Department of Neurology, University of Southern California, Los Angeles, CA, 91007, United States.
Department of Neurology, University of Southern California, Los Angeles, CA, 91007, United States; Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, 91007, United States.
Neurobiol Dis. 2017 Sep;105:15-32. doi: 10.1016/j.nbd.2017.05.004. Epub 2017 May 11.
Depression, cognitive impairments, and other neuropsychiatric disturbances are common during the prodromal phase of Huntington's disease (HD) well before the onset of classical motor symptoms of this degenerative disorder. The purpose of this study was to examine the potential impact of physical activity in the form of exercise on a motorized treadmill on non-motor behavioral features including depression-like behavior and cognition in the CAG knock-in (KI) mouse model of HD. The CAG KI mouse model has a long lifespan compared to other HD rodent models with HD motor deficits emerging after 12months of age and thus provides the opportunity to investigate early life interventions such as exercise on disease progression. Motorized treadmill running was initiated at 4weeks of age (1h per session, 3 times per week) and continued for 6months. Non-motor behaviors were assessed up to 6months of age and included analysis of depression-like behavior (using the tail-suspension and forced-swim tests) and cognition (using the T-maze and object recognition tests). At both 4 and 6months of age, CAG KI mice displayed significant depression-like behavior in the forced swim and tail suspension tests and cognitive impairment by deficits in reversal relearning in the T-maze test. These deficits were not evident in mice engaged in treadmill running. In addition, exercise restored striatal dopamine D2 receptor expression and dopamine neurotransmitter levels both reduced in sedentary HD mice. Finally, we examined the pattern of striatal expression of mutant huntingtin (mHTT) protein and showed that the number and intensity of immunohistochemical staining patterns of intranuclear aggregates were significantly reduced with exercise. Altogether these findings begin to address the potential impact of lifestyle and early intervention such as exercise on modifying HD progression.
抑郁、认知障碍和其他神经精神障碍在亨廷顿病（HD）的前驱期很常见，远在这种退行性疾病出现典型运动症状之前。本研究的目的是研究以运动跑步机形式进行的身体活动对 CAG 敲入（KI）HD 小鼠模型中非运动行为特征（包括抑郁样行为和认知）的潜在影响。与其他具有 HD 运动缺陷的 HD 啮齿动物模型相比，CAG KI 小鼠模型具有较长的寿命，HD 运动缺陷在 12 个月后出现，因此为研究运动等早期生活干预措施对疾病进展的影响提供了机会。从 4 周龄开始进行电动跑步机跑步（每次 1 小时，每周 3 次），持续 6 个月。在 6 个月的年龄内评估非运动行为，包括抑郁样行为（使用尾部悬挂和强迫游泳测试）和认知（使用 T 迷宫和物体识别测试）的分析。在 4 个月和 6 个月时，CAG KI 小鼠在强迫游泳和尾部悬挂测试中表现出明显的抑郁样行为，在 T 迷宫测试中表现出认知障碍，反转学习能力下降。这些缺陷在进行跑步机跑步的小鼠中并不明显。此外，运动恢复了纹状体多巴胺 D2 受体的表达，而静止不动的 HD 小鼠中多巴胺神经递质水平降低。最后，我们检查了纹状体中突变亨廷顿蛋白（mHTT）蛋白的表达模式，并显示运动可显著减少核内聚集体的数量和免疫组织化学染色模式的强度。总之，这些发现开始探讨生活方式和早期干预（如运动）对改变 HD 进展的潜在影响。
