Optogenetic control of neuronal pathways that mediate repetitive behavior

项目摘要 限制性的重复行为是指包括刻板动作在内的多种行为类别， 强迫和仪式重复行为是自闭症谱系障碍（ASD）的诊断， 在综合征型和非综合征型智力和发育残疾（IDD）中普遍存在，在 某些神经系统疾病（如图雷特综合征、额颞叶痴呆）。尽管其临床 重要的是，缺乏对重复行为的有效干预，至少部分原因是， 对调节这种行为的相关神经回路的初步了解。离散神经网络 控制重复行为的通路是确定神经生物学机制和发展的关键。 有效的治疗。我们先前的工作，使用两个重复行为的小鼠模型，已经确定了皮质- 基底神经节电路失调，特别是与以下相关的大脑区域中的神经元活化减少 间接基底神经节通路。然而，缺乏的是离散基底神经节的直接证据 控制重复行为表达的投射。因此，本项目的总体目标是 确定控制重复行为的特定皮质基底神经节通路。我们将测试两个假设： 通过丘脑底核（subthalamic nucleus，简称STN）的去抑制来激活间接基底神经节通路， 显著并迅速减少重复行为，抑制超直接途径将加剧 重复的行为为了测试这些假设，我们将采用体内光遗传学来操纵， 必要的时间和空间分辨率，关键功能电路假设调解表达 重复的行为。使用这种方法，我们建议直接测试的重要性，间接和 超直接基底神经节通路介导重复行为。这将使用近交系小鼠完成 菌株（C58）表现出良好特征的、稳健的重复行为表型。剥离基底动脉 控制重复行为表达的神经节回路将是创新和有影响力的，并指导 开发涉及异常重复行为的疾病的新治疗方法。

Project Summary Restricted, repetitive behavior refers to multiple behavioral categories that include stereotyped movements, compulsions, and rituals. Repetitive behavior is diagnostic for autism spectrum disorders (ASD), highly prevalent in syndromic and non-syndromic intellectual and developmental disability (IDD), and common in certain neurological disorders (e.g. Tourette syndrome, fronto-temporal dementia). Despite its clinical importance, effective interventions for repetitive behavior are lacking owing, at least in part, to only a rudimentary understanding of the relevant neural circuitry mediating such behavior. Identifying discrete neural pathways controlling repetitive behaviors is key to determining neurobiological mechanisms and developing effective treatments. Our prior work, using two mouse models of repetitive behavior, has identified cortico- basal ganglia circuitry dysregulation, specifically decreased neuronal activation in brain areas associated with the indirect basal ganglia pathway. What is lacking, however, is direct evidence of discrete basal ganglia projections that control the expression of repetitive behavior. Thus, the overall goal of this project is to determine specific cortical basal ganglia pathways that control repetitive behavior. We will test two hypotheses: activation of the indirect basal ganglia pathway via disinhibition of the subthalamic nucleus (STN) will significantly and rapidly reduce repetitive behavior and inhibition of the hyperdirect pathway will exacerbate repetitive behavior. To test these hypotheses, we will employ in vivo optogenetics to manipulate, with the requisite temporal and spatial resolution, the critical functional circuitry hypothesized to mediate the expression of repetitive behavior. Using this approach, we propose to test directly the importance of the indirect and the hyperdirect basal ganglia pathways in mediating repetitive behavior. This will be done using an inbred mouse strain (C58) that exhibits a well-characterized, robust repetitive behavior phenotype. Dissecting the basal ganglia circuitry controlling the expression of repetitive behavior will be innovative and impactful and guide the development of novel treatments in disorders involving aberrant repetitive behavior.