Synaptic Circuit Organization of Motor Cortex

项目摘要 手臂和手的感觉引导运动对于许多日常生活活动至关重要。病理 损害调节这些行为的皮层回路的过程是残疾的常见原因。到 为了更好地理解和治疗这些疾病，理解这些疾病的细胞机制将是重要的。 电路.我们在上一个资助期的进展有助于阐明电路的许多方面 小鼠新皮层前肢区域中初级运动皮层（M1）神经元的组织。但 一个基本的问题仍然知之甚少：前肢M1神经元是如何整合到功能性神经元中的？ 与初级躯体感觉皮层（S1）的细胞和回路的突触回路？这一点很重要 确定，因为虽然躯体感觉在控制运动中的重要性很好， 建立，在这个系统中介导感觉运动整合的电路没有得到很好的表征。我们 工作假设是，前肢S1-M1回路是由其细胞类型特异性连接配置的。 皮层和丘脑投射神经元支持前馈体感→运动信号沿着 复杂但高度特异性的多突触通路，导致皮质脊髓神经元的兴奋。定义 这种皮层回路的细胞成分将是阐明触觉信息如何 与运动皮层神经元通信并被其整合，以影响到脊髓的皮层输出， 流体意志前肢运动的服务。我们提出了一个研究计划，以测试一系列 关于前肢S1-M1回路的细胞组织的预测。总体目标是确定 介导前肢之间通信的关键长距离兴奋回路连接的细胞基础 S1和M1，以及这些区域与丘脑中的躯体感觉和运动核团之间，特别是 腹后、后和腹外侧核。为此，体内标记和离体光遗传学- 电生理学方法将用于系统地描绘细胞类型特异性连接 调节丘脑→皮质（Aim 1）、皮质→丘脑（Aim 2）和皮质→皮质（Aim 3）的通讯。 这个感觉运动回路总的来说，我们认为，拟议的研究计划是重要的和创新的， 因为它将产生关于细胞/突触机制的基本新信息， 在新皮层和丘脑的细胞类型特异性回路水平上的躯体感觉→运动转换， 因此也是关于前肢感觉运动功能的机械基础。

PROJECT SUMMARY Sensory-guided movements of the arms and hands are essential for many activities of daily living. Pathological processes that impair the cortical circuits mediating these behaviors are a common cause of disability. To better understand and treat these disorders, it will be important to understand the cellular mechanisms in these circuits. Our progress in the previous grant period has helped to elucidate many aspects of the circuit organization of primary motor cortex (M1) neurons in the forelimb area of mouse neocortex. However, a fundamental question remains poorly understood: how are forelimb M1 neurons integrated into functional synaptic circuits with the cells and circuits of primary somatosensory cortex (S1)? This is important to determine, because while the critical importance of somatosensation in controlling movements is well established, the circuits mediating sensorimotor integration in this system are not well characterized. Our working hypothesis is that the forelimb S1—M1 circuit is configured by the cell-type-specific connections of its cortical and thalamic projection neurons to support feedforward somatosensory→motor signaling along complex yet highly specific polysynaptic pathways, leading to excitation of corticospinal neurons. Defining the cellular components of this transcortical loop would be a major step toward elucidating how tactile information is communicated to and integrated by motor cortex neurons to influence cortical output to the spinal cord, in the service of fluid volitional forelimb movements. We propose a research program to test a series of predictions about the cellular organization of the forelimb S1—M1 circuit. The overall aim is to determine the cellular basis for key long-range excitatory circuit connections that mediate communication between forelimb S1 and M1, and between these areas and somatosensory and motor nuclei in the thalamus, particularly the ventral posterior, posterior, and ventrolateral nuclei. To this end, in vivo labeling and ex vivo optogenetic- electrophysiological methods will be used to systematically delineate the cell-type-specific connections mediating thalamus→cortex (Aim 1), cortex→thalamus (Aim 2), and cortex→cortex (Aim 3) communication in this sensorimotor circuit. Overall, the proposed research program is significant and innovative, we believe, because it will generate basic new information about the cellular/synaptic mechanisms underlying the somatosensory→motor transformations at the level of cell-type-specific circuits of the neocortex and thalamus, and thus about the mechanistic basis for sensorimotor functions of the forelimb.