# Circuit-Inspired Strategies to Restore Basal Ganglia Function in Mouse Models of Parkinson’s Disease

> **NIH NIH R35** · CARNEGIE-MELLON UNIVERSITY · 2024 · $754,344

## Abstract

Project Summary
The external segment of the globus pallidus (GPe) is a neuronally diverse and highly interconnected nucleus
within the basal ganglia. Under conditions of low dopamine, plasticity in the GPe promotes the emergence of
pathological firing patterns that contribute to widespread basal ganglia dysfunction. In Parkinson’s disease (PD),
deep brain stimulation (DBS) in the GPe can alleviate motor symptoms, suggesting there is a mechanistic link
between neuronal dysfunction in the GPe and motor symptoms of PD. Using optogenetics to target neuronal
subpopulations in the GPe, we discovered that persistent behavioral rescue could be induced by interventions
that excited parvalbumin-expressing GPe neurons (PV-GPe) and inhibited Lim homeobox 6-expressing GPe
neurons (Lhhx6-GPe). Differences in the synaptic inputs onto these neuronal subpopulations enabled us to
develop a human-translatable electrical DBS protocol that could achieve the same cell-type specificity of
optogenetics. In parkinsonian mice, these circuit-inspired burst DBS protocols provided superior therapeutic
benefit over conventional protocols, extending the therapeutic duration for hours beyond the period of active
stimulation. We are now collaborating with neurosurgeons at Allegheny General in Pittsburgh to test the
therapeutic efficacy of circuit-inspired DBS protocols in humans. Results from in vivo physiological recordings
revealed that GPe interventions reverse parkinsonian pathophysiology in the basal ganglia for hours following
stimulation, raising the intriguing possibility that GPe interventions induce therapeutic plasticity that restores
circuit function in disease. This would represent a transformative advance in PD therapeutics. But a number of
questions still remain about how transient interventions in the GPe translate into long-lasting therapeutic effects
at the behavioral level. This proposal will use electrophysiological, optogenetic, and behavioral approaches to
identify the therapeutic mechanisms of persistent behavioral rescue by achieving three main goals: (1) We will
map the neural pathways required for persistent behavioral rescue, including testing an innovative hypothesis
that both motor and arousal circuits are involved (2) We will identify short-term and long-term effects of GPe
interventions on basal ganglia physiology, testing the hypothesis that GPe interventions drive therapeutic
plasticity in dopamine depleted mice, and (3) We will assess the therapeutic efficacy of GPe interventions
delivered at different stages of dopamine depletion on both motor and non-motor symptoms to further study the
neural circuits involved, as well as to advance preclinical testing of GPe interventions for continued therapeutic
development. These studies will advance the development of circuit-inspired approaches that repair, rather than
mask circuit dysfunction for long-term recovery of brain function in disease.

## Key facts

- **NIH application ID:** 10835123
- **Project number:** 5R35NS132213-02
- **Recipient organization:** CARNEGIE-MELLON UNIVERSITY
- **Principal Investigator:** Aryn Hilary Gittis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $754,344
- **Award type:** 5
- **Project period:** 2023-05-01 → 2031-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835123

## Citation

> US National Institutes of Health, RePORTER application 10835123, Circuit-Inspired Strategies to Restore Basal Ganglia Function in Mouse Models of Parkinson’s Disease (5R35NS132213-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10835123. Licensed CC0.

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