Functional and anatomical characterization of the striosomal system

基底节位于运动和动机之间的关键界面。纹状体，最大的纹状体 这些深层构造的结构，是来自上覆新皮质的输入的枢纽，也是主要的 通过基底节输出核向大脑其他部分输出的分配者。这一系统牵涉到一起 大范围的神经和神经精神障碍。它受神经调节剂的调节，包括通过 来自中脑的多巴胺，在帕金森氏症中缺乏。背侧纹状体，这项提议的重点， 从黑质致密部(SNc)接受含有多巴胺的输入。这个黑质纹状体 帕金森氏症中的回路退化，是运动行为和反应的主要控制器 强化和激励控制。我们在拟议的研究中的目标是阐明生理学和 剖析这一系统，着重于与这些控制机制相关的关键问题。首先，我们的 初步工作表明，纹状体被组织成解剖上不同的隔室，即 纹状体和周围的基质在行为方面是至关重要的。纹状体接受来自一种 一组受限的动机/情绪/情绪相关的新皮质区域，是纹状体的主要来源 向下丘脑多巴胺神经元的投射对情绪和运动控制非常重要。这一证据 提示纹状体具有特殊功能，但这些功能是什么还不清楚。我们的初步和最近的 然而，研究表明，纹状体可能专门用于成本效益决策，在这种决策中，成本 我们必须权衡在任何情况下提出的好处，才能采取行动。这样的决策 对生存至关重要，而且在一些神经精神疾病中受到干扰。我们建议在 目的1在新的基因工程小鼠中使用最先进的生理和成像方法来测试 这种假设认为纹状体构成了这种决策的基础。第二，我们的前期工作显示出 纹状体-SNC连接的显著解剖组织，表明纹状体可以发挥作用 对含有多巴胺的黑质神经元进行强大的控制。我们建议用新奇的方式来检验这个系统 光遗传学和生理学实验与解剖学相结合(目标2)。第三，尽管 越来越多的证据表明，纹状体-矩阵组织是一种根本上重要的组织属性 纹状体，这种组织如何与临床上将纹状体输出通路划分为直接的 而间接的运动控制途径还不清楚。我们的目标是通过使用特殊的 经过改造的小鼠可以直接在生理、成像和行为方面测试这种关系 实验。决策和运动控制中成本与收益平衡的干扰 在许多神经学和神经精神障碍中至关重要，从帕金森氏症到 从强迫症到精神病。因此，建议的实验直接与 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.