# Striatal Microcircuit Mechanisms of Tardive Dyskinesia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $397,876

## Abstract

Project Summary/Abstract
Long-term treatment with dopamine D2/D3 receptor antagonists (neuroleptics) often causes
involuntary orofacial movements (lip smacking, tongue protrusion), termed tardive dyskinesia
(TD). Once established, TD is often irreversible. Given the crucial role these medications play in
the treatment of psychiatric disease, as well as their common usage in gastrointestinal disorders,
migraine, and other conditions, TD is unfortunately quite common. However, we know very little
about the physiological underpinnings of its induction or expression. Longstanding theories focus
on D2 receptor blockade and upregulation, but many tools used to develop these theories cannot
distinguish between D2 and D3 receptors, nor the role of receptors expressed in multiple cell
types. For this reason, it is unclear which dopamine receptors are critical to the induction of TD.
In addition, existing studies implicate dopamine signaling in both acute and chronic responses to
neuroleptics, but few if any studies have measured dopamine release or the physiological activity
of its striatal targets in freely moving animals experiencing TD. To address some of these gaps in
our understanding of TD, the proposed project will use an established mouse model of TD, based
on chronic administration of haloperidol, in conjunction with cell type-specific genetic and
physiological tools. First, we will test the necessity for D2 or D3 receptors in the induction and
expression of TD, through targeted deletion in specific cell types. Second, we will test the role of
striatal dopamine release in the induction and expression of TD in freely moving mice, monitoring
dopamine with the fluorescent dopamine sensor, dLight and manipulating dopamine with
chemogenetics. Third, we will test the role of striatal projection neurons in TD by monitoring or
manipulating neural activity with cell type-specific electrophysiology and photometry, or
optogenetics. In these latter components, we will use a head-mounted selfie-cam and automated
behavior detection to identify individual dyskinetic mouth movements at high temporal resolution.
This last innovation will permit alignment of dyskinetic movements to striatal dopamine release
and neural activity. Through these efforts, we hope to test longstanding hypotheses regarding the
origins of TD, but moreover to identify the physiological correlates of individual dyskinetic
movements. We hope these findings will point to new areas for therapeutic development, but also
deepen our understanding of how striatal microcircuit function contributes to the control of
voluntary (versus involuntary) movement.

## Key facts

- **NIH application ID:** 10634474
- **Project number:** 1R01NS131276-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alexandra Nelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $397,876
- **Award type:** 1
- **Project period:** 2023-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10634474

## Citation

> US National Institutes of Health, RePORTER application 10634474, Striatal Microcircuit Mechanisms of Tardive Dyskinesia (1R01NS131276-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10634474. Licensed CC0.

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