# Striatal Neuroplasticity Mechanisms that Preserve Motor Behavior in a model of Parkinson’s Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $409,141

## Abstract

Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which loss of
dopamine (DA) leads to cognitive and motor impairments. Motor symptoms include
resting tremor, rigidity, altered gait, and bradykinesia. The DA precursor L-dopamine (L-
3, 4-dihydroxyphenyalanine) is the gold standard therapy, but it can lose efficacy and
produce dyskinesias. The work proposed in this grant application will focus on identifying
and characterizing synaptic and network level changes in the striatum that preserve motor
function in models of PD. Our preliminary data indicate that a transient elevation of
nigrostriatal DA triggers mechanisms of long-term plasticity that prevent the development
of motor impairments after induction of a dorsal striatal 6-hydroxydopamine model of PD.
To gain mechanistic insight into this form of plasticity, in Aim 1 we will perform a number
of experiments that address its induction and maintenance, including determining how
long the normalized motor behavior persists, whether DA receptor agonists (rather than
endogenous DA) are able to induce the neuroplasticity to normalize motor behavior, and
whether the plasticity occurs in other common and, in some cases, more complete models
of PD. Since motor behavior is strongly influenced by the balance of activity in striatal
direct and indirect pathway output neurons, the other two Aims of this grant application
will determine synaptic and circuit level changes in the striatal output neurons. In Aim2,
we will use electrophysiology to measure changes in the excitability of the striatal output
neurons and their connections to cortico- and thalamostriatal inputs, the major drivers of
striatal activity. In Aim 3, we will use in vivo calcium imaging to measure the activity
patterns of these two neuronal populations while monitoring motor behavior after
induction of the novel plasticity mechanism in the striatal PD model. Work described in
this proposal provides a rare and exciting opportunity to gain insight into how striatal DA
signaling and plasticity affect movement normally and in PD, and set the stage to identify
improved therapeutic approaches. Additionally, the work will lay the foundation for
investigation into similar dopamine-mediated neuroplasticity mechanisms that may exist
in other regions of the brain and affect the cognitive and emotional aspects of the disease.

## Key facts

- **NIH application ID:** 10475642
- **Project number:** 5R01NS082650-09
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** REBECCA P SEAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,141
- **Award type:** 5
- **Project period:** 2013-04-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475642

## Citation

> US National Institutes of Health, RePORTER application 10475642, Striatal Neuroplasticity Mechanisms that Preserve Motor Behavior in a model of Parkinson’s Disease (5R01NS082650-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475642. Licensed CC0.

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