# Development of an Animal Model of Task Specific Dystonia

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $429,791

## Abstract

ABSTRACT
The circuit mechanisms that cause dystonia are poorly understood. A prominent hypothesis is that dystonia is
caused by aberrant plasticity within motor structures, especially cortical-basal ganglia circuits. The lack of a
suitable animal model is a critical barrier to progress. Our preliminary data indicate that we have
developed a strategy to generate the first rodent model of human task specific dystonia by uniquely combining
genetic and behavioral manipulations. This strategy is based on observations suggesting that dystonia requires
“two hits”: a genetic predisposition to abnormal plasticity and a plasticity-inducing environmental trigger (e.g.,
repetition of specific dexterous movements as with musician's dystonia). We modeled the genetic
predisposition with our established model of DYT1 dystonia, caused by inherited mutation in the gene
encoding torsinA. TorsinA mutant “Dlx-CKO” mice do not show abnormal movements at baseline, but exhibit
selective abnormalities of striatal cholinergic interneurons (ChIs), providing a substrate for striatal dysfunction.
Strikingly, Dlx-CKO mice trained to repetitively perform a dexterous paw reaching task develop
abnormal, phasic, dystonic-like movements. In contrast, these mice do not develop abnormal movements
after repetitively performing a non-dexterous rotarod task. This proposal will focus on establishing the
validity and utility of this long-sought model of dystonia. We hypothesize that abnormal function of ChIs in
the setting of repetitive dexterous limb movements causes abnormal striatal activity which leads to task-
specific dystonic-like movements in Dlx-CKO mice. We will test this hypothesis with three Specific Aims. In
Aim 1, we will define the necessary and sufficient behavioral conditions for these mice to develop abnormal
movements, and attempt to extend our findings to DYT1 knock-in mice. In Aim 2, we will examine striatal
electrophysiology as these movements develop. In translational Aim 3, we will use chemogenetic technology
to selectively manipulate ChI activity in Dlx-CKO mice to determine whether modulation of this specific cell type
can suppress dystonic-like movements and to define the striatal mechanism of these effects. Successful
completion of these Aims will establish a unique model of task specific dystonia with high construct,
face and predictive validity. This model will exert a powerful impact on the dystonia community by allowing
detailed study of network mechanisms in dystonia and suggesting novel therapeutic approaches. More
generally, this model will improve understanding of normal interactions between extrapyramidal and pyramidal
motor systems, with broad relevance for a range of movement disorders.

## Key facts

- **NIH application ID:** 9818152
- **Project number:** 1R01NS109227-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** WILLIAM T. DAUER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,791
- **Award type:** 1
- **Project period:** 2020-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9818152

## Citation

> US National Institutes of Health, RePORTER application 9818152, Development of an Animal Model of Task Specific Dystonia (1R01NS109227-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9818152. Licensed CC0.

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