Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
eNeuro. 2017 Sep 18;4(5). doi: 10.1523/ENEURO.0141-17.2017. eCollection 2017 Sep-Oct.
Behavioral testing is a critical step in assessing the validity of rodent models of neurodegenerative disease, as well as evaluating the efficacy of pharmacological interventions. In models of Huntington's disease (HD), a gradual progression of impairments is observed across ages, increasing the need for sensitive, high-throughput and longitudinal assessments. Recently, a number of automated systems have been developed to perform behavioral profiling of animals within their own home-cage, allowing for 24-h monitoring and minimizing experimenter interaction. However, as of yet, few of these have had functionality for the assessment of skilled motor learning, a relevant behavior for movement disorders such as HD. To address this, we assess a lever positioning task within the mouse home-cage. Animals first acquire a simple operant response, before moving to a second phase where they must learn to hold the lever for progressively longer in a rewarded position range. Testing with this paradigm has revealed the presence of distinct phenotypes in the YAC128 mouse model of HD at three early symptomatic time points. YAC128 mice at two months old, but not older, had a motor learning deficit when required to adapt their response to changes in task requirements. In contrast, six-month-old YAC128 mice had disruptions of normal circadian activity and displayed kinematic abnormalities during performance of the task, suggesting an impairment in motor control. This system holds promise for facilitating high throughput behavioral assessment of HD mouse models for preclinical therapeutic screening.
行为测试是评估神经退行性疾病啮齿动物模型有效性以及评估药物干预效果的关键步骤。在亨廷顿病 (HD) 模型中，随着年龄的增长，会观察到逐渐出现的损伤，这就需要进行敏感、高通量和纵向评估。最近，已经开发出许多自动化系统来在动物的自家笼中进行行为分析，从而实现 24 小时监测并最大程度减少实验人员的干预。然而，到目前为止，这些系统中很少有用于评估熟练运动学习的功能，而这是 HD 等运动障碍的相关行为。为了解决这个问题，我们在小鼠自家笼中评估了一个杠杆定位任务。动物首先习得一个简单的操作性反应，然后进入第二阶段，在这个阶段，它们必须学会在奖励位置范围内保持杠杆更长时间。使用这种范式进行测试，揭示了 YAC128 型 HD 小鼠模型在三个早期症状时间点存在不同的表型。两个月大但不超过两个月大的 YAC128 小鼠在需要适应任务要求变化时存在运动学习缺陷。相比之下，六个月大的 YAC128 小鼠的正常昼夜节律活动受到干扰，并且在执行任务期间表现出运动学异常，这表明其运动控制受损。该系统有望促进用于临床前治疗筛选的 HD 小鼠模型的高通量行为评估。
