Neuronal synchrony is driven by interval states correlated with goal-directed behavior in the auditory coretex of rats Public Deposited

The prognosis for patients with the genetic neurological disorder Huntington’s disease (HD) is incredibly poor. HD onsets in midlife, causes a variety of severe and debilitating symptoms, progresses over 10‐15 years, and always leads to death. There are currently no treatments that can slow the progression of the disease in any way. Thus, there is tremendous need to discover new therapeutic approaches that can slow or halt disease progression and thereby improve quality of life for patients. In the studies presented here, I characterized the roles of glucocorticoids and the anterior cingulate cortex in HD symptomology, with the overarching goal of assessing the suitability of these two systems as possible points of therapeutic intervention for HD. In Chapter 2, I verified that the R6/2 mouse HD model has elevated glucocorticoid levels, and demonstrated that chronically elevated glucocorticoid levels worsens HD symptomology in this model by exacerbating weight loss and shortening lifespan. In Chapter 3, I further demonstrated that not only do elevated glucorticoid contribute to HD symptomology, but that normalizing glucocorticoids to wild‐type levels in R6/2 mice attenuates HD metabolic symptomology and neuropathology. In Chapter 4, I assessed the role of the anterior cingulate cortex (ACC) in HD mood symptoms. Here, I tested the hypothesis that reducing mHTT expression in the ACC in the BACHD mouse model of HD would reduce depressive‐ and anxiety‐like behavior. These data show that reducing mHTT expression in the ACC leads to a reduction in depressive‐like symptomology but has no effect on anxiety‐like symptoms, thus confirming that mHTT toxicity in the ACC is causal to some HD mood symptomology. Accordingly, the findings from this dissertation confirm that both of these pathophysiological systems, elevated glucocorticoids and mHTT toxicity in the ACC, do directly contribute to HD symptomology and that ameliorating pathology in these systems could possibly lead to symptom improvement for patients.

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