Abstract
Huntington's disease (HD) is a rare, autosomal dominant inherited neurodegenerative disorder caused by an expanded polyglutamine sequence in the huntingtin gene (HTT) encoding for mutant huntingtin (mHTT). HD neuropathology is characterized by basal ganglia neurodegeneration, leading to progressive motor, psychiatric, and cognitive impairments, and ultimately death. While the pathogenic mechanisms by which mHTT causes selective dysfunction of the medium-size spiny neurons (MSNs) in the basal ganglia remain uncertain, we have extensive (pre)clinical evidence on the progressive loss of both D1 receptors (D1R) and D2 receptors (D2R), involved in direct and indirect dopaminergic pathways, respectively. Although MSN degeneration occurs roughly in equal proportions for D1R and D2R, the indirect dopaminergic pathway is affected first, resulting in the occurrence of the involuntary movements (hyperkinesia) characteristic of HD. As of today, there is a substantial knowledge gap in understanding the relationship between dopaminergic receptor density and the functional signalling of both direct and indirect dopaminergic pathways. In this project, a multimodal approach will be applied consisting of advanced non-invasive functional magnetic resonance imaging (fMRI), electrophysiology, behaviour, and post-mortem techniques in HD mouse models, with specific modulation of the direct or indirect dopamine pathway. The outcome will increase our understanding of the functional integrity of both dopaminergic pathways of the basal ganglia in HD.
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