# Connectome of Motor Corticofugal Neurons in Parkinsonian Monkeys

> **NIH NIH P50** · EMORY UNIVERSITY · 2023 · $455,000

## Abstract

Project Summary - Project 3
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.

## Key facts

- **NIH application ID:** 10695051
- **Project number:** 5P50NS123103-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Yoland Smith
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $455,000
- **Award type:** 5
- **Project period:** 2021-09-29 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695051

## Citation

> US National Institutes of Health, RePORTER application 10695051, Connectome of Motor Corticofugal Neurons in Parkinsonian Monkeys (5P50NS123103-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10695051. Licensed CC0.

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