Functions of the Motor Cortical-Thalamic Circuit

 描述（由申请人提供）：运动丘脑（VL）与初级运动皮层（M1）紧密相连，同时，VL是小脑和基底神经节影响M1功能的主要通道。因此，VL是脊椎动物运动控制系统的核心。本提案中的实验将推进我们对这种基本但研究较少的M1-VL电路的基本理解。实验将对比两个 VL功能视图：a）作为将从皮层下输入接收到的信息传输到M1的中继器，以及B）作为在运动指令的动态生成中与M1紧密互连的伙伴。现有证据表明VL的小脑受体部分（VLp）近似于简单的“中继”观点，将小脑来源的信息传递给M1。关于VL的基底节受体部分（VLa）仍然存在很大的不确定性。我们的临时假设是，在VLa的活动是由M1驱动，但雕刻或偏见的抑制信号从基底神经节。我们将使用非人类灵长类动物训练的顺序手臂运动和手臂扰动的任务，预计区分VLp和VLa的神经元的活动。将通过逆向识别来确定单个丘脑-皮质和皮质-丘脑神经元对臂相关M1-VL回路的成员资格。在M1或VLp和VLa的手臂相关部位植入宏电极，将用于诱发逆行尖峰，或者监测局部场电位（LFP）。将使用LFP和尖峰数据的格兰杰因果关系分析估计VL和M1之间的信息流方向。目的1将测试是否任务相关的活动M1投射神经元在VLp和VLa不同，目前的理论将预测从皮层下的输入收到：VLp神经元可能编码运动学和目标适当的反馈信号，与小脑在预测运动命令的感觉后果的作用假设一致。VLa神经元可能反而发出任务上下文的信号，这与基底神经节在上下文依赖性选择中的作用一致。目的二是研究M1区皮质丘脑神经元是否向VLp和VLa传递不同的任务相关信息。目标1和2的结果的比较将确定VLp和VLa中编码的任务信息是否可以通过从M1传输到这些核的信息来解释。目标1和2的LFP和尖峰数据的格兰杰因果关系分析将确定M1和VLp/VLa之间的信息流方向。最后，目标3将测试VL中局灶性失活对任务表现的因果影响。VLp的失活可能会导致独立于任务上下文的全局共济失调样损伤，而VLa的失活可能会选择性地损害上下文相关的任务性能调制。这个项目将阐明一个电路的基本功能，这个电路是帕金森氏病、肌张力障碍、特发性震颤和共济失调等运动障碍的病理生理学中的一个中心。目标3具有特殊意义，因为它将识别可能伴随神经外科干预的后遗症（即，丘脑切开术和深部脑刺激）。

 DESCRIPTION (provided by applicant): The motor thalamus (VL) is densely interconnected with the primary motor cortex (M1) and, at the same time, VL serves as the main gateway by which cerebellum and the basal ganglia influence M1 function. Thus, VL lies at the heart of the vertebrate motor control system. The experiments in this proposal will advance our basic understanding of this essential but little-studied M1-VL circuit. The experiments will contrast two views of VL function: a) as a relay that transmits to M1 the information received from sub-cortical inputs, and b) as a closely interconnected partner with M1 in the dynamic generation of motor commands. Available evidence suggests that the cerebellar-recipient part of VL (VLp) approximates the simple "relay" view, transmitting cerebellum- derived information to M1. A great deal of uncertainty remains regarding the basal ganglia-recipient part of VL (VLa). Our provisional hypothesis is that activity in VLa is driven by M1, but sculpted or biased by the inhibitory signals received from the basal ganglia. We will use non-human primates trained on sequential arm movement and arm perturbation tasks that are predicted to differentiate the activity of neurons in VLp and VLa. The membership of individual thalamo-cortical and cortico-thalamic neurons to an arm-related M1-VL circuit will be determined by antidromic identification. Macroelectrodes implanted at arm-related sites in M1, or in VLp and VLa, will be used to evoke antidromic spikes and, alternatively, to monitor local field potentials (LFPs). The direction of information flow between VL and M1 will be estimated using a Granger causality analysis of LFP and spike data. Aim 1 will test whether the task-related activity of M1-projecting neurons in VLp and VLa differ as current theory would predict from the subcortical inputs received: VLp neurons may encode kinematics and goal-appropriate feedback signals, consistent with the role hypothesized for cerebellum in predicting sensory consequences of motor commands. VLa neurons may instead signal task context, consistent with a role for the basal ganglia in context-dependent selection. Aim 2 will determine if cortico-thalamic neurons in M1 transmit different task-related information to VLp and VLa. A comparison of the results from Aims 1 and 2 will determine if the task information encoded in VLp and VLa can be explained by the information transmitted to those nuclei from M1. Granger causality analyses of LFP and spike data from Aims 1 and 2 will determine the direction of information flow between M1 and VLp/VLa. Finally, Aim 3 will test the causal influence on task performance of focal inactivations in VL. Inactivations in VLp may induce global ataxia-like impairments independent of task context whereas inactivations in VLa may selectively impair context-dependent modulations of task performance. This project will shed light on the basic functions of a circuit that is a central plaer in the pathophysiology of disorders of movement such as Parkinson's disease, dystonia, essential tremor and ataxia. Aim 3 has particular significance because it will identify sequelae that may accompany neurosurgical interventions (i.e., thalamotomy and deep brain stimulation) that target the VLp and VLa.