Optogenetic control of neuronal pathways that mediate repetitive behavior

项目摘要 受限的重复行为指的是包括刻板印象的动作的多种行为类别， 强迫症和仪式。重复行为是自闭症谱系障碍(ASD)的高度诊断 流行于症状性和非症状性智力和发育障碍(IDD)，常见于 某些神经系统疾病(如抽动症、额-颞叶痴呆)。尽管它在临床上 重要的是，对重复行为的有效干预是缺乏的，至少部分原因是 对调节这种行为的相关神经回路有初步的了解。离散神经网络的辨识 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 有效的治疗方法。我们之前的工作，使用了两种重复行为的小鼠模型，已经确定了皮质- 基底节回路失调，特别是与以下相关的脑区神经元激活减少 间接基底节通路。然而，缺乏离散的基底节的直接证据。 控制重复行为表达的投射。因此，这个项目的总体目标是 确定控制重复行为的特定皮质基底节通路。我们将检验两个假设： 通过去抑制丘脑底核(STN)激活间接基底节通路将 显著而迅速地减少重复行为和抑制超直接通路将加剧 重复的行为。为了验证这些假说，我们将使用活体光遗传学来操纵， 必要的时间和空间分辨率，假设为调节表达的关键功能电路 重复的行为。使用这种方法，我们建议直接测试间接和 在调节重复行为中的超直接基底节通路。这将使用近亲交配的小鼠来完成 菌株(C58)，表现出良好的特性，健壮的重复行为表型。解剖基底骨 控制重复行为表达的神经节回路将是创新和有效的，并引导 涉及异常重复行为障碍的新治疗方法的开发。

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.