# CIRCUIT MECHANISMS UNDERLYING LONG-LASTING RECOVERY OF MOVEMENT IN DOPAMINE DPELETED MICE INDUCED BY OPTOGENETIC INTERVENTION IN THE GPe

> **NIH NIH R01** · CARNEGIE-MELLON UNIVERSITY · 2021 · $336,821

## Abstract

Abstract
A major challenge in the treatment of neurological diseases is the elaborate and diffuse nature of neural
circuits, where physically proximal neurons are engaged in functionally different pathways. The ability to target
neurons based on function, rather than location, is critical to improving treatments for disease. In Parkinson's
disease, improved treatments have been driven by the discovery of cell type diversity in the striatum, providing
access to functionally opposing circuits: the direct and indirect pathways. However, with the exception of
neuronal diversity in the striatum, all other downstream nuclei in the basal ganglia are depicted as
homogeneous relay nuclei, an oversimplification whose limits are increasingly apparent as techniques to study
circuit function become more sophisticated. Recently, my lab has pioneered the use of transgenic mouse lines
to subdivide neurons in the external globus pallidus (GPe) into subpopulations that differ in anatomy and
electrophysiological properties. Leveraging tools to optogenetically manipulate these genetic subpopulations,
we are now in position to discover their contributions to behavior. In a recent study, we found that optogenetic
interventions targeted to particular subpopulations in the GPe (but not global stimulation of the entire nucleus)
restores motor function in acutely dopamine depleted mice, and the effects persisted for hours after
stimulation. This finding challenges long-standing models of circuit organization in the basal ganglia and has
relevance for PD, where current interventions provide only transient relief of motor symptoms that rapidly
return once stimulation stops. Experiments in this proposal will test the ability of GPe interventions to rescue
movement in a chronic dopamine depletion model (Aim 1) and will elucidate the pathways through which GPe
subpopulations mediate their effects (Aim 2). Aim 1, will use optogenetics and in vivo recordings to assess the
impact of modulating genetically-defined neuronal subpopulations on local circuit dynamics in the GPe and
their effects on behavior. Specifically, we will test the hypothesis that recovered movements following
optogenetic stimulation are goal-directed and restore the ability of mice to seek out food, social interactions,
and avoid anxiety-provoking environments. In Aim 2, we will use in vivo recordings, coupled with viral-assisted
circuit mapping, to elucidate the pathways through which neuronal subpopulations in the GPe exert their
prokinetic effects on movement. Our preliminary data suggest that therapeutic interventions share a common
mechanism of reversing pathological firing patterns in the substantia nigra reticulata (SNr), the primary basal
ganglia output nucleus in rodents. Our proposed experiments will determine whether this effect is mediated by
direct projections of GPe neurons to the SNr, or whether it is mediated through a disynaptic pathway involving
the subthalamic nucleus (STN). Combined, result...

## Key facts

- **NIH application ID:** 10069409
- **Project number:** 5R01NS101016-04
- **Recipient organization:** CARNEGIE-MELLON UNIVERSITY
- **Principal Investigator:** Aryn Hilary Gittis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,821
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10069409

## Citation

> US National Institutes of Health, RePORTER application 10069409, CIRCUIT MECHANISMS UNDERLYING LONG-LASTING RECOVERY OF MOVEMENT IN DOPAMINE DPELETED MICE INDUCED BY OPTOGENETIC INTERVENTION IN THE GPe (5R01NS101016-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10069409. Licensed CC0.

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