# Corticosubthalamic Plasticity in the Parkinsonian State

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $682,102

## Abstract

ABST RACT
In current schemes of the pathophysiology of Parkinson’s disease (PD), neuronal activity changes in the sen-
sorimotor region of the subthalamic nucleus (STN) play a central role in the development of parkinsonism. Until
recently, the changes in STN activity were thought to result solely from reduced inhibition from the external
globus pallidus (GPe). However, recent findings from animal models of advanced parkinsonism have suggested
that a profound loss of glutamatergic cortico-subthalamic terminals and an increased strength of GABAergic
pallidosubthalamic synapses may contribute to activity changes in the STN and to the development of parkin-
sonism. Our preliminary data demonstrate that a loss of cortico-subthalamic terminals is also present in the
sensorimotor STN territory of people with advanced PD. It remains unclear, however, how these anatomical and
physiologic changes relate to the degree of nigrostriatal dopamine loss and to the expression of parkinsonism.
Further, it is unknown if these changes also affect non-motor regions of the STN, perhaps contributing to cogni-
tive or affective PD symptoms. We will examine these issues with neuropathological and electrophysiological
studies in monkeys with different degrees of MPTP-induced dopamine loss (Aim 1), and with longitudinal 7T
ultra-high field MRI studies in people with early PD (Aim 2). In Aim 1, we will record responses of STN neurons
to optogenetic activation of cortical and pallidal inputs in monkeys that remained either asymptomatic after ex-
posure to small dose of the dopamine-depleting neurotoxin MPTP or became parkinsonian after exposure to
(larger doses of) MPTP. We will also assess changes in local field potentials (LFPs) and abnormal spiking
activity in STN, and in the coherence between STN LFPs and motor cortical electrocorticograms. In postmortem
studies of the same animals, we will use high resolution microscopic immunohistochemical studies and 3D-EM
reconstructions to assess whether the number, localization, and morphology of glutamatergic and GABAergic
synapses in the STN changes as a function of dopamine loss. We will also compare the number of cortico-
subthalamic terminals and examine changes in GABAergic markers in STN tissue from patients with PD and
age-matched controls. In Aim 2, we will use state-of-the-art diffusion and resting state functional MRI to test
whether humans with early stage PD exhibit significant changes in the volume and microstructural organization
of the STN and its cortical and pallidal afferents, and determine if these changes are related to the expression
and progression of motor and non-motor impairments. The same patients will be studied at enrollment and 30
months later to examine changes in the MRI measures. The results of this project will increase our understanding
of the temporal evolution of parkinsonism-associated plastic changes in the STN, and determine their potential
relationships to the development and severity of mo...

## Key facts

- **NIH application ID:** 10477285
- **Project number:** 5R01NS113746-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** NOAM HAREL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $682,102
- **Award type:** 5
- **Project period:** 2019-09-18 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477285

## Citation

> US National Institutes of Health, RePORTER application 10477285, Corticosubthalamic Plasticity in the Parkinsonian State (5R01NS113746-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477285. Licensed CC0.

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