Synaptic Circuit Organization of Motor Cortex

项目总结 感官引导的手臂和手的运动对日常生活的许多活动都是必不可少的。病理性的 损害调节这些行为的大脑皮层回路的过程是导致残疾的常见原因。至 为了更好地了解和治疗这些疾病，了解这些疾病的细胞机制将是重要的 电路。我们在前一次拨款期间的进展有助于阐明巡回电路的许多方面 初级运动皮质(M1)神经元在小鼠新皮质前肢区域的组织。然而，a 基本问题仍然知之甚少：前肢M1神经元是如何整合到功能中的 与初级躯体感觉皮质(S1)的细胞和回路的突触回路？这一点很重要 确定，因为尽管躯体感觉在控制运动方面的关键重要性很好 已建立的，在这个系统中调节感觉-运动整合的电路并不是很好的特征。我们的 工作假设是，前肢S1-M1电路是由其细胞类型特定的连接构成的 皮质和丘脑投射神经元支持前馈躯体感觉→运动信号 复杂但高度特异的多突触通路，导致皮质脊髓神经元的兴奋。定义 这一跨皮质环路的细胞成分将是阐明触觉信息如何 与运动皮质神经元沟通和整合，从而影响脊髓的皮质输出，在 流畅的、有意志的前肢动作的服务。我们提出了一个研究计划，以测试一系列 关于前肢S1-M1回路细胞组织的预测。总体目标是确定 调解前肢之间通信的关键远程兴奋电路连接的蜂窝基础 S1和M1，以及这些区域与丘脑的躯体感觉核和运动核之间的联系，尤其是 腹侧后核、后核和腹外侧核。为此，体内标记和体外光遗传- 电生理学方法将被用来系统地描绘细胞类型特定的连接 介导丘脑→皮质(Aim 1)、丘脑→皮质(Aim 2)和皮层→皮质(Aim 3)的信息传递 这个感应器运动电路。总体而言，我们认为，拟议的研究计划具有重大意义和创新性， 因为它将产生关于细胞/突触机制的基本新信息 在新皮质和丘脑细胞类型特定回路水平上的体感→运动转换， 从而了解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.