# Neuronal mechanisms underlying sex differences in dystonia

> **NIH NIH R56** · EMORY UNIVERSITY · 2021 · $538,671

## Abstract

Dystonia, the third most common movement disorder, is characterized by involuntary muscle contractions that
cause twisting movements and postures. Epidemiologic studies demonstrate that many dystonias are more
common in women than men yet the mechanisms underlying these sex differences are largely unexplored. Basal
ganglia dysfunction is consistently implicated across many forms of dystonia. The major input structure of the
basal ganglia is the striatum where estrogen exerts neuromodulatory effects. In fact, the physiological properties
of striatal spiny projection neurons (SPNs) are known to vary depending on biological sex and estrous cycle
phase. Direct pathway SPNs (dSPNs) project to the internal globus pallidus to promote movement. Indirect
pathway SPNs (iSPNs) project to the external globus pallidus to inhibit movement. Although dSPNs and iSPNs
are segregated into separate pathways, they act in concert to mediate and refine movements. In dystonia
patients, this coordinated activity is disrupted as functional imaging studies and microelectrode recordings
suggest that both dSPNs and iSPNs are dysfunctional. However, the mechanisms underlying both SPN
pathophysiology and sex differences in dystonia remain unknown.
Several challenges have stymied our ability to understand the pathophysiology and the relationship to biological
sex in dystonia. First, information obtained by studying patients is, by necessity, quite limited. Second, despite
the epidemiological studies demonstrating sex differences in the expression of dystonia, sex as a biological
variable is rarely incorporated into studies examining mechanisms underlying dystonia in patients or animal
models. Third, we lack foundational studies in healthy controls that disentangle the effects of biological sex on
striatal cell types. Indeed, studies characterizing sex differences in normal striatal physiology have not
distinguished between SPN subtypes, while studies examining the molecular properties of dSPNs and iSPNs
have not examined sex as a biological variable. This proposal addresses these gaps in knowledge.
Our understanding of the pathophysiology of dystonia has also been hampered by the lack of animal models
with sexually dimorphic dystonia caused by striatal dysfunction. To address this gap, we created a knockin
mouse model of DOPA-responsive dystonia (DRD). In patients, DRD is female predominant, like many forms of
dystonia in humans. DRD is also the prototype disorder for understanding basal ganglia dysfunction in dystonia
In DRD mice, the striatum plays a central role in mediating dystonia, dSPN and iSPN signaling is disrupted and
the dystonia is mediated by the estrous cycle. Thus, for the first time, it is possible to elucidate the neural code
of dystonia in the context of the mechanisms that drive the sex differences. The Specific Aims are:
1. to determine the role of ovarian hormones in the expression of dystonia.
2. to identify sex differences in the molecular signature of dy...

## Key facts

- **NIH application ID:** 10488542
- **Project number:** 1R56NS124764-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ELLEN J. HESS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,671
- **Award type:** 1
- **Project period:** 2021-09-29 → 2022-09-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488542

## Citation

> US National Institutes of Health, RePORTER application 10488542, Neuronal mechanisms underlying sex differences in dystonia (1R56NS124764-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10488542. Licensed CC0.

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