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Project #3 (PI: Yoland Smith, Ph.D.): Connectome of Motor Corticofugal Neurons in Parkinsonian Monkeys

Overview

The loss of midbrain dopamine neurons in Parkinson’s disease (PD) induces complex anatomical and functional changes throughout the basal ganglia-thalamocortical circuitry and downstream targets. Although our understanding of neuronal activity changes in basal ganglia output nuclei and the subthalamic nucleus has increased significantly over the past decade, much remains to be known about the pathophysiology of the corticospinal system in the parkinsonian state. In this project, we provide strong preliminary evidence that there is a significant breakdown of the thalamocortical system and major changes in the morphology of pyramidal cells in the primary motor cortex (M1) and supplementary motor area (SMA) of monkeys that have been rendered parkinsonian with chronic administration of the neurotoxin MPTP.  Combined with findings from the literature suggesting that corticospinal neurons display abnormal activity in M1 of MPTP-treated parkinsonian monkeys, one of the hypotheses of our project is that corticospinal neurons in M1 and SMA undergo complex structural and morphological changes that hamper their synaptic connectivity with the thalamocortical afferents, thereby contributing to the dysregulation of functional connectivity between basal ganglia and motor cortices in parkinsonism. Another major roadblock that significantly limited progress in our understanding of the pathophysiology of motor cortices and the corticospinal system in PD has been the lack of reliable tools to study the full connectome of corticospinal neurons. Although conventional tracing studies have demonstrated that both M1 and SMA are enriched in a large variety of overlapping projection neurons that innervate a wide array of basal ganglia, thalamic, brainstem and spinal cord regions, the extent to which these projections originate from distinct or common neuronal populations remains largely unknown, or relies on data gathered from small samples of identified pyramidal neurons.

In this project, we will take advantage of the unique and highly efficient retrograde transport properties of a newly developed designer variant of adeno-associated virus to map and compare the connectome of corticospinal neurons between control and parkinsonian monkeys. Because the behavioral functions of specific subtypes of corticofugal neurons derive from their complex output projection patterns, not just their final termination site, an in-depth knowledge of the axonal branching pattern of corticospinal axons in normal and parkinsonian states is of utmost significance in our understanding of the pathophysiology of cortical outflow in Parkinson’s disease. Together with functional studies proposed in the other projects of this application, our findings will lay the foundation for the development of new therapeutic approaches, such as chemogenetic methods, to directly manipulate the activity of specific subsets of corticospinal neurons in PD.                     

Link to Dr. Smith's Recent Publications