Dissertation

In vivo Multi-Modal Neuroimaging in Mouse Models of DYT1 Dystonia

DeSimone, Jesse C

2019

Overview

Dystonia musculorum deformans (early-onset generalized dystonia or DYT1 dystonia) is a neurological movement disorder that causes a loss of muscle control, unintentional movements, and disabling postures. The genetic hallmark includes a 3-bp deletion in the DYT1/TOR1A gene encoding the protein torsinA. The pathophysiology of dystonia is not well understood, which presents an obstacle to the development of effective symptomatic and disease-modifying therapies. Convergent evidence from human and animal studies has led to the conceptual view that dystonia represents a network disorder involving dysfunction of connected motor regions of the cortex, basal ganglia, and cerebellum. What is missing from this perspective is a deep understanding of how torsinA deficiency within specific cell types of these regions cause changes in dystonia-related phenotype and systems-level brain pathophysiology. Developing an in vivo perspective of brain pathophysiology related to cell-specific loss of torsinA is fundamental to our understanding of the neural substrates underlying dystonia and developing effective therapeutic strategies. In the present work, high-field (11.1 Tesla) multi-modal neuroimaging was performed in three mouse models of dystonia characterized by distinct cellular insults to the torsinA protein. Adaptations in brain function and microstructure were examined using functional and diffusion MRI, respectively. The results from these experiments yielded several important findings. First, mice carrying the corresponding gene mutation to human DYT1 dystonia or exhibiting the conditional knockout of torsinA within forebrain cholinergic and GABAergic cells exhibited widespread changes in the spatio-temporal correlation between low-frequency fluctuations in resting-state brain signal (i.e., functional connectivity). Second, the conditional knockout of torsinA from striatum-specific dopamine type-2 receptor expressing cells impaired blood-oxygen-level dependent signal activation and connectivity of sensorimotor regions, which correlated with motor performance deficits. Lastly, evidence from these studies establish the utility of advanced multi-compartment diffusion models as a potentially sensitive method to monitor microstructural adaptations in vivo.

• Publisher: ProQuest Dissertations & Theses
• Subject: Kinesiology
• ISBN: 9798209987802