# Project 3: Structural pathology of the motor thalamo-cortico-thalamic system in Parkinson's disease

> **NIH NIH P50** · EMORY UNIVERSITY · 2020 · $325,250

## Abstract

Project Summary – Project 3
Models of the activity changes in the basal ganglia-thalamocortical circuitry in Parkinson's disease have been
instrumental for the development of new surgical and pharmacologic antiparkinsonian therapies. However, it
has become clear that these models do not fully explain the complex alterations in the patterns of neuronal
activity and abnormal network oscillations in the parkinsonian brain. Especially, our knowledge of the
anatomical, functional, and pathological changes in the thalamocortical and corticothalamic systems in
Parkinson's disease is very limited. In conjunction with the functional studies of projects 1 and 2, and the
technical support of Core B, the proposed studies will help us to gain a detailed understanding of the
organization and pathology of the synaptic networks through which basal ganglia, thalamic and cortical
neurons interact. Our preliminary studies provide strong evidence that the synaptic microcircuits that mediate
the communication between the basal ganglia receiving portion of the thalamus and motor cortices display
significant pathology in the non-human primate model of Parkinson's disease. At the cortical level, a loss of
dendritic spines on projection neurons and a prominent decrease in the thalamic innervation of deep cortical
layers was found in M1 of MPTP-treated parkinsonian monkeys. Both findings are strong indicators of
pathologic disturbances of thalamocortical communication in parkinsonism. Interestingly, it appears that these
changes are particularly prominent in M1, suggesting that the network dysfunction is regionally specific.
Combined with recent electrophysiological data showing that the activity of corticospinal, but not corticostriatal,
neurons is disrupted in M1 of parkinsonian monkeys, we hypothesize that pathological changes in
thalamocortical synaptic connections may differentially affect corticospinal over corticostriatal neurons. Our
preliminary data also suggest that the relationships between the thalamus and motor cortices may be impaired
by synaptic changes at the thalamic level in parkinsonian monkeys, such that the synaptic connectivity of
cortical afferents with GABAergic interneurons and projection neurons is altered. In light of these preliminary
findings, we propose a series of morphological, neuropathological, and ultrastructural studies to further assess
and quantify the changes in the architecture of the thalamocortical and corticothalamic synaptic networks in
normal and MPTP-treated parkinsonian monkeys, as well as in normal and 6-OHDA-treated mice (for
comparisons with the studies in primates). The results of these studies will be of critical importance for our
understanding of the pathophysiology of parkinsonism, and will aid the interpretation of the functional data
obtained in the other projects.

## Key facts

- **NIH application ID:** 9975945
- **Project number:** 5P50NS098685-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Yoland Smith
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,250
- **Award type:** 5
- **Project period:** — → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975945

## Citation

> US National Institutes of Health, RePORTER application 9975945, Project 3: Structural pathology of the motor thalamo-cortico-thalamic system in Parkinson's disease (5P50NS098685-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975945. Licensed CC0.

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