unwelcome stress to an already vulnerable system )] TJ ET 0.267 0.267 0.267 rg BT 446.758 94.845 Td /F1 9.8 Tf [([38])] TJ ET 0.271 0.267 0.267 rg BT 463.021 94.845 Td /F1 9.8 Tf [( . Further impairments in )] TJ ET BT 26.250 82.940 Td /F1 9.8 Tf [(the minimal spatial learning and neurogenesis levels may not be possible, but the exacerbation of motor symptoms and )] TJ ET BT 26.250 71.035 Td /F1 9.8 Tf [(acceleration of disease onset may have resulted. Indeed, stress may hasten the appearance of certain neurodegenerative )] TJ ET BT 26.250 59.130 Td /F1 9.8 Tf [(diseases or other pathologies )] TJ ET 0.267 0.267 0.267 rg BT 156.315 59.130 Td /F1 9.8 Tf [([39] [40] [41] [42])] TJ ET 0.271 0.267 0.267 rg BT 229.498 59.130 Td /F1 9.8 Tf [( . It has been shown that exercise may have detrimental effects following stroke )] TJ ET 0.267 0.267 0.267 rg BT 26.250 47.226 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 42.513 47.226 Td /F1 9.8 Tf [( . 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In our study, the accelerating rotarod revealed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(motor deficits only in the HD runners in the latency to fall. It is possible that running resulted in earlier striatal atrophy. Although )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(a change in striatal volume in HD runners was not observed in mice used for the motor behavioral tests \(S\), it was reduced in )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(the lifespan group \(L\). This raises the possibility of a subtle, but detrimental effect of exercise that translated to the motor )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(impairments. While this is the first animal study making observations that exercise may not be beneficial in HD, there is )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(evidence from human studies that points in the same direction. Recently, a study in humans indicated that physical exercise )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(may not prevent or delay disease onset or progression )] TJ ET 0.267 0.267 0.267 rg BT 264.150 652.833 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 299.387 652.833 Td /F1 9.8 Tf [( . A case study of a HD marathon runner presented with )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(myopathy years before the predicted disease onset. In fact, this patient had onset of HD symptoms almost twenty years before )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(the median age of onset for 41 CAG repeats, indicating that regular exercise certainly did not delay the disease development)] TJ ET 0.267 0.267 0.267 rg BT 26.250 617.119 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 61.486 617.119 Td /F1 9.8 Tf [( . Indeed, prescription of exercise protocols to patients with neurodegenerative diseases should be done with caution )] TJ ET 0.267 0.267 0.267 rg BT 26.250 605.214 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 42.513 605.214 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 585.810 Td /F1 9.8 Tf [(Huntingtons disease is often defined as affecting the striatum and cortex )] TJ ET 0.267 0.267 0.267 rg BT 342.745 585.810 Td /F1 9.8 Tf [([15] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 396.955 585.810 Td /F1 9.8 Tf [( . However, the hippocampus also shows )] TJ ET BT 26.250 573.905 Td /F1 9.8 Tf [(profound neuronal loss in HD patients and animal models )] TJ ET 0.267 0.267 0.267 rg BT 276.611 573.905 Td /F1 9.8 Tf [([13] [27] [28] [29] [47] [48] [49])] TJ ET 0.271 0.267 0.267 rg BT 406.715 573.905 Td /F1 9.8 Tf [( . In the present study, we observed a )] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(decrease in hippocampal volume and neurogenesis. Exercise did not reverse these deficits in N171-82Q mice similar to )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(previous research in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 163.335 550.095 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 179.598 550.095 Td /F1 9.8 Tf [( , nor was the number of cells with mHtt )] TJ ET BT 352.992 553.984 Td /F1 8.7 Tf [(+)] TJ ET BT 358.053 550.095 Td /F1 9.8 Tf [( intranuclear inclusions changed. In addition, )] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(consistent with R6/2 mice, a significant increase in the percentage of newborn cells that took on a mature neuronal phenotype )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(was observed but this did not translate to an increase in total neuron number )] TJ ET 0.267 0.267 0.267 rg BT 359.544 526.286 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 375.807 526.286 Td /F1 9.8 Tf [( . Furthermore, a reduced percentage of hilar )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 514.381 Td /F1 9.8 Tf [( cells was observed in HD runners as compared to sedentary controls. While this could be considered a positive effect of )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(running, the immature neuronal marker doublecortin showed that cells did not extend processes into the molecular layer, )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(suggesting neurite extension and maturation deficits in both groups of transgenic mice. Likely, the hippocampal )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(microenvironment plays an important role)] TJ ET 0.267 0.267 0.267 rg BT 205.055 478.667 Td /F1 9.8 Tf [( [50])] TJ ET 0.271 0.267 0.267 rg BT 224.029 478.667 Td /F1 9.8 Tf [( . Indeed, the exercise-induced survival factor BDNF )] TJ ET 0.267 0.267 0.267 rg BT 452.159 478.667 Td /F1 9.8 Tf [([2] [51])] TJ ET 0.271 0.267 0.267 rg BT 481.975 478.667 Td /F1 9.8 Tf [( is reduced in HD )] TJ ET BT 26.250 466.762 Td /F1 9.8 Tf [(mice and not increased by running )] TJ ET 0.267 0.267 0.267 rg BT 177.989 466.762 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 188.831 466.762 Td /F1 9.8 Tf [( . Administration of this factor did enhance striatal neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 465.751 466.762 Td /F1 9.8 Tf [([52])] TJ ET 0.271 0.267 0.267 rg BT 482.014 466.762 Td /F1 9.8 Tf [( and may have a )] TJ ET BT 26.250 454.857 Td /F1 9.8 Tf [(similar effect in the hippocampus.)] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Running improves performance in spatial memory tasks under normal physiological conditions. This is thought to be mediated, )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(at least in part by increased synaptic plasticity and neurogenesis [4] . In our study, we found no improvement in HD mice as a )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(result of running in spatial learning in the Morris water maze, correlating with the severe reduction in adult neurogenesis. One )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(possible confounding factor in our behavioral assessment of spatial memory was that the HD mice displayed a reduced swim )] TJ ET BT 26.250 387.834 Td /F1 9.8 Tf [(speed, possibly due to the onset of motor impairments [15] [19] [20] . However, further evidence that the poor performance was )] TJ ET BT 26.250 375.929 Td /F1 9.8 Tf [(indeed a cognitive deficit was that the HD mice did not have any learning curve, even at reduced speed. The HD mice did not )] TJ ET BT 26.250 364.024 Td /F1 9.8 Tf [(differ in their latency to find the hidden platform from day 1 to day 8 indicating that they could not learn the task. In addition, in )] TJ ET BT 26.250 352.119 Td /F1 9.8 Tf [(the probe trial they showed no preference for the platform quadrant. WT runners had the best performance, as expected [4] [21] )] TJ ET BT 26.250 340.215 Td /F1 9.8 Tf [(. It is possible that the water maze task is not ideal to test the possible benefit of therapeutic interventions in HD mice. Further )] TJ ET BT 26.250 328.310 Td /F1 9.8 Tf [(research using memory tasks with low motor demand [53] [54] may be better suited to test cognition in these mouse models.)] TJ ET BT 26.250 308.905 Td /F1 9.8 Tf [(It is clear from our study that running did not prevent or delay symptoms of HD but appeared to worsen the outcome in HD mice. )] TJ ET BT 26.250 297.000 Td /F1 9.8 Tf [(Moreover, cognitive and neurogenic deficits were not reversed by running. Taken together, our research suggests that exercise )] TJ ET BT 26.250 285.096 Td /F1 9.8 Tf [(is not beneficial and may even be detrimental in this animal model.)] TJ ET BT 26.250 248.493 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 228.539 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 191.936 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 171.982 Td /F1 9.8 Tf [(We thank Linda R. Kitabayashi for help with figure preparation. We thank Dr. Bronwen Martin for helpful advice, and Dr. Tali )] TJ ET BT 26.250 160.077 Td /F1 9.8 Tf [(Kobilo, David Creer, Kriti Gandhi and Robert Rowe for assistance with histology. Statistical assistance was kindly provided by )] TJ ET BT 26.250 148.173 Td /F1 9.8 Tf [(Dr. Susan Resnick, Dr. Yang An and Dr. Larry Brant.)] TJ ET BT 26.250 119.070 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nature Rev )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(Neurosci 2008; 9:58-65.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(and nerve growth factor in rat brain. Brain Res 1996; 726:49-56.)] TJ ET Q q 15.000 38.521 577.500 738.479 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(negative impact of running by possibly releasing as of yet unidentified aberrant factors into the bloodstream that could lead to )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(functional impairments.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(In the R6/1 mice, running has been shown to normalize rearing behavior and delay a deficit in rear-paw clasping and motor )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(coordination on a static rod but did not improve rotarod performance )] TJ ET 0.267 0.267 0.267 rg BT 322.679 724.262 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 347.074 724.262 Td /F1 9.8 Tf [( . In our study, the accelerating rotarod revealed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(motor deficits only in the HD runners in the latency to fall. It is possible that running resulted in earlier striatal atrophy. Although )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(a change in striatal volume in HD runners was not observed in mice used for the motor behavioral tests \(S\), it was reduced in )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(the lifespan group \(L\). This raises the possibility of a subtle, but detrimental effect of exercise that translated to the motor )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(impairments. While this is the first animal study making observations that exercise may not be beneficial in HD, there is )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(evidence from human studies that points in the same direction. Recently, a study in humans indicated that physical exercise )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(may not prevent or delay disease onset or progression )] TJ ET 0.267 0.267 0.267 rg BT 264.150 652.833 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 299.387 652.833 Td /F1 9.8 Tf [( . A case study of a HD marathon runner presented with )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(myopathy years before the predicted disease onset. In fact, this patient had onset of HD symptoms almost twenty years before )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(the median age of onset for 41 CAG repeats, indicating that regular exercise certainly did not delay the disease development)] TJ ET 0.267 0.267 0.267 rg BT 26.250 617.119 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 61.486 617.119 Td /F1 9.8 Tf [( . Indeed, prescription of exercise protocols to patients with neurodegenerative diseases should be done with caution )] TJ ET 0.267 0.267 0.267 rg BT 26.250 605.214 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 42.513 605.214 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 585.810 Td /F1 9.8 Tf [(Huntingtons disease is often defined as affecting the striatum and cortex )] TJ ET 0.267 0.267 0.267 rg BT 342.745 585.810 Td /F1 9.8 Tf [([15] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 396.955 585.810 Td /F1 9.8 Tf [( . However, the hippocampus also shows )] TJ ET BT 26.250 573.905 Td /F1 9.8 Tf [(profound neuronal loss in HD patients and animal models )] TJ ET 0.267 0.267 0.267 rg BT 276.611 573.905 Td /F1 9.8 Tf [([13] [27] [28] [29] [47] [48] [49])] TJ ET 0.271 0.267 0.267 rg BT 406.715 573.905 Td /F1 9.8 Tf [( . In the present study, we observed a )] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(decrease in hippocampal volume and neurogenesis. Exercise did not reverse these deficits in N171-82Q mice similar to )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(previous research in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 163.335 550.095 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 179.598 550.095 Td /F1 9.8 Tf [( , nor was the number of cells with mHtt )] TJ ET BT 352.992 553.984 Td /F1 8.7 Tf [(+)] TJ ET BT 358.053 550.095 Td /F1 9.8 Tf [( intranuclear inclusions changed. In addition, )] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(consistent with R6/2 mice, a significant increase in the percentage of newborn cells that took on a mature neuronal phenotype )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(was observed but this did not translate to an increase in total neuron number )] TJ ET 0.267 0.267 0.267 rg BT 359.544 526.286 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 375.807 526.286 Td /F1 9.8 Tf [( . Furthermore, a reduced percentage of hilar )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 514.381 Td /F1 9.8 Tf [( cells was observed in HD runners as compared to sedentary controls. While this could be considered a positive effect of )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(running, the immature neuronal marker doublecortin showed that cells did not extend processes into the molecular layer, )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(suggesting neurite extension and maturation deficits in both groups of transgenic mice. Likely, the hippocampal )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(microenvironment plays an important role)] TJ ET 0.267 0.267 0.267 rg BT 205.055 478.667 Td /F1 9.8 Tf [( [50])] TJ ET 0.271 0.267 0.267 rg BT 224.029 478.667 Td /F1 9.8 Tf [( . Indeed, the exercise-induced survival factor BDNF )] TJ ET 0.267 0.267 0.267 rg BT 452.159 478.667 Td /F1 9.8 Tf [([2] [51])] TJ ET 0.271 0.267 0.267 rg BT 481.975 478.667 Td /F1 9.8 Tf [( is reduced in HD )] TJ ET BT 26.250 466.762 Td /F1 9.8 Tf [(mice and not increased by running )] TJ ET 0.267 0.267 0.267 rg BT 177.989 466.762 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 188.831 466.762 Td /F1 9.8 Tf [( . Administration of this factor did enhance striatal neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 465.751 466.762 Td /F1 9.8 Tf [([52])] TJ ET 0.271 0.267 0.267 rg BT 482.014 466.762 Td /F1 9.8 Tf [( and may have a )] TJ ET BT 26.250 454.857 Td /F1 9.8 Tf [(similar effect in the hippocampus.)] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Running improves performance in spatial memory tasks under normal physiological conditions. This is thought to be mediated, )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(at least in part by increased synaptic plasticity and neurogenesis [4] . In our study, we found no improvement in HD mice as a )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(result of running in spatial learning in the Morris water maze, correlating with the severe reduction in adult neurogenesis. One )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(possible confounding factor in our behavioral assessment of spatial memory was that the HD mice displayed a reduced swim )] TJ ET BT 26.250 387.834 Td /F1 9.8 Tf [(speed, possibly due to the onset of motor impairments [15] [19] [20] . However, further evidence that the poor performance was )] TJ ET BT 26.250 375.929 Td /F1 9.8 Tf [(indeed a cognitive deficit was that the HD mice did not have any learning curve, even at reduced speed. The HD mice did not )] TJ ET BT 26.250 364.024 Td /F1 9.8 Tf [(differ in their latency to find the hidden platform from day 1 to day 8 indicating that they could not learn the task. In addition, in )] TJ ET BT 26.250 352.119 Td /F1 9.8 Tf [(the probe trial they showed no preference for the platform quadrant. WT runners had the best performance, as expected [4] [21] )] TJ ET BT 26.250 340.215 Td /F1 9.8 Tf [(. It is possible that the water maze task is not ideal to test the possible benefit of therapeutic interventions in HD mice. Further )] TJ ET BT 26.250 328.310 Td /F1 9.8 Tf [(research using memory tasks with low motor demand [53] [54] may be better suited to test cognition in these mouse models.)] TJ ET BT 26.250 308.905 Td /F1 9.8 Tf [(It is clear from our study that running did not prevent or delay symptoms of HD but appeared to worsen the outcome in HD mice. )] TJ ET BT 26.250 297.000 Td /F1 9.8 Tf [(Moreover, cognitive and neurogenic deficits were not reversed by running. Taken together, our research suggests that exercise )] TJ ET BT 26.250 285.096 Td /F1 9.8 Tf [(is not beneficial and may even be detrimental in this animal model.)] TJ ET BT 26.250 248.493 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 228.539 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 191.936 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 171.982 Td /F1 9.8 Tf [(We thank Linda R. Kitabayashi for help with figure preparation. We thank Dr. Bronwen Martin for helpful advice, and Dr. Tali )] TJ ET BT 26.250 160.077 Td /F1 9.8 Tf [(Kobilo, David Creer, Kriti Gandhi and Robert Rowe for assistance with histology. Statistical assistance was kindly provided by )] TJ ET BT 26.250 148.173 Td /F1 9.8 Tf [(Dr. Susan Resnick, Dr. Yang An and Dr. Larry Brant.)] TJ ET BT 26.250 119.070 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nature Rev )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(Neurosci 2008; 9:58-65.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(and nerve growth factor in rat brain. Brain Res 1996; 726:49-56.)] TJ ET Q q 15.000 38.521 577.500 738.479 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(negative impact of running by possibly releasing as of yet unidentified aberrant factors into the bloodstream that could lead to )] TJ ET BT 26.250 755.571 Td /F1 9.8 Tf [(functional impairments.)] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(In the R6/1 mice, running has been shown to normalize rearing behavior and delay a deficit in rear-paw clasping and motor )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(coordination on a static rod but did not improve rotarod performance )] TJ ET 0.267 0.267 0.267 rg BT 322.679 724.262 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 347.074 724.262 Td /F1 9.8 Tf [( . In our study, the accelerating rotarod revealed )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(motor deficits only in the HD runners in the latency to fall. It is possible that running resulted in earlier striatal atrophy. Although )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(a change in striatal volume in HD runners was not observed in mice used for the motor behavioral tests \(S\), it was reduced in )] TJ ET BT 26.250 688.548 Td /F1 9.8 Tf [(the lifespan group \(L\). This raises the possibility of a subtle, but detrimental effect of exercise that translated to the motor )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(impairments. While this is the first animal study making observations that exercise may not be beneficial in HD, there is )] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(evidence from human studies that points in the same direction. Recently, a study in humans indicated that physical exercise )] TJ ET BT 26.250 652.833 Td /F1 9.8 Tf [(may not prevent or delay disease onset or progression )] TJ ET 0.267 0.267 0.267 rg BT 264.150 652.833 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 299.387 652.833 Td /F1 9.8 Tf [( . A case study of a HD marathon runner presented with )] TJ ET BT 26.250 640.929 Td /F1 9.8 Tf [(myopathy years before the predicted disease onset. In fact, this patient had onset of HD symptoms almost twenty years before )] TJ ET BT 26.250 629.024 Td /F1 9.8 Tf [(the median age of onset for 41 CAG repeats, indicating that regular exercise certainly did not delay the disease development)] TJ ET 0.267 0.267 0.267 rg BT 26.250 617.119 Td /F1 9.8 Tf [([44] [45])] TJ ET 0.271 0.267 0.267 rg BT 61.486 617.119 Td /F1 9.8 Tf [( . Indeed, prescription of exercise protocols to patients with neurodegenerative diseases should be done with caution )] TJ ET 0.267 0.267 0.267 rg BT 26.250 605.214 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 42.513 605.214 Td /F1 9.8 Tf [( .)] TJ ET BT 26.250 585.810 Td /F1 9.8 Tf [(Huntingtons disease is often defined as affecting the striatum and cortex )] TJ ET 0.267 0.267 0.267 rg BT 342.745 585.810 Td /F1 9.8 Tf [([15] [19] [20])] TJ ET 0.271 0.267 0.267 rg BT 396.955 585.810 Td /F1 9.8 Tf [( . However, the hippocampus also shows )] TJ ET BT 26.250 573.905 Td /F1 9.8 Tf [(profound neuronal loss in HD patients and animal models )] TJ ET 0.267 0.267 0.267 rg BT 276.611 573.905 Td /F1 9.8 Tf [([13] [27] [28] [29] [47] [48] [49])] TJ ET 0.271 0.267 0.267 rg BT 406.715 573.905 Td /F1 9.8 Tf [( . In the present study, we observed a )] TJ ET BT 26.250 562.000 Td /F1 9.8 Tf [(decrease in hippocampal volume and neurogenesis. Exercise did not reverse these deficits in N171-82Q mice similar to )] TJ ET BT 26.250 550.095 Td /F1 9.8 Tf [(previous research in R6/2 mice )] TJ ET 0.267 0.267 0.267 rg BT 163.335 550.095 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 179.598 550.095 Td /F1 9.8 Tf [( , nor was the number of cells with mHtt )] TJ ET BT 352.992 553.984 Td /F1 8.7 Tf [(+)] TJ ET BT 358.053 550.095 Td /F1 9.8 Tf [( intranuclear inclusions changed. In addition, )] TJ ET BT 26.250 538.191 Td /F1 9.8 Tf [(consistent with R6/2 mice, a significant increase in the percentage of newborn cells that took on a mature neuronal phenotype )] TJ ET BT 26.250 526.286 Td /F1 9.8 Tf [(was observed but this did not translate to an increase in total neuron number )] TJ ET 0.267 0.267 0.267 rg BT 359.544 526.286 Td /F1 9.8 Tf [([13])] TJ ET 0.271 0.267 0.267 rg BT 375.807 526.286 Td /F1 9.8 Tf [( . Furthermore, a reduced percentage of hilar )] TJ ET BT 26.250 514.381 Td /F1 9.8 Tf [(BrdU )] TJ ET BT 51.171 518.269 Td /F1 8.7 Tf [(+)] TJ ET BT 56.232 514.381 Td /F1 9.8 Tf [( cells was observed in HD runners as compared to sedentary controls. While this could be considered a positive effect of )] TJ ET BT 26.250 502.476 Td /F1 9.8 Tf [(running, the immature neuronal marker doublecortin showed that cells did not extend processes into the molecular layer, )] TJ ET BT 26.250 490.572 Td /F1 9.8 Tf [(suggesting neurite extension and maturation deficits in both groups of transgenic mice. Likely, the hippocampal )] TJ ET BT 26.250 478.667 Td /F1 9.8 Tf [(microenvironment plays an important role)] TJ ET 0.267 0.267 0.267 rg BT 205.055 478.667 Td /F1 9.8 Tf [( [50])] TJ ET 0.271 0.267 0.267 rg BT 224.029 478.667 Td /F1 9.8 Tf [( . Indeed, the exercise-induced survival factor BDNF )] TJ ET 0.267 0.267 0.267 rg BT 452.159 478.667 Td /F1 9.8 Tf [([2] [51])] TJ ET 0.271 0.267 0.267 rg BT 481.975 478.667 Td /F1 9.8 Tf [( is reduced in HD )] TJ ET BT 26.250 466.762 Td /F1 9.8 Tf [(mice and not increased by running )] TJ ET 0.267 0.267 0.267 rg BT 177.989 466.762 Td /F1 9.8 Tf [([7])] TJ ET 0.271 0.267 0.267 rg BT 188.831 466.762 Td /F1 9.8 Tf [( . Administration of this factor did enhance striatal neurogenesis )] TJ ET 0.267 0.267 0.267 rg BT 465.751 466.762 Td /F1 9.8 Tf [([52])] TJ ET 0.271 0.267 0.267 rg BT 482.014 466.762 Td /F1 9.8 Tf [( and may have a )] TJ ET BT 26.250 454.857 Td /F1 9.8 Tf [(similar effect in the hippocampus.)] TJ ET BT 26.250 435.453 Td /F1 9.8 Tf [(Running improves performance in spatial memory tasks under normal physiological conditions. This is thought to be mediated, )] TJ ET BT 26.250 423.548 Td /F1 9.8 Tf [(at least in part by increased synaptic plasticity and neurogenesis [4] . In our study, we found no improvement in HD mice as a )] TJ ET BT 26.250 411.643 Td /F1 9.8 Tf [(result of running in spatial learning in the Morris water maze, correlating with the severe reduction in adult neurogenesis. One )] TJ ET BT 26.250 399.738 Td /F1 9.8 Tf [(possible confounding factor in our behavioral assessment of spatial memory was that the HD mice displayed a reduced swim )] TJ ET BT 26.250 387.834 Td /F1 9.8 Tf [(speed, possibly due to the onset of motor impairments [15] [19] [20] . However, further evidence that the poor performance was )] TJ ET BT 26.250 375.929 Td /F1 9.8 Tf [(indeed a cognitive deficit was that the HD mice did not have any learning curve, even at reduced speed. The HD mice did not )] TJ ET BT 26.250 364.024 Td /F1 9.8 Tf [(differ in their latency to find the hidden platform from day 1 to day 8 indicating that they could not learn the task. In addition, in )] TJ ET BT 26.250 352.119 Td /F1 9.8 Tf [(the probe trial they showed no preference for the platform quadrant. WT runners had the best performance, as expected [4] [21] )] TJ ET BT 26.250 340.215 Td /F1 9.8 Tf [(. It is possible that the water maze task is not ideal to test the possible benefit of therapeutic interventions in HD mice. Further )] TJ ET BT 26.250 328.310 Td /F1 9.8 Tf [(research using memory tasks with low motor demand [53] [54] may be better suited to test cognition in these mouse models.)] TJ ET BT 26.250 308.905 Td /F1 9.8 Tf [(It is clear from our study that running did not prevent or delay symptoms of HD but appeared to worsen the outcome in HD mice. )] TJ ET BT 26.250 297.000 Td /F1 9.8 Tf [(Moreover, cognitive and neurogenic deficits were not reversed by running. Taken together, our research suggests that exercise )] TJ ET BT 26.250 285.096 Td /F1 9.8 Tf [(is not beneficial and may even be detrimental in this animal model.)] TJ ET BT 26.250 248.493 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 228.539 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 191.936 Td /F4 12.0 Tf [(Acknowledgements)] TJ ET BT 26.250 171.982 Td /F1 9.8 Tf [(We thank Linda R. Kitabayashi for help with figure preparation. We thank Dr. Bronwen Martin for helpful advice, and Dr. Tali )] TJ ET BT 26.250 160.077 Td /F1 9.8 Tf [(Kobilo, David Creer, Kriti Gandhi and Robert Rowe for assistance with histology. Statistical assistance was kindly provided by )] TJ ET BT 26.250 148.173 Td /F1 9.8 Tf [(Dr. Susan Resnick, Dr. Yang An and Dr. Larry Brant.)] TJ ET BT 26.250 119.070 Td /F4 12.0 Tf [(References)] TJ ET BT 26.250 91.616 Td /F1 9.8 Tf [(1.)] TJ ET BT 38.132 91.616 Td /F1 9.8 Tf [(Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nature Rev )] TJ ET BT 26.250 79.711 Td /F1 9.8 Tf [(Neurosci 2008; 9:58-65.)] TJ ET BT 26.250 60.306 Td /F1 9.8 Tf [(2.)] TJ ET BT 38.132 60.306 Td /F1 9.8 Tf [(Neeper SA, Gomez-Pinilla F, Choi J, Cotman CW. Physical activity increases mRNA for brain-derived neurotrophic factor )] TJ ET BT 26.250 48.402 Td /F1 9.8 Tf [(and nerve growth factor in rat brain. Brain Res 1996; 726:49-56.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(9)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 373 0 obj << /Type /Annot /Subtype /Link /A 374 0 R /Border [0 0 0] /H /I /Rect [ 322.6793 723.3601 347.0738 733.2807 ] >> endobj 374 0 obj << /Type /Action >> endobj 375 0 obj << /Type /Annot /Subtype /Link /A 376 0 R /Border [0 0 0] /H /I /Rect [ 264.1500 651.9316 299.3865 661.8522 ] >> endobj 376 0 obj << /Type /Action >> endobj 377 0 obj << /Type /Annot /Subtype /Link /A 378 0 R /Border [0 0 0] /H /I /Rect [ 563.3093 628.1221 566.0198 638.0427 ] >> endobj 378 0 obj << /Type /Action >> endobj 379 0 obj << /Type /Annot /Subtype /Link /A 380 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 616.2173 61.4865 626.1379 ] >> endobj 380 0 obj << /Type /Action >> endobj 381 0 obj << /Type /Annot /Subtype /Link /A 382 0 R /Border [0 0 0] /H /I /Rect [ 26.2500 604.3126 42.5130 614.2332 ] >> endobj 382 0 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Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Trends Neurosci 2007; 30:464-472.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(van Praag H. Neurogenesis and exercise: past and future directions. Neuromol Med 2008; 10:128-140.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, et al. Delaying the onset of Huntingtons in mice. Nature 2000; 404:721-722.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci 2000; 1:191-)] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(198.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Pang TYC, Stam NC, Nithianantharajah J et al. Differential effects of voluntary physical exercise on behavioral and brain-)] TJ ET BT 26.250 646.643 Td /F1 9.8 Tf [(derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience 2006; 141:569-584.)] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 627.238 Td /F1 9.8 Tf [(van Dellen A, Cordery PM, Spires TL et al. Wheel running from a juvenile age delays onset of specific motor deficits but does )] TJ ET BT 26.250 615.333 Td /F1 9.8 Tf [(not alter protein aggregate density in a mouse model of Huntingtons disease. BMC Neurosci 2008; 9:34.)] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 595.929 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA et al. Rescuing the corticostriatal synaptic disconnection in the R6/2 mouse model of )] TJ ET BT 26.250 584.024 Td /F1 9.8 Tf [(Huntington's disease: exercise, adenosine receptors and ampakines. PLoS Curr. 2010; Sep 20;2.)] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 564.619 Td /F1 9.8 Tf [(Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp )] TJ ET BT 26.250 552.714 Td /F1 9.8 Tf [(Neurol 1965; 124:319-335.)] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 533.310 Td /F1 9.8 Tf [(Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132:645-660.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Lie DC, Song H, Colamarino SA. et al. Neurogenesis in the adult brain: new strategies for central nervous system diseases. )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Annu Rev Pharmacol Toxico 2004; 44:399-421.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Kohl Z, Kandasamy M, Winner B et al. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(model of Huntingtons disease. Brain Res 2007; 1155:24-33.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(progressive neurological phenotype in transgenic mice. Cell 1996; 87:493-506.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Menalled LB, Chesselet M-F. Mouse models of Huntingtons disease. Trends Pharmacol Sci 2002; 23:32-39.)] TJ ET BT 26.250 400.572 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 400.572 Td /F1 9.8 Tf [(Lazic SE, Grote H, Blakemore C et al. Neurogenesis in the R6/1 transgenic mouse model of Huntingtons disease: effects of )] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(environmental enrichment. Eur J Neurosci 2006; 23:1829-1838.)] TJ ET BT 26.250 369.262 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 369.262 Td /F1 9.8 Tf [(Schilling G, Becher MW, Sharp AH et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a )] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(mutant N-terminal fragment of huntingtin. Human Mol Gen 1999; 8:397-407.)] TJ ET BT 26.250 337.953 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 337.953 Td /F1 9.8 Tf [(Duan W, Guo Z, Jiang H et al. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease )] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 2003; 100:2911-2916.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Ramaswamy S, McBride JL, Kordower JH. Animal models of Huntingtons disease. ILAR Journal 2007; 48:356-373.)] TJ ET BT 26.250 287.238 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 287.238 Td /F1 9.8 Tf [(Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntingtons disease. Neurobiol Dis 2008; 32:1-9.)] TJ ET BT 26.250 267.834 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 267.834 Td /F1 9.8 Tf [(van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in )] TJ ET BT 26.250 255.929 Td /F1 9.8 Tf [(mice. Proc Natl Acad Sci USA 1999;96:13427-13431.)] TJ ET BT 26.250 236.524 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 236.524 Td /F1 9.8 Tf [(Thambisetty M, Wan J, Carass A et al. Longitudinal changes in cortical thickness associated with normal aging. )] TJ ET BT 26.250 224.619 Td /F1 9.8 Tf [(Neuroimage 2010; 52:1215-1223.)] TJ ET BT 26.250 205.215 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 205.215 Td /F1 9.8 Tf [(Farrer LA. Diabetes mellitus in Huntingtons disease. Clinical Gen 1985; 27:62-67.)] TJ ET BT 26.250 185.810 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 185.810 Td /F1 9.8 Tf [(Hurlbert MS, Zhou W, Wasmeier C et al. Mice transgenic for an expanded CAG repeat in the Huntingtons disease gene )] TJ ET BT 26.250 173.905 Td /F1 9.8 Tf [(develop diabetes. Diabetes 1999; 48:649-651.)] TJ ET BT 26.250 154.500 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 154.500 Td /F1 9.8 Tf [(Olah J, Klivenyi P, Gardian G et al. Increased glucose metabolism and ATP level in brain tissue of Huntingtons disease )] TJ ET BT 26.250 142.596 Td /F1 9.8 Tf [(transgenic mice. FEBS Journal 2008; 275:4740-4755.)] TJ ET BT 26.250 123.191 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 123.191 Td /F1 9.8 Tf [(Morris RG, Garrud P, Rawlins JN, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; )] TJ ET BT 26.250 111.286 Td /F1 9.8 Tf [(297:681-683.)] TJ ET BT 26.250 91.881 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 91.881 Td /F1 9.8 Tf [(Lazic SE, Grote H, Armstrong RJE et al. Decreased hippocampal cell proliferation in R6/1 Huntingtons mice. Neuroreport )] TJ ET BT 26.250 79.977 Td /F1 9.8 Tf [(2004; 15:811-813.)] TJ ET BT 26.250 60.572 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 60.572 Td /F1 9.8 Tf [(Gil JM, Mohapel P, Araujo IM et al. Reduced hippocampal neurogenesis in R6/2 transgenic Huntingtons disease mice. )] TJ ET BT 26.250 48.667 Td /F1 9.8 Tf [(Neurobiol Dis 2005; 20:744-751.)] TJ ET Q q 15.000 38.786 577.500 738.214 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Trends Neurosci 2007; 30:464-472.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(van Praag H. Neurogenesis and exercise: past and future directions. Neuromol Med 2008; 10:128-140.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, et al. Delaying the onset of Huntingtons in mice. Nature 2000; 404:721-722.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci 2000; 1:191-)] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(198.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Pang TYC, Stam NC, Nithianantharajah J et al. Differential effects of voluntary physical exercise on behavioral and brain-)] TJ ET BT 26.250 646.643 Td /F1 9.8 Tf [(derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience 2006; 141:569-584.)] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 627.238 Td /F1 9.8 Tf [(van Dellen A, Cordery PM, Spires TL et al. Wheel running from a juvenile age delays onset of specific motor deficits but does )] TJ ET BT 26.250 615.333 Td /F1 9.8 Tf [(not alter protein aggregate density in a mouse model of Huntingtons disease. BMC Neurosci 2008; 9:34.)] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 595.929 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA et al. Rescuing the corticostriatal synaptic disconnection in the R6/2 mouse model of )] TJ ET BT 26.250 584.024 Td /F1 9.8 Tf [(Huntington's disease: exercise, adenosine receptors and ampakines. PLoS Curr. 2010; Sep 20;2.)] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 564.619 Td /F1 9.8 Tf [(Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp )] TJ ET BT 26.250 552.714 Td /F1 9.8 Tf [(Neurol 1965; 124:319-335.)] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 533.310 Td /F1 9.8 Tf [(Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132:645-660.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Lie DC, Song H, Colamarino SA. et al. Neurogenesis in the adult brain: new strategies for central nervous system diseases. )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Annu Rev Pharmacol Toxico 2004; 44:399-421.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Kohl Z, Kandasamy M, Winner B et al. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(model of Huntingtons disease. Brain Res 2007; 1155:24-33.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(progressive neurological phenotype in transgenic mice. Cell 1996; 87:493-506.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Menalled LB, Chesselet M-F. Mouse models of Huntingtons disease. Trends Pharmacol Sci 2002; 23:32-39.)] TJ ET BT 26.250 400.572 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 400.572 Td /F1 9.8 Tf [(Lazic SE, Grote H, Blakemore C et al. Neurogenesis in the R6/1 transgenic mouse model of Huntingtons disease: effects of )] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(environmental enrichment. Eur J Neurosci 2006; 23:1829-1838.)] TJ ET BT 26.250 369.262 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 369.262 Td /F1 9.8 Tf [(Schilling G, Becher MW, Sharp AH et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a )] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(mutant N-terminal fragment of huntingtin. Human Mol Gen 1999; 8:397-407.)] TJ ET BT 26.250 337.953 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 337.953 Td /F1 9.8 Tf [(Duan W, Guo Z, Jiang H et al. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease )] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 2003; 100:2911-2916.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Ramaswamy S, McBride JL, Kordower JH. Animal models of Huntingtons disease. ILAR Journal 2007; 48:356-373.)] TJ ET BT 26.250 287.238 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 287.238 Td /F1 9.8 Tf [(Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntingtons disease. Neurobiol Dis 2008; 32:1-9.)] TJ ET BT 26.250 267.834 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 267.834 Td /F1 9.8 Tf [(van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in )] TJ ET BT 26.250 255.929 Td /F1 9.8 Tf [(mice. Proc Natl Acad Sci USA 1999;96:13427-13431.)] TJ ET BT 26.250 236.524 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 236.524 Td /F1 9.8 Tf [(Thambisetty M, Wan J, Carass A et al. Longitudinal changes in cortical thickness associated with normal aging. )] TJ ET BT 26.250 224.619 Td /F1 9.8 Tf [(Neuroimage 2010; 52:1215-1223.)] TJ ET BT 26.250 205.215 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 205.215 Td /F1 9.8 Tf [(Farrer LA. Diabetes mellitus in Huntingtons disease. Clinical Gen 1985; 27:62-67.)] TJ ET BT 26.250 185.810 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 185.810 Td /F1 9.8 Tf [(Hurlbert MS, Zhou W, Wasmeier C et al. Mice transgenic for an expanded CAG repeat in the Huntingtons disease gene )] TJ ET BT 26.250 173.905 Td /F1 9.8 Tf [(develop diabetes. Diabetes 1999; 48:649-651.)] TJ ET BT 26.250 154.500 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 154.500 Td /F1 9.8 Tf [(Olah J, Klivenyi P, Gardian G et al. Increased glucose metabolism and ATP level in brain tissue of Huntingtons disease )] TJ ET BT 26.250 142.596 Td /F1 9.8 Tf [(transgenic mice. FEBS Journal 2008; 275:4740-4755.)] TJ ET BT 26.250 123.191 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 123.191 Td /F1 9.8 Tf [(Morris RG, Garrud P, Rawlins JN, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; )] TJ ET BT 26.250 111.286 Td /F1 9.8 Tf [(297:681-683.)] TJ ET BT 26.250 91.881 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 91.881 Td /F1 9.8 Tf [(Lazic SE, Grote H, Armstrong RJE et al. Decreased hippocampal cell proliferation in R6/1 Huntingtons mice. Neuroreport )] TJ ET BT 26.250 79.977 Td /F1 9.8 Tf [(2004; 15:811-813.)] TJ ET BT 26.250 60.572 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 60.572 Td /F1 9.8 Tf [(Gil JM, Mohapel P, Araujo IM et al. Reduced hippocampal neurogenesis in R6/2 transgenic Huntingtons disease mice. )] TJ ET BT 26.250 48.667 Td /F1 9.8 Tf [(Neurobiol Dis 2005; 20:744-751.)] TJ ET Q q 15.000 38.786 577.500 738.214 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(3.)] TJ ET BT 38.132 759.976 Td /F1 9.8 Tf [(Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(Trends Neurosci 2007; 30:464-472.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(4.)] TJ ET BT 38.132 728.667 Td /F1 9.8 Tf [(van Praag H. Neurogenesis and exercise: past and future directions. Neuromol Med 2008; 10:128-140.)] TJ ET BT 26.250 709.262 Td /F1 9.8 Tf [(5.)] TJ ET BT 38.132 709.262 Td /F1 9.8 Tf [(van Dellen A, Blakemore C, Deacon R, et al. Delaying the onset of Huntingtons in mice. Nature 2000; 404:721-722.)] TJ ET BT 26.250 689.857 Td /F1 9.8 Tf [(6.)] TJ ET BT 38.132 689.857 Td /F1 9.8 Tf [(van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci 2000; 1:191-)] TJ ET BT 26.250 677.952 Td /F1 9.8 Tf [(198.)] TJ ET BT 26.250 658.548 Td /F1 9.8 Tf [(7.)] TJ ET BT 38.132 658.548 Td /F1 9.8 Tf [(Pang TYC, Stam NC, Nithianantharajah J et al. Differential effects of voluntary physical exercise on behavioral and brain-)] TJ ET BT 26.250 646.643 Td /F1 9.8 Tf [(derived neurotrophic factor expression deficits in Huntingtons disease transgenic mice. Neuroscience 2006; 141:569-584.)] TJ ET BT 26.250 627.238 Td /F1 9.8 Tf [(8.)] TJ ET BT 38.132 627.238 Td /F1 9.8 Tf [(van Dellen A, Cordery PM, Spires TL et al. Wheel running from a juvenile age delays onset of specific motor deficits but does )] TJ ET BT 26.250 615.333 Td /F1 9.8 Tf [(not alter protein aggregate density in a mouse model of Huntingtons disease. BMC Neurosci 2008; 9:34.)] TJ ET BT 26.250 595.929 Td /F1 9.8 Tf [(9.)] TJ ET BT 38.132 595.929 Td /F1 9.8 Tf [(Cepeda C, Cummings DM, Hickey MA et al. Rescuing the corticostriatal synaptic disconnection in the R6/2 mouse model of )] TJ ET BT 26.250 584.024 Td /F1 9.8 Tf [(Huntington's disease: exercise, adenosine receptors and ampakines. PLoS Curr. 2010; Sep 20;2.)] TJ ET BT 26.250 564.619 Td /F1 9.8 Tf [(10.)] TJ ET BT 43.553 564.619 Td /F1 9.8 Tf [(Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp )] TJ ET BT 26.250 552.714 Td /F1 9.8 Tf [(Neurol 1965; 124:319-335.)] TJ ET BT 26.250 533.310 Td /F1 9.8 Tf [(11.)] TJ ET BT 43.553 533.310 Td /F1 9.8 Tf [(Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132:645-660.)] TJ ET BT 26.250 513.905 Td /F1 9.8 Tf [(12.)] TJ ET BT 43.553 513.905 Td /F1 9.8 Tf [(Lie DC, Song H, Colamarino SA. et al. Neurogenesis in the adult brain: new strategies for central nervous system diseases. )] TJ ET BT 26.250 502.000 Td /F1 9.8 Tf [(Annu Rev Pharmacol Toxico 2004; 44:399-421.)] TJ ET BT 26.250 482.595 Td /F1 9.8 Tf [(13.)] TJ ET BT 43.553 482.595 Td /F1 9.8 Tf [(Kohl Z, Kandasamy M, Winner B et al. Physical activity fails to rescue hippocampal neurogenesis deficits in the R6/2 mouse )] TJ ET BT 26.250 470.691 Td /F1 9.8 Tf [(model of Huntingtons disease. Brain Res 2007; 1155:24-33.)] TJ ET BT 26.250 451.286 Td /F1 9.8 Tf [(14.)] TJ ET BT 43.553 451.286 Td /F1 9.8 Tf [(Mangiarini L, Sathasivam K, Seller M et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a )] TJ ET BT 26.250 439.381 Td /F1 9.8 Tf [(progressive neurological phenotype in transgenic mice. Cell 1996; 87:493-506.)] TJ ET BT 26.250 419.976 Td /F1 9.8 Tf [(15.)] TJ ET BT 43.553 419.976 Td /F1 9.8 Tf [(Menalled LB, Chesselet M-F. Mouse models of Huntingtons disease. Trends Pharmacol Sci 2002; 23:32-39.)] TJ ET BT 26.250 400.572 Td /F1 9.8 Tf [(16.)] TJ ET BT 43.553 400.572 Td /F1 9.8 Tf [(Lazic SE, Grote H, Blakemore C et al. Neurogenesis in the R6/1 transgenic mouse model of Huntingtons disease: effects of )] TJ ET BT 26.250 388.667 Td /F1 9.8 Tf [(environmental enrichment. Eur J Neurosci 2006; 23:1829-1838.)] TJ ET BT 26.250 369.262 Td /F1 9.8 Tf [(17.)] TJ ET BT 43.553 369.262 Td /F1 9.8 Tf [(Schilling G, Becher MW, Sharp AH et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a )] TJ ET BT 26.250 357.357 Td /F1 9.8 Tf [(mutant N-terminal fragment of huntingtin. Human Mol Gen 1999; 8:397-407.)] TJ ET BT 26.250 337.953 Td /F1 9.8 Tf [(18.)] TJ ET BT 43.553 337.953 Td /F1 9.8 Tf [(Duan W, Guo Z, Jiang H et al. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease )] TJ ET BT 26.250 326.048 Td /F1 9.8 Tf [(progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 2003; 100:2911-2916.)] TJ ET BT 26.250 306.643 Td /F1 9.8 Tf [(19.)] TJ ET BT 43.553 306.643 Td /F1 9.8 Tf [(Ramaswamy S, McBride JL, Kordower JH. Animal models of Huntingtons disease. ILAR Journal 2007; 48:356-373.)] TJ ET BT 26.250 287.238 Td /F1 9.8 Tf [(20.)] TJ ET BT 43.553 287.238 Td /F1 9.8 Tf [(Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntingtons disease. Neurobiol Dis 2008; 32:1-9.)] TJ ET BT 26.250 267.834 Td /F1 9.8 Tf [(21.)] TJ ET BT 43.553 267.834 Td /F1 9.8 Tf [(van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in )] TJ ET BT 26.250 255.929 Td /F1 9.8 Tf [(mice. Proc Natl Acad Sci USA 1999;96:13427-13431.)] TJ ET BT 26.250 236.524 Td /F1 9.8 Tf [(22.)] TJ ET BT 43.553 236.524 Td /F1 9.8 Tf [(Thambisetty M, Wan J, Carass A et al. Longitudinal changes in cortical thickness associated with normal aging. )] TJ ET BT 26.250 224.619 Td /F1 9.8 Tf [(Neuroimage 2010; 52:1215-1223.)] TJ ET BT 26.250 205.215 Td /F1 9.8 Tf [(23.)] TJ ET BT 43.553 205.215 Td /F1 9.8 Tf [(Farrer LA. Diabetes mellitus in Huntingtons disease. Clinical Gen 1985; 27:62-67.)] TJ ET BT 26.250 185.810 Td /F1 9.8 Tf [(24.)] TJ ET BT 43.553 185.810 Td /F1 9.8 Tf [(Hurlbert MS, Zhou W, Wasmeier C et al. Mice transgenic for an expanded CAG repeat in the Huntingtons disease gene )] TJ ET BT 26.250 173.905 Td /F1 9.8 Tf [(develop diabetes. Diabetes 1999; 48:649-651.)] TJ ET BT 26.250 154.500 Td /F1 9.8 Tf [(25.)] TJ ET BT 43.553 154.500 Td /F1 9.8 Tf [(Olah J, Klivenyi P, Gardian G et al. Increased glucose metabolism and ATP level in brain tissue of Huntingtons disease )] TJ ET BT 26.250 142.596 Td /F1 9.8 Tf [(transgenic mice. FEBS Journal 2008; 275:4740-4755.)] TJ ET BT 26.250 123.191 Td /F1 9.8 Tf [(26.)] TJ ET BT 43.553 123.191 Td /F1 9.8 Tf [(Morris RG, Garrud P, Rawlins JN, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 1982; )] TJ ET BT 26.250 111.286 Td /F1 9.8 Tf [(297:681-683.)] TJ ET BT 26.250 91.881 Td /F1 9.8 Tf [(27.)] TJ ET BT 43.553 91.881 Td /F1 9.8 Tf [(Lazic SE, Grote H, Armstrong RJE et al. Decreased hippocampal cell proliferation in R6/1 Huntingtons mice. Neuroreport )] TJ ET BT 26.250 79.977 Td /F1 9.8 Tf [(2004; 15:811-813.)] TJ ET BT 26.250 60.572 Td /F1 9.8 Tf [(28.)] TJ ET BT 43.553 60.572 Td /F1 9.8 Tf [(Gil JM, Mohapel P, Araujo IM et al. Reduced hippocampal neurogenesis in R6/2 transgenic Huntingtons disease mice. )] TJ ET BT 26.250 48.667 Td /F1 9.8 Tf [(Neurobiol Dis 2005; 20:744-751.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(10)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 453 0 obj << /Type /Page /Parent 3 0 R /Contents 454 0 R >> endobj 454 0 obj << /Length 21311 >> stream 0.271 0.267 0.267 rg q 15.000 49.381 577.500 727.619 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Grote HE, Bull ND, Howard ML et al. Cognitive disorders and neurogenesis deficits in Huntingtons disease mice are )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(rescued by fluoxetine. Eur J Neurosci 2005; 22:2081-2088.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Andreassen OA, Dedeoglu A, Ferrante RJ et al. Creatine increase survival and delays motor symptoms in a transgenic )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(animal model of Huntingtons disease. Neurobiol Dis 2001; 8:479-491.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Davies SW, Turmaine M, Cozens BA et al. Formation on neuronal intranuclear inclusions underlies the neurological )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(dysfunction in mice transgenic for the HD mutation. Cell 1997; 90: 537-548.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Duan W, Peng Q, Masuda N et al. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(model of Huntingtons disease. Neurobiol Dis 2008; 30:312-322.)] TJ ET BT 26.250 634.738 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 634.738 Td /F1 9.8 Tf [(Peng Q, Masuda N, Jiang M et al. The antidepressant sertraline improves the phenotype, promotes neurogenesis and )] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(increases BDNF levels in the R6/2 Huntington's disease mouse model. Exp Neurol 2008; 210:154-163.)] TJ ET BT 26.250 603.429 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 603.429 Td /F1 9.8 Tf [(Kannangara TS, Lucero MJ, Gil-Mohapel J et al. Running reduces stress and enhances cell genesis in aged mice. )] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(Neurobiol Aging 2010; Epub ahead of print.)] TJ ET BT 26.250 572.119 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 572.119 Td /F1 9.8 Tf [(Carter RJ, Hunt MJ, Morton AJ Environmental stimulation increases survival in mice transgenic for exon 1 of the )] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(Huntingtons disease gene. Mov Disord 2000; 15:925-937.)] TJ ET BT 26.250 540.810 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 540.810 Td /F1 9.8 Tf [(Laviola G, Hannan AJ, Macri S et al. Effects of enriched environment on animal models of neurodegenerative diseases and )] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(psychiatric disorders. Neurobiol Dis 2008; 31:159-168.)] TJ ET BT 26.250 509.500 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 509.500 Td /F1 9.8 Tf [(Stranahan AM, Lee K, Mattson MP. Central mechanisms of HPA regulation by voluntary exercise. Neuromol Med 2008; )] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(10:118-127.)] TJ ET BT 26.250 478.191 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 478.191 Td /F1 9.8 Tf [(Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron )] TJ ET BT 26.250 466.286 Td /F1 9.8 Tf [(2009; 64:33-39.)] TJ ET BT 26.250 446.881 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 446.881 Td /F1 9.8 Tf [(Esch T, Stefano GB, Fricchione GL, Benson H. The role of stress in neurodegenerative diseases and mental disorders. )] TJ ET BT 26.250 434.976 Td /F1 9.8 Tf [(Neuro Endocrinol Lett 2002; 23:199-208.)] TJ ET BT 26.250 415.572 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 415.572 Td /F1 9.8 Tf [(Sotiropoulos I, Cerqueira JJ, Catania C et al. Stress and glucocorticoid footprints in the brain - The path from depression to )] TJ ET BT 26.250 403.667 Td /F1 9.8 Tf [(Alzheimers disease. Neurosci & Biobehav Rev 2008; 32:1161-1173.)] TJ ET BT 26.250 384.262 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 384.262 Td /F1 9.8 Tf [(Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and )] TJ ET BT 26.250 372.357 Td /F1 9.8 Tf [(cognition. Nat Rev Neurosci 2009; 10:434-45.)] TJ ET BT 26.250 352.953 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 352.953 Td /F1 9.8 Tf [(Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of )] TJ ET BT 26.250 341.048 Td /F1 9.8 Tf [(neurogenesis in the hippocampus. Proc Natl Acad Sci U S A. 2000; 97:11032-7.)] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 321.643 Td /F1 9.8 Tf [(Komitova M, Zhao LR, Gido G et al. Postischemic exercise attenuates whereas enriched environment has certain )] TJ ET BT 26.250 309.738 Td /F1 9.8 Tf [(enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur J Neurosci 2005; 21:2397-2405.)] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 290.334 Td /F1 9.8 Tf [(Altschuler, EL. Strenuous, intensive, long-term exercise does not prevent or delay the onset of Huntingtons disease. Med )] TJ ET BT 26.250 278.429 Td /F1 9.8 Tf [(Hypoth 2006; 67:1429-1430.)] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 259.024 Td /F1 9.8 Tf [(Kosinski CM, Schlangen C, Gellerich FN et al. Myopathy as a first symptom of Huntingtons disease in a marathon runner. )] TJ ET BT 26.250 247.119 Td /F1 9.8 Tf [(Mov Disord 2007;22:1637-1640.)] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 227.715 Td /F1 9.8 Tf [(Quinn L, Busse, M, Khalil H et al. Client and therapist views on exercise programmes for early-mid stage Parkinsons )] TJ ET BT 26.250 215.810 Td /F1 9.8 Tf [(disease and Huntingtons disease. Disab & Rehab 2009; 32:917-928.)] TJ ET BT 26.250 196.405 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 196.405 Td /F1 9.8 Tf [(Halliday GM, McRitchie DA, MacDonald V et al. Regional specificity of brain atrophy in Huntingtons disease. Exp Neurol )] TJ ET BT 26.250 184.500 Td /F1 9.8 Tf [(1998;154:663-672.)] TJ ET BT 26.250 165.096 Td /F1 9.8 Tf [(48.)] TJ ET BT 43.553 165.096 Td /F1 9.8 Tf [(Spargo E, Everall IP, Lantos PL. Neuronal loss in the hippocampus in Huntingtons disease: a comparison with HIV )] TJ ET BT 26.250 153.191 Td /F1 9.8 Tf [(infection. J Neurol Neurosurg & Psych 1993;56:487-491.)] TJ ET BT 26.250 133.786 Td /F1 9.8 Tf [(49.)] TJ ET BT 43.553 133.786 Td /F1 9.8 Tf [(Rosas HD, Koroshetz WJ, Chen YI et al. Evidence for more widespread cerebral pathology in early HD. Neurology )] TJ ET BT 26.250 121.881 Td /F1 9.8 Tf [(2003;60:1615-1620.)] TJ ET BT 26.250 102.477 Td /F1 9.8 Tf [(50.)] TJ ET BT 43.553 102.477 Td /F1 9.8 Tf [(Phillips W, Morton AJ, Barker RA. Abnormalities of neurogenesis in the R6/2 mouse model of Huntingtons disease are )] TJ ET BT 26.250 90.572 Td /F1 9.8 Tf [(attributable to the in vivo microenvironment. J Neurosci 2005; 25:11564-11576.)] TJ ET BT 26.250 71.167 Td /F1 9.8 Tf [(51.)] TJ ET BT 43.553 71.167 Td /F1 9.8 Tf [(Kitamura T, Mishina M, Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice )] TJ ET BT 26.250 59.262 Td /F1 9.8 Tf [(lacking NMDA receptor epsilon 1 subunit. Neurosci Res 2003;47:55-63.)] TJ ET Q q 15.000 49.381 577.500 727.619 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Grote HE, Bull ND, Howard ML et al. Cognitive disorders and neurogenesis deficits in Huntingtons disease mice are )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(rescued by fluoxetine. Eur J Neurosci 2005; 22:2081-2088.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Andreassen OA, Dedeoglu A, Ferrante RJ et al. Creatine increase survival and delays motor symptoms in a transgenic )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(animal model of Huntingtons disease. Neurobiol Dis 2001; 8:479-491.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Davies SW, Turmaine M, Cozens BA et al. Formation on neuronal intranuclear inclusions underlies the neurological )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(dysfunction in mice transgenic for the HD mutation. Cell 1997; 90: 537-548.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Duan W, Peng Q, Masuda N et al. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(model of Huntingtons disease. Neurobiol Dis 2008; 30:312-322.)] TJ ET BT 26.250 634.738 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 634.738 Td /F1 9.8 Tf [(Peng Q, Masuda N, Jiang M et al. The antidepressant sertraline improves the phenotype, promotes neurogenesis and )] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(increases BDNF levels in the R6/2 Huntington's disease mouse model. Exp Neurol 2008; 210:154-163.)] TJ ET BT 26.250 603.429 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 603.429 Td /F1 9.8 Tf [(Kannangara TS, Lucero MJ, Gil-Mohapel J et al. Running reduces stress and enhances cell genesis in aged mice. )] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(Neurobiol Aging 2010; Epub ahead of print.)] TJ ET BT 26.250 572.119 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 572.119 Td /F1 9.8 Tf [(Carter RJ, Hunt MJ, Morton AJ Environmental stimulation increases survival in mice transgenic for exon 1 of the )] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(Huntingtons disease gene. Mov Disord 2000; 15:925-937.)] TJ ET BT 26.250 540.810 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 540.810 Td /F1 9.8 Tf [(Laviola G, Hannan AJ, Macri S et al. Effects of enriched environment on animal models of neurodegenerative diseases and )] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(psychiatric disorders. Neurobiol Dis 2008; 31:159-168.)] TJ ET BT 26.250 509.500 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 509.500 Td /F1 9.8 Tf [(Stranahan AM, Lee K, Mattson MP. Central mechanisms of HPA regulation by voluntary exercise. Neuromol Med 2008; )] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(10:118-127.)] TJ ET BT 26.250 478.191 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 478.191 Td /F1 9.8 Tf [(Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron )] TJ ET BT 26.250 466.286 Td /F1 9.8 Tf [(2009; 64:33-39.)] TJ ET BT 26.250 446.881 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 446.881 Td /F1 9.8 Tf [(Esch T, Stefano GB, Fricchione GL, Benson H. The role of stress in neurodegenerative diseases and mental disorders. )] TJ ET BT 26.250 434.976 Td /F1 9.8 Tf [(Neuro Endocrinol Lett 2002; 23:199-208.)] TJ ET BT 26.250 415.572 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 415.572 Td /F1 9.8 Tf [(Sotiropoulos I, Cerqueira JJ, Catania C et al. Stress and glucocorticoid footprints in the brain - The path from depression to )] TJ ET BT 26.250 403.667 Td /F1 9.8 Tf [(Alzheimers disease. Neurosci & Biobehav Rev 2008; 32:1161-1173.)] TJ ET BT 26.250 384.262 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 384.262 Td /F1 9.8 Tf [(Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and )] TJ ET BT 26.250 372.357 Td /F1 9.8 Tf [(cognition. Nat Rev Neurosci 2009; 10:434-45.)] TJ ET BT 26.250 352.953 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 352.953 Td /F1 9.8 Tf [(Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of )] TJ ET BT 26.250 341.048 Td /F1 9.8 Tf [(neurogenesis in the hippocampus. Proc Natl Acad Sci U S A. 2000; 97:11032-7.)] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 321.643 Td /F1 9.8 Tf [(Komitova M, Zhao LR, Gido G et al. Postischemic exercise attenuates whereas enriched environment has certain )] TJ ET BT 26.250 309.738 Td /F1 9.8 Tf [(enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur J Neurosci 2005; 21:2397-2405.)] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 290.334 Td /F1 9.8 Tf [(Altschuler, EL. Strenuous, intensive, long-term exercise does not prevent or delay the onset of Huntingtons disease. Med )] TJ ET BT 26.250 278.429 Td /F1 9.8 Tf [(Hypoth 2006; 67:1429-1430.)] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 259.024 Td /F1 9.8 Tf [(Kosinski CM, Schlangen C, Gellerich FN et al. Myopathy as a first symptom of Huntingtons disease in a marathon runner. )] TJ ET BT 26.250 247.119 Td /F1 9.8 Tf [(Mov Disord 2007;22:1637-1640.)] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 227.715 Td /F1 9.8 Tf [(Quinn L, Busse, M, Khalil H et al. Client and therapist views on exercise programmes for early-mid stage Parkinsons )] TJ ET BT 26.250 215.810 Td /F1 9.8 Tf [(disease and Huntingtons disease. Disab & Rehab 2009; 32:917-928.)] TJ ET BT 26.250 196.405 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 196.405 Td /F1 9.8 Tf [(Halliday GM, McRitchie DA, MacDonald V et al. Regional specificity of brain atrophy in Huntingtons disease. Exp Neurol )] TJ ET BT 26.250 184.500 Td /F1 9.8 Tf [(1998;154:663-672.)] TJ ET BT 26.250 165.096 Td /F1 9.8 Tf [(48.)] TJ ET BT 43.553 165.096 Td /F1 9.8 Tf [(Spargo E, Everall IP, Lantos PL. Neuronal loss in the hippocampus in Huntingtons disease: a comparison with HIV )] TJ ET BT 26.250 153.191 Td /F1 9.8 Tf [(infection. J Neurol Neurosurg & Psych 1993;56:487-491.)] TJ ET BT 26.250 133.786 Td /F1 9.8 Tf [(49.)] TJ ET BT 43.553 133.786 Td /F1 9.8 Tf [(Rosas HD, Koroshetz WJ, Chen YI et al. Evidence for more widespread cerebral pathology in early HD. Neurology )] TJ ET BT 26.250 121.881 Td /F1 9.8 Tf [(2003;60:1615-1620.)] TJ ET BT 26.250 102.477 Td /F1 9.8 Tf [(50.)] TJ ET BT 43.553 102.477 Td /F1 9.8 Tf [(Phillips W, Morton AJ, Barker RA. Abnormalities of neurogenesis in the R6/2 mouse model of Huntingtons disease are )] TJ ET BT 26.250 90.572 Td /F1 9.8 Tf [(attributable to the in vivo microenvironment. J Neurosci 2005; 25:11564-11576.)] TJ ET BT 26.250 71.167 Td /F1 9.8 Tf [(51.)] TJ ET BT 43.553 71.167 Td /F1 9.8 Tf [(Kitamura T, Mishina M, Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice )] TJ ET BT 26.250 59.262 Td /F1 9.8 Tf [(lacking NMDA receptor epsilon 1 subunit. Neurosci Res 2003;47:55-63.)] TJ ET Q q 15.000 49.381 577.500 727.619 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(29.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Grote HE, Bull ND, Howard ML et al. Cognitive disorders and neurogenesis deficits in Huntingtons disease mice are )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(rescued by fluoxetine. Eur J Neurosci 2005; 22:2081-2088.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(30.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Andreassen OA, Dedeoglu A, Ferrante RJ et al. Creatine increase survival and delays motor symptoms in a transgenic )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(animal model of Huntingtons disease. Neurobiol Dis 2001; 8:479-491.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(31.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Davies SW, Turmaine M, Cozens BA et al. Formation on neuronal intranuclear inclusions underlies the neurological )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(dysfunction in mice transgenic for the HD mutation. Cell 1997; 90: 537-548.)] TJ ET BT 26.250 666.048 Td /F1 9.8 Tf [(32.)] TJ ET BT 43.553 666.048 Td /F1 9.8 Tf [(Duan W, Peng Q, Masuda N et al. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse )] TJ ET BT 26.250 654.143 Td /F1 9.8 Tf [(model of Huntingtons disease. Neurobiol Dis 2008; 30:312-322.)] TJ ET BT 26.250 634.738 Td /F1 9.8 Tf [(33.)] TJ ET BT 43.553 634.738 Td /F1 9.8 Tf [(Peng Q, Masuda N, Jiang M et al. The antidepressant sertraline improves the phenotype, promotes neurogenesis and )] TJ ET BT 26.250 622.833 Td /F1 9.8 Tf [(increases BDNF levels in the R6/2 Huntington's disease mouse model. Exp Neurol 2008; 210:154-163.)] TJ ET BT 26.250 603.429 Td /F1 9.8 Tf [(34.)] TJ ET BT 43.553 603.429 Td /F1 9.8 Tf [(Kannangara TS, Lucero MJ, Gil-Mohapel J et al. Running reduces stress and enhances cell genesis in aged mice. )] TJ ET BT 26.250 591.524 Td /F1 9.8 Tf [(Neurobiol Aging 2010; Epub ahead of print.)] TJ ET BT 26.250 572.119 Td /F1 9.8 Tf [(35.)] TJ ET BT 43.553 572.119 Td /F1 9.8 Tf [(Carter RJ, Hunt MJ, Morton AJ Environmental stimulation increases survival in mice transgenic for exon 1 of the )] TJ ET BT 26.250 560.214 Td /F1 9.8 Tf [(Huntingtons disease gene. Mov Disord 2000; 15:925-937.)] TJ ET BT 26.250 540.810 Td /F1 9.8 Tf [(36.)] TJ ET BT 43.553 540.810 Td /F1 9.8 Tf [(Laviola G, Hannan AJ, Macri S et al. Effects of enriched environment on animal models of neurodegenerative diseases and )] TJ ET BT 26.250 528.905 Td /F1 9.8 Tf [(psychiatric disorders. Neurobiol Dis 2008; 31:159-168.)] TJ ET BT 26.250 509.500 Td /F1 9.8 Tf [(37.)] TJ ET BT 43.553 509.500 Td /F1 9.8 Tf [(Stranahan AM, Lee K, Mattson MP. Central mechanisms of HPA regulation by voluntary exercise. Neuromol Med 2008; )] TJ ET BT 26.250 497.595 Td /F1 9.8 Tf [(10:118-127.)] TJ ET BT 26.250 478.191 Td /F1 9.8 Tf [(38.)] TJ ET BT 43.553 478.191 Td /F1 9.8 Tf [(Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron )] TJ ET BT 26.250 466.286 Td /F1 9.8 Tf [(2009; 64:33-39.)] TJ ET BT 26.250 446.881 Td /F1 9.8 Tf [(39.)] TJ ET BT 43.553 446.881 Td /F1 9.8 Tf [(Esch T, Stefano GB, Fricchione GL, Benson H. The role of stress in neurodegenerative diseases and mental disorders. )] TJ ET BT 26.250 434.976 Td /F1 9.8 Tf [(Neuro Endocrinol Lett 2002; 23:199-208.)] TJ ET BT 26.250 415.572 Td /F1 9.8 Tf [(40.)] TJ ET BT 43.553 415.572 Td /F1 9.8 Tf [(Sotiropoulos I, Cerqueira JJ, Catania C et al. Stress and glucocorticoid footprints in the brain - The path from depression to )] TJ ET BT 26.250 403.667 Td /F1 9.8 Tf [(Alzheimers disease. Neurosci & Biobehav Rev 2008; 32:1161-1173.)] TJ ET BT 26.250 384.262 Td /F1 9.8 Tf [(41.)] TJ ET BT 43.553 384.262 Td /F1 9.8 Tf [(Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and )] TJ ET BT 26.250 372.357 Td /F1 9.8 Tf [(cognition. Nat Rev Neurosci 2009; 10:434-45.)] TJ ET BT 26.250 352.953 Td /F1 9.8 Tf [(42.)] TJ ET BT 43.553 352.953 Td /F1 9.8 Tf [(Lemaire V, Koehl M, Le Moal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of )] TJ ET BT 26.250 341.048 Td /F1 9.8 Tf [(neurogenesis in the hippocampus. Proc Natl Acad Sci U S A. 2000; 97:11032-7.)] TJ ET BT 26.250 321.643 Td /F1 9.8 Tf [(43.)] TJ ET BT 43.553 321.643 Td /F1 9.8 Tf [(Komitova M, Zhao LR, Gido G et al. Postischemic exercise attenuates whereas enriched environment has certain )] TJ ET BT 26.250 309.738 Td /F1 9.8 Tf [(enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur J Neurosci 2005; 21:2397-2405.)] TJ ET BT 26.250 290.334 Td /F1 9.8 Tf [(44.)] TJ ET BT 43.553 290.334 Td /F1 9.8 Tf [(Altschuler, EL. Strenuous, intensive, long-term exercise does not prevent or delay the onset of Huntingtons disease. Med )] TJ ET BT 26.250 278.429 Td /F1 9.8 Tf [(Hypoth 2006; 67:1429-1430.)] TJ ET BT 26.250 259.024 Td /F1 9.8 Tf [(45.)] TJ ET BT 43.553 259.024 Td /F1 9.8 Tf [(Kosinski CM, Schlangen C, Gellerich FN et al. Myopathy as a first symptom of Huntingtons disease in a marathon runner. )] TJ ET BT 26.250 247.119 Td /F1 9.8 Tf [(Mov Disord 2007;22:1637-1640.)] TJ ET BT 26.250 227.715 Td /F1 9.8 Tf [(46.)] TJ ET BT 43.553 227.715 Td /F1 9.8 Tf [(Quinn L, Busse, M, Khalil H et al. Client and therapist views on exercise programmes for early-mid stage Parkinsons )] TJ ET BT 26.250 215.810 Td /F1 9.8 Tf [(disease and Huntingtons disease. Disab & Rehab 2009; 32:917-928.)] TJ ET BT 26.250 196.405 Td /F1 9.8 Tf [(47.)] TJ ET BT 43.553 196.405 Td /F1 9.8 Tf [(Halliday GM, McRitchie DA, MacDonald V et al. Regional specificity of brain atrophy in Huntingtons disease. Exp Neurol )] TJ ET BT 26.250 184.500 Td /F1 9.8 Tf [(1998;154:663-672.)] TJ ET BT 26.250 165.096 Td /F1 9.8 Tf [(48.)] TJ ET BT 43.553 165.096 Td /F1 9.8 Tf [(Spargo E, Everall IP, Lantos PL. Neuronal loss in the hippocampus in Huntingtons disease: a comparison with HIV )] TJ ET BT 26.250 153.191 Td /F1 9.8 Tf [(infection. J Neurol Neurosurg & Psych 1993;56:487-491.)] TJ ET BT 26.250 133.786 Td /F1 9.8 Tf [(49.)] TJ ET BT 43.553 133.786 Td /F1 9.8 Tf [(Rosas HD, Koroshetz WJ, Chen YI et al. Evidence for more widespread cerebral pathology in early HD. Neurology )] TJ ET BT 26.250 121.881 Td /F1 9.8 Tf [(2003;60:1615-1620.)] TJ ET BT 26.250 102.477 Td /F1 9.8 Tf [(50.)] TJ ET BT 43.553 102.477 Td /F1 9.8 Tf [(Phillips W, Morton AJ, Barker RA. Abnormalities of neurogenesis in the R6/2 mouse model of Huntingtons disease are )] TJ ET BT 26.250 90.572 Td /F1 9.8 Tf [(attributable to the in vivo microenvironment. J Neurosci 2005; 25:11564-11576.)] TJ ET BT 26.250 71.167 Td /F1 9.8 Tf [(51.)] TJ ET BT 43.553 71.167 Td /F1 9.8 Tf [(Kitamura T, Mishina M, Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice )] TJ ET BT 26.250 59.262 Td /F1 9.8 Tf [(lacking NMDA receptor epsilon 1 subunit. Neurosci Res 2003;47:55-63.)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(11)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Huntington Disease)] TJ ET Q endstream endobj 455 0 obj << /Type /Page /Parent 3 0 R /Contents 456 0 R >> endobj 456 0 obj << /Length 3047 >> stream 0.271 0.267 0.267 rg q 15.000 668.072 577.500 108.929 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(52.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Cho SR, Benraiss A, Chmielnicki E et al. Induction of neostriatal neurogenesis slows disease progression in a transgenic )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(murine model of Huntington disease. J Clin Invest 2007;117:2889-2902.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(53.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Creer DJ, Romberg C, Saksida LM et al. Running enhances spatial pattern separation in mice. Proc Natl Acad Sci USA )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(2010;107:2367-2372.)] TJ ET BT 26.250 697.357 Td /F1 9.8 Tf [(54.)] TJ ET BT 43.553 697.357 Td /F1 9.8 Tf [(Morton AJ, Skillings E, Bussey TJ, Saksida LM. Measuring cognitive deficits in disabled mice using an automated )] TJ ET BT 26.250 685.452 Td /F1 9.8 Tf [(interactive touchscreen system. Nat Methods 2006;3:767.)] TJ ET Q q 15.000 668.072 577.500 108.929 re W n 0.271 0.267 0.267 rg BT 26.250 759.976 Td /F1 9.8 Tf [(52.)] TJ ET BT 43.553 759.976 Td /F1 9.8 Tf [(Cho SR, Benraiss A, Chmielnicki E et al. Induction of neostriatal neurogenesis slows disease progression in a transgenic )] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(murine model of Huntington disease. J Clin Invest 2007;117:2889-2902.)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(53.)] TJ ET BT 43.553 728.667 Td /F1 9.8 Tf [(Creer DJ, Romberg C, Saksida LM et al. Running enhances spatial pattern separation in mice. 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