# The Role of Striatal Cholinergic Interneurons in Dystonia

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $598,438

## Abstract

PROJECT SUMMARY
There is a fundamental gap in understanding the pathophysiology of isolated adult-onset dystonia due to
genotypic and phenotypic heterogeneity. Determining common pathophysiologic mechanisms across dystonia
subtypes is a critical step toward developing more generalizable and effective therapies. Emerging evidence
points to striatal cholinergic interneurons (ChIs) playing a key role in the pathophysiology of dystonia, including
biochemical and network-level dysfunction. In addition to offering a common therapeutic target, our findings
are likely to benefit gene discovery and research on other disabling, less common forms of dystonia. Over the
long term, results could guide researchers to perform greater in depth histopathological and biochemical studies
in the brain that can lead to identification of new targets for therapeutic intervention. Our goal is to apply a
recently developed PET radioligand, [18F]VAT, which possesses high selectivity for vesicular acetylcholine
transporters, to investigate striatal ChIs. Structural and resting state functional MRI will examine the
relationship of striatal ChIs to related brain networks across different focal dystonia subtypes. Identification of
network-level changes across dystonia subtypes will provide better understanding of common pathophysiology
and could potentially provide means to assess target engagement for future therapeutic interventions. The
central hypothesis is that striatal ChIs contribute to a common pathophysiological mechanism in humans with
isolated adult-onset focal dystonia, and that cholinergic integrity relates to striatal functional connectivity and
clinical features of dystonia. The rationale for the proposed research is the likely involvement of striatal ChIs in
a) normal motor control and b) animal models of dystonia. ChIs are autonomously active and mediate a baseline
presynaptic inhibitory tone on striatal medium spiny neurons against the excitatory cortical drive, likely via
modulation of dopamine release via presynaptic cholinergic receptors on nigrostriatal dopaminergic terminals.
They also receive input from intralaminar thalamic neurons innervated by cerebellar afferents, that when
dysfunctional may contribute to dystonic phenotypes. Thus, ChIs may contribute to a common pathogenic
mechanism involving cortico-striata-thalamic or cerebello-thalamo-striatal networks. This hypothesis will be
tested by pursuing three specific aims: Determine if 1) dysfunction of striatal ChIs is a common
mechanism across isolated dystonia subtypes; 2) common aberrations in functional striatal
brain networks underlie the isolated dystonia subtypes; 3) clinical characteristics relate to
markers of ChIs and brain network dysfunction across different isolated adult-onset focal
dystonias. This approach is innovative as it uses comprehensive multimodal imaging to investigate novel PET-
measured cholinergic integrity and related functional networks. The proposed research is significan...

## Key facts

- **NIH application ID:** 10754853
- **Project number:** 5R01NS124789-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Scott Allen Norris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,438
- **Award type:** 5
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754853

## Citation

> US National Institutes of Health, RePORTER application 10754853, The Role of Striatal Cholinergic Interneurons in Dystonia (5R01NS124789-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10754853. Licensed CC0.

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