Functional and anatomical characterization of the striosomal system

基底神经节位于运动和动机之间的关键界面。最大的纹状体 这些深层结构的结构，是来自上覆新皮层的输入的枢纽，是一个主要的 通过基底神经节输出核将输出分配到大脑的其他部分。该系统涉及一个 大范围的神经和神经精神疾病。它是由神经调质，包括 中脑的多巴胺，帕金森氏症患者缺乏。背侧纹状体，这个提议的重点， 接收来自黑质（SNc）的腹侧部的含多巴胺的输入。这个黑质纹状体 帕金森氏病中的回路退化，并且是运动行为和对运动的反应的主要控制器。 强化和动机控制。我们的目标是在拟议的研究是阐明生理和 解剖这个系统，重点是与这些控制机制有关的关键问题。一是我们 初步工作表明，纹状体的组织结构在解剖学上是不同的， 纹状体和周围的基质，在行为方面至关重要。纹状体从一个神经元接受选择性输入， 动机/情绪/情感相关的新皮层区域的限制集，并且是纹状体的主要来源。 神经元投射到对情绪和运动控制非常重要的SNc多巴胺神经元。这一证据 提示了纹状体的特殊功能，但这些功能是什么还不清楚。我们初步的和最近的 然而，研究表明，纹状体可能专门用于成本效益决策，其中成本 在任何情况下，我们都必须权衡利益，以便采取行动。这类决策 对生存至关重要，而且在许多神经精神疾病中受到干扰。我们建议在 目的1在新型基因工程小鼠中使用最先进的生理学和成像方法来测试 这一假说认为，纹状体是这种决策的基础。第二，我们的初步工作表明， 纹状体-SNc连接的显著解剖组织，表明纹状体可以发挥 对含有多巴胺的SNc神经元的强大控制。我们建议用新的方法来研究这个系统。 光遗传学和生理学实验结合解剖学的组合（目标2）。三是尽管 越来越多的证据表明，纹状体基质组织是一个根本重要的组织性质， 纹状体，这个组织是如何与临床上重要的纹状体输出通路的直接分裂相关的？ 而间接运动控制途径尚不清楚。我们的目标是填补这一空白， 工程小鼠允许在生理、成像和行为方面直接测试这种关系 实验决策和调度中成本效益平衡失调 在许多神经和神经精神疾病中是至关重要的， 从强迫症到精神病因此，所提出的实验直接与 NIMH的使命是了解、预防和治疗精神疾病。

The basal ganglia lie at the critical interface between movement and motivation. The striatum, the largest structure of these deep-lying structures, is a hub for inputs from the overlying neocortex and is a main distributor of output to other parts of the brain via basal ganglia output nuclei. This system is implicated in a large range of neurological and neuropsychiatric disorders. It is modulated by neuromodulators, including by dopamine from the midbrain, deficient in Parkinson's disease. The dorsal striatum, the focus of this proposal, receives dopamine-containing input from the pars compacta of the substantia nigra (SNc). This nigrostriatal circuit degenerates in Parkinson's disease, and is a major controller of both motor behavior and responses to reinforcement and to motivational control. Our goal in the proposed research is to elucidate the physiology and anatomy of this system, focusing on critical questions related to these control mechanisms. First, our preliminary work suggests that the organization of the striatum into anatomically distinct compartments, the striosomes and surrounding matrix, is crucial in terms of behavior. Striosomes receive selective input from a restricted set of motivation/mood/emotion-related neocortical regions and are a main origin of the striatal projection to the SNc dopamine-containing neurons so important for mood and motor control. This evidence suggests special functions for striosomes, but what these functions are is not clear. Our preliminary and recent work suggests, however, that striosomes may be specialized for cost-benefit decision-making, in which costs and benefits presented in any situation have to be weighed in order for us to act. This kind of decision-making is critical for survival and, moreover, is disturbed in a number of neuropsychiatric conditions. We propose in Aim 1 to use state-of-the-art physiological and imaging methods in novel genetically engineered mice to test the hypothesis that striosomes underlie such decision-making. Second, our preliminary work has shown a remarkable anatomical organization of the striosome-SNc connection, suggesting that striosomes could exert powerful control over dopamine-containing SNc neurons. We propose to examine this system with novel combinations of optogenetic and physiological experiments combined with anatomy (Aim 2). Third, despite mounting evidence that striosome-matrix organization is a fundamentally important organizing property of the striatum, how this organization relates to the clinically critical division of the striatal output pathways into direct and indirect movement-control pathways is not understood. We aim to fill this gap by using specially engineered mice allowing direct testing of this relationship in physiological, imaging and behavioral experiments. Disturbances in the balance between cost and benefit in decision-making and movement control are critical in a number of neurologic and neuropsychiatric disorders ranging from Parkinson's disease to obsessive-compulsive disorder to psychosis. Thus, the experiments proposed are directly related to the mission of the NIMH to understand, prevent and cure mental illness.