# A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice

> **NIH NIH F32** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $70,282

## Abstract

ABSTRACT
Dystonia is neurodevelopmental disease characterized by involuntary twisting movements. Effective dystonia
treatments remain elusive because the dysfunctional circuit(s) that cause and perpetuate the motor abnormalities
is largely uncharacterized. One limitation to advancing our understanding of dystonia pathophysiology and
developing novel therapeutic strategies is the lack of etiologically based animal models that exhibit overt
dystonia-like behaviors. We overcame this limitation by engineering a mouse model that exhibits robust motor
abnormalities starting in juvenile development, following a disruption of the dystonia gene, TOR1A.TorsinA, the
protein that is made from the TOR1A, is important during brain development for synaptogenesis and its loss
results in abnormal functional connectivity. I will use our novel mouse model to investigate how a loss of torsinA
function in brain motor circuits causes dystonia. I will test a new idea: that dystonia results from sequential insults.
First, genetic mutations cause a small but critical group of neurons to make aberrant anatomical connections.
Then, sustained circuit dysfunction reinforces abnormal movements. These studies are possible because of
multiple uniquely designed “tools" my lab has created and the advanced brain imaging methods that have been
developed at UT Southwestern, where the study will be performed. This proposal will also advance our
understanding of dystonia by identifying the brain circuit changes required to propagate and suppress motor
dysfunction. This understanding will inform future work aimed at developing effective therapies for dystonia.

## Key facts

- **NIH application ID:** 10508076
- **Project number:** 1F32NS128000-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Lauren Nicole Miterko
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $70,282
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508076

## Citation

> US National Institutes of Health, RePORTER application 10508076, A two-hit hypothesis for dystonia pathophysiology: Cerebello-thalamo-striatal dysfunction and connectivity in DYT1 mice (1F32NS128000-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10508076. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*