Cortical Connectivity and Activity Changes in Motor Preparation and Execution in 6-OHDA-Lesioned Mice

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Project Summary – Project 1 Parkinsonian motor signs in rodents are frequently studied with dopamine depletion initiated by unilateral or bilateral 6-OHDA injections into the median forebrain bundle or striatum. The striatal dopamine loss leads to abnormal neuronal activity in elements of the basal ganglia-thalamocortical motor circuit, including an increase of beta frequency oscillations, increased bursting activities of neurons, increased synchrony between neurons, and changed spike rates. These changes are principally similar to those found in MPTP treated primates and human patients with Parkinson’s disease. The pathological activity patterns have been followed from their stria- tal origin to the globus pallidus, substantia nigra pars reticulata, and the subthalamic nucleus. An important gap in our understanding of the consequences of dopamine depletion is the lack of data concerning the neural pro- cessing in the parkinsonian condition in motor and premotor areas. Investigations into this issue require a cell type-specific analysis of neural activity in cortex, as the complex cortical microcircuitry leads to the expectation that different subtypes of neurons engage differentially in parkinsonian activity patterns. In this project, we lev- erage our ability to combine behavioral studies and mechanistic studies on the single-neuron level available in rodents to address the overall hypothesis that corticospinal projection neurons (CSNs) and STN projecting py- ramidal tract neurons (PT-STN) are differentially involved in parkinsonian activity patterns. About 1/3rd of PT- STN neurons also project to the spinal cord, but are expected to be a minority of CSNs and likely project to dif- ferent spinal cord targets. Under aim 1, we will address this hypothesis at the systems level by studying CSN and PT-STN activity in the caudal and rostral forelimb areas of mice (CFA and RFA, respectively) in relation to a locomotor task, response inhibition, and food reaching behavior in mice that are bilaterally dopamine-de- pleted through 6-OHDA injections into the dorsolateral striatum. To assess parkinsonian network activity pat- terns, we will employ cell type-specific voltage imaging with genetically expressed voltage indicators (GEVIs). Further, we will record single unit activities in CFA and RFA with chronically implanted silicon probes and opto- tagging of CSNs and PT-STN neurons. In aim 2, we will study the cellular basis of dysfunction in these cell types through brain slice recordings to uncover intrinsic and synaptic property changes. We will use computer modeling to determine the impact of the observed changes on the synaptic integration properties of both cell types. The planned studies are closely aligned with project 2 that addresses corticospinal neuron activity in the primate supplementary motor area and primary motor cortex following dopamine depletion with MPTP, with project 3 that examines changes in synaptic connectivity in the cortical network, and with project 4 that looks at oscillatory components in motor cortical activity in human Parkinson’s disease patients and behavioral perfor- mance in a response inhibition task.