Functions of the Motor Cortical-Thalamic Circuit

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 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.