Characterization and connectomics of striatal interneurons

项目总结/摘要 纹状体是基底神经节的主要输入结构，这一系统不仅对自主神经系统至关重要， 运动控制，但也用于认知介导的学习和更高的认知功能。的重要性 纹状体表现为与许多神经和神经病相关的严重残疾， 影响这种大脑结构的疾病 最近引进的基因和生理上的靶向和操纵方法 细胞类型的定义正在彻底改变我们对新纹状体的理解。我们的初步研究， 最近的研究表明，传统的已知细胞类型占不到三分之一， 纹状体中的中间神经元类，并揭示了这些神经元的复杂和精确组织的回路。 神经元该研究将测试4个新的假设，这些假设是在初步研究的基础上提出的。 数据和捕获纹状体中间神经元网络组织的功能重要原则。 首先，我们将研究遗传鉴定的中间神经元的连接性，并测试以下假设： 它们的连接是高度细胞类型特异性的，并且被构造成形成至少2个独立的中间神经元亚细胞， 新纹状体内的网络。其次，基于我们以前的研究和新的初步数据， 假设胆碱能中间神经元（CIN），传统上被认为是 神经调节元件，参与快速双向突触网络与多种GABA能 利用烟碱兴奋性连接的中间神经元。重要的是，我们的初步数据还表明， 存在一种来自脑干的烟碱兴奋的新来源，该来源似乎选择性地靶向一种独特的 GABA能中间神经元的子集。第三，我们将检验一个假设，即中间神经元的子集是 存在一类或多类中间神经元，它们专门 控制其他中间神经元的活动。这些中间神经元特异性的中间神经元非常有趣，因为 它们的影响可能会广泛分布，并通过对其他组织的分级控制而被放大。 中间神经元。最后，基于初步数据，我们假设一类新的GABA能中间神经元 是正常的目标导向行为所必需的，我们将探讨这些神经元的作用机制。 使用体内电生理学和Ca 2+成像方法。这些实验将产生重要的新成果 深入了解纹状体的功能，并可能有助于确定新的细胞基质， 在各种神经和神经精神疾病的干预。

Project Summary/Abstract The striatum is the main input structure of the basal ganglia, a system that is crucial not only for voluntary motor control, but also for reinforcement-mediated learning and higher cognitive functions. The importance of the striatum is illustrated by the severe disabilities associated with numerous neurological and neuropsy- chiatric conditions that affect this brain structure. The recent introduction of methods for targeting and manipulating genetically and physiologically defined cell types is currently revolutionizing our understanding of the neostriatum. Our preliminary studies, together with recent research demonstrate that the classically known cell types represent less than a third of the interneuron classes in the striatum, and reveal an intricate and precisely organized circuitry of these neurons. The prosed study will test 4 novel hypotheses which were formulated on the basis of preliminary data and capture functionally important principles of organization of the network of striatal interneurons. First, we will investigate the connectivity of genetically identified interneurons and test the hypotheses that their connectivity is highly cell type specific and structured to form at least 2 separate interneuron sub- networks within the neostriatum. Second, building on our previous research and novel preliminary data we hypothesize that cholinergic interneurons (CINs), which traditionally have been thought of as neuromodulatory elements, participate in a fast bi-directional synaptic network with multiple GABAergic interneurons utilizing nicotinic excitatory connections. Importantly, our preliminary data also suggest the existence of a novel source of nicotinic excitation from the brainstem that appears to selectively target a distinct subset of GABAergic interneurons. Third, we will test the hypothesis that a subset of interneurons are hierarchically organized in the sense that one or more classes of interneurons exist which are specialized to control the activity of other interneurons. These interneuron-specific interneurons are of great interest because their impact may be widely distributed and disproportionally amplified via hierarchical control of other interneurons. Finally, based on preliminary data we hypothesize that a class of novel GABAergic interneurons are essential for normal goal-directed behavior, and we will explore the mechanism of action of these neurons using in vivo electrophysiological and Ca2+-imaging methods. These experiments will yield important new insights into the functioning of the striatum and may help to identify new cellular substrates for therapeutic interventions in a variety of neurological and neuropsychiatric disorders.