Functions of the Motor Cortical-Thalamic Circuit

 描述(申请人提供)：运动丘脑(VL)与初级运动皮质(M1)紧密相连，同时VL是小脑和基底节影响M1功能的主要通道。因此，VL位于脊椎动物运动控制系统的核心。这一方案中的实验将促进我们对这一基本但鲜有研究的M1-VL电路的基本理解。这些实验将把两个 对VL功能的看法：a)作为将从皮质下输入接收到的信息传输到M1的中继器，以及b)作为M1在动态生成运动指令方面与M1紧密相连的伙伴。现有证据表明，VL(VLP)的小脑受体部分近似于简单的“接力”观点，将来自小脑的信息传递到M1。关于VL的基底神经节受体部分(VLA)仍有很大的不确定性。我们的临时假设是，VLA的活动是由M1驱动的，但受到从基底节接收的抑制信号的影响或偏向。我们将使用在顺序手臂运动和手臂扰动任务中训练的非人类灵长类动物，这些任务被预测为区分VLP和VLA中神经元的活动。单个丘脑皮质神经元和皮质丘脑神经元参与手臂相关的M1-VL环路的成员将通过逆行识别来确定。植入M1或VLP和VLA的手臂相关部位的大电极将被用来诱发逆行尖峰，或者监测局部场电位(LFP)。VL和M1之间的信息流方向将使用LFP和SPEKE数据的格兰杰因果关系分析来估计。目标1将测试VLP和VLA内M1投射神经元的任务相关活动是否与当前理论预测的皮质下输入不同：VLP神经元可能编码运动学和目标适当的反馈信号，这与假设小脑在预测运动命令的感觉后果中的作用一致。相反，VLA神经元可能发出任务背景信号，这与基底神经节在上下文相关选择中的作用一致。目标2将确定M1中的皮质丘脑神经元是否向VLP和VLA传递不同的任务相关信息。对目标1和目标2的结果进行比较，将确定以VLP和VLA编码的任务信息是否可以用从M1传输到这些核的信息来解释。对目标1和目标2的LFP和SPEKE数据的格兰杰因果关系分析将决定M1和VLP/VLA之间的信息流方向。最后，目标3将检验VL中焦点失活对任务绩效的因果影响。VLP中的失活可能导致不依赖于任务情境的全局性共济失调样损伤，而VLA中的失活可能选择性地损害任务绩效的上下文相关调制。这个项目将阐明在帕金森氏病、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起中心作用的回路的基本功能。AIM 3具有特殊的意义，因为它将识别可能伴随着针对VLP和VLA的神经外科干预(即丘脑切开术和脑深部刺激)而产生的后遗症。

 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.