# Circuit Mechanisms of Bradykinesia in Mouse Models of Parkinson’s Disease

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $254,250

## Abstract

PROJECT SUMMARY
The degeneration of dopamine (DA) neurons within the basal ganglia (BG) causes Parkinson's disease (PD).
One of its cardinal symptoms is the slowing of volitional movements of the hands, arms and/or legs, known as
bradykinesia. Although much has been learned over the past several decades about the physiological
consequences of DA neuron loss on the activity of neurons within the BG, much less in understood about how
dysfunction of the BG ultimately impacts downstream brain regions to impair motor and cognitive abilities. Our
long-term goal is to address this gap in knowledge in the hopes of identifying novel therapies to alleviate PD’s
motor and non-motor symptoms. This exploratory R21 proposal represents the first step in this endeavor: it aims
to distinguish the relative contribution of two main neural projections out of the BG – one feeding back to cortex
via the thalamus vs. one feeding forward to brainstem nuclei – to bradykinesia. This proposal leverages a
combination of imaging and optogenetic manipulations in mice performing a dexterous forelimb motor task before
and after DA neuron lesions with 6-hydroxydopamine. Our experiments will test the hypothesis that bradykinesia
results from impairments in BG feedback to cortex via thalamus by comparing and contrasting the activity of BG
output neurons in the substantia nigra pars reticulata (SNr) that project to thalamus or brainstem using axonal
Ca2+ photometry (Aim 1) and by testing the ability of BG efferents to restore vigorous forelimb movements using
optogenetic manipulations (Aim 2). We will benchmark our findings to levodopa treatment to concentrate on
therapeutically-effective pathways and validate them in a mouse genetic model of PD in which DA neurons
degenerate progressively. Our findings will deepen our understanding of the mechanistic underpinnings of PD’s
symptoms and stimulate investigations into novel, DA-independent therapeutic targets outside the BG to provide
effective and continued symptomatic relief from motor impairments.

## Key facts

- **NIH application ID:** 10888580
- **Project number:** 1R21NS133640-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Un Jung Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2024-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888580

## Citation

> US National Institutes of Health, RePORTER application 10888580, Circuit Mechanisms of Bradykinesia in Mouse Models of Parkinson’s Disease (1R21NS133640-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10888580. Licensed CC0.

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