study rationale

Mutations in the GNAL gene, which encodes Gαolf, cause a form of adult-onset dystonia that is clinically similar to idiopathic dystonia. Understanding how the loss of Gαolf affects the brain’s signaling pathways is crucial to uncovering the underlying mechanisms of dystonia. Despite the significant impact of dystonia on patients’ quality of life, few treatments exist, and this research aims to provide insights that could lead to novel therapies.

hypothesis

Loss of Gnal in either the striatum or cerebellum results in dysfunctional signaling between these regions, leading to dystonia. The hypothesis is that dysfunction in one region induces network dysfunction in the other, and both are required to produce dystonic symptoms.

study design

This project utilizes an innovative mouse model that conditionally removes Gnal from either the striatum or cerebellum. Using advanced MRI techniques, including 7 Tesla preclinical neuroimaging, the study will investigate how the loss of Gnal affects brain connectivity and functional pathways. Two key aims will be addressed:

  • Aim 1: Analyze how Gnal loss in the striatum or cerebellum alters functional connectivity and whether dysfunction in one region impacts the other.
  • Aim 2: Correlate changes in functional brain circuits with the severity of dystonic motor symptoms using neuroimaging and behavioral tests in mice.

impact on dystonia treatment

This study represents a critical advancement in understanding the neural circuits that contribute to dystonia. The research could pave the way for targeted therapeutic interventions, offering hope for more effective treatments. By uncovering how the striatum and cerebellum interact in dystonia, it may be possible to develop novel approaches that disrupt these dysfunctional networks and alleviate symptoms.

next steps for development

Successful completion of this pilot study will generate preliminary data for larger proposals, including submissions to the NIH and the Department of Defense for further research. Future studies will explore broader applications of this model and delve deeper into how specific brain circuits contribute to dystonia, with the potential for developing targeted treatments.

additional information

  • Innovative Approach: This is the first model of GNAL-linked dystonia with overt dystonic symptoms, allowing direct investigation of the neural circuits involved.
  • Collaborative Expertise: The study leverages the combined strengths of the Moehle and Vaillancourt labs in dystonia research and small animal neuroimaging.
  • Pilot Funding: A total of $38,810 has been requested for this one-year study to support neuroimaging, data analysis, and animal care

collaboration

This collaboration between the Moehle and Vaillancourt Labs focuses on studying the brain circuits involved in dystonia. The Moehle Lab has developed a new model of dystonia in mice, and their role is to induce dystonia in these mice by injecting a specific virus into targeted brain regions (the striatum or cerebellum). Once the dystonia develops, the mice will be transferred to the Vaillancourt Lab, where their expertise in advanced small animal MRI will be used to image the mice’s brains and analyze how the disease affects brain function. 

Dr. Bradley Wilkes, a research assistant professor in the Vaillancourt Lab, will perform the imaging and analysis. Both labs will then collaborate to compare the MRI results with the severity of dystonia symptoms in the mice, helping to reveal the underlying neural mechanisms of the disorder. This partnership combines the strengths of both labs to generate valuable data for future, larger studies.