OT-HD

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the Huntingtin gene, for which no cure currently exists beyond palliative treatments. While gene silencing strategies have been explored, recent clinical trials have been discontinued due to ineffectiveness and potential harm, leaving an urgent need for new therapeutic approaches. Beyond the characteristic choreiform movements, HD patients suffer from severe psychiatric and cognitive non-motor symptoms that profoundly impair their autonomy, quality of life, and social functioning. HD primarily affects medium-sized spiny neurons in the striatum, which express oxytocin receptors (OTRs) involved in the regulation of emotional and social behavior. Notably, oxytocin (OT) levels in the cerebrospinal fluid of HD patients are significantly reduced and correlate with depressive, social, and cognitive symptoms. Based on these observations, this project hypothesizes that the psychiatric features of HD may result from oxytocinergic system dysfunction in the HD striatum. To test this, the study will combine single-cell transcriptomics, electrophysiology, behavioral analyses, and neuropathology in an OT-treated HD mouse model, also employing Patch-Seq to simultaneously couple electrophysiological and transcriptional characterization of individual cells. The project aims to assess the therapeutic potential of OT for HD psychiatric symptoms, characterize OT-mediated modulation of striatal networks, and define cell-type-specific transcriptional profiles before and after treatment. If successful, OT could rapidly enter HD clinical trials, as it is already commercially available, has been tested for cognitive and psychiatric symptoms in other diseases, and can be easily administered intranasally with no documented side effects in HD patients.