Limbic-basal ganglia connectivity in a non-human primate model of Huntington's disease

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Huntington's disease (HD) is a degenerative neurological disorder caused by an expanded CAG repeat sequence in the dominantly-inherited HTT gene on chromosome 4. When the CAG repeat stretch exceeds 40 repeats the encoded mutant huntingtin protein (mHTT) misfolds, resulting in a toxic gain of function that is neurodegenerative. HD symptoms are detrimental to the patient's quality of life, as they suffer from a progressive hyperkinetic movement disorder accompanied by deteriorating cognitive function and profound personality changes/mood disturbances. The emotional and physical burden on both the patient and the caregiver are tremendous, and patients often report their mood symptoms to be the most burdensome to both themselves and their caretakers. To address this need, the central goal of my project will be to characterize the impact of HD neuropathology on limbic-basal ganglia connectivity and behavioral phenotypes relevant to the mood/psychiatric symptoms. I will use behavioral assays to assess mood and affect in our HD animal model, and I will perform neuroimaging, histological, and molecular analyses, focusing on specific regions of interest in limbic (amygdala, anterior cingulate cortex, orbitofrontal cortex) and basal ganglia (caudate and putamen) regions. In sum, I will take a multifaceted approach using both in vivo (neuroimaging and behavioral assays in Aim 1 and 2) and ex vivo (histological and molecular in Aim 3) techniques. The strength of my studies lays in their ability to identify prospective neuroimaging changes that can be connected with a wide array of behavioral and neuropathological phenotypes of HD.