A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice
A Touchscreen Motivation Assessment Evaluated in Huntington's Disease Patients and R6/1 Model Mice
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DOI：
10.3389/fneur.2019.00858
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发表时间：
2019-08-09
影响因子：
3.4
通讯作者：
Sahakian, Barbara J.
中科院分区：
文献类型：
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作者：
Heath, Christopher J.;O'Callaghan, Claire;Sahakian, Barbara J.
冷漠在许多神经精神疾病中普遍存在，但机制特征不佳，因此靶向治疗干预仍然难以捉摸。一个关键的障碍是缺乏经过验证的评估工具，以促进临床前疾病模型和患者之间有希望的发现的转化。冷漠是亨廷顿病的常见症状。由于其已建立的遗传基础和定义的动物模型的可用性，这种疾病提供了一个强大的翻译框架，用于将动机行为与潜在的神经生物学和理想的背景联系起来，以评估定量的翻译冷漠评估方法。因此，在这项研究中，我们的目的是证明使用触摸屏提供的渐进比例任务的有效性，以反映冷漠评估亨廷顿病患者和一个代表性的小鼠模型。为此，我们使用触摸屏提供的渐进比例任务评估了亨廷顿病患者（n = 23）和年龄匹配的健康对照组（n = 20），以及雄性R6/1小鼠（n = 23）和野生型对照组（n = 29）的冷漠样行为。评估的主要结果指标是断点，定义为任务参与停止前发出的最高触摸屏响应数量。发现患者和R6/1小鼠相对于其各自的对照组均表现出显著降低的断点，与冷漠样行为一致。这种表现也与两个物种的运动差异无关。这些数据证明了触摸屏传递的渐进比率任务在检测亨廷顿病的临床相关动机缺陷中的实用性。这种方法可以提供一个平台，从临床相关的机制的见解有关的动机症状，可以得出，并提供了一个有效的途径翻译有前途的临床前研究结果转化为可行的治疗干预措施。
Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.