Study Rationale
DYT1 dystonia, caused by mutations in the TOR1A gene, results in significant motor disability and currently lacks effective treatments. This research aims to bridge the knowledge gap on how torsinA dysfunction in medium spiny neurons (MSNs) within the basal ganglia contributes to dystonia. Previous models with the ΔGAG mutation showed motor deficits without overt dystonia; this study introduces a new double-hit model to replicate both the genetic and symptomatic features of the disorder in a more etiologically accurate way.
Hypothesis
MSN dysfunction in the basal ganglia initiates network impairments that propagate to the cerebellum, with combined dysfunction across both regions required to produce dystonic symptoms. By understanding these interactions, we can identify potential intervention points for new treatments.
study design
This project will leverage an innovative mouse model with the Rgs9-ΔGAG double mutation to explore torsinA dysfunction’s effects across two key aims:
Aim 1: Characterize cellular changes in MSNs using in vitro electrophysiology to study firing patterns and neuronal properties affected by the Rgs9-ΔGAG mutation.
Aim 2: Examine brain network alterations using advanced functional and diffusion MRI, focusing on basal ganglia, cortical, and cerebellar connectivity to determine how MSN dysfunction impacts these broader brain regions.
impact on dystonia treatment
The insights from this study may highlight neural circuits critical to dystonia’s pathology, paving the way for targeted interventions. By detailing how the basal ganglia and cerebellum contribute to dystonia, this research may lead to approaches that disrupt dysfunctional circuits to alleviate symptoms.
next steps for development
Upon completion, this study will yield preliminary data for larger research initiatives, including NIH proposals. Future studies will focus on the role of specific brain circuits in dystonia, broadening the model’s application to potentially develop targeted, circuit-based treatments.
other relevant information
A $40,000 budget, requested to fund neuroimaging, electrophysiology, and animal care expenses, supports the one-year study. This funding and the University of Florida’s additional contributions ensure resources for personnel, travel, and educational stipends.
collaboration
This project combines the Vaillancourt, Wilkes, and Li labs, combining expertise in dystonia research, neuroimaging, and electrophysiology. Dr. Wilkes will lead data analysis, while Dr. Vaillancourt’s lab will contribute advanced MRI analysis techniques, and Dr. Li’s lab will support electrophysiology. Together, they aim to create a foundation for future studies on dystonia’s neural mechanisms.