Emma Reid

Huntington’s disease (HD) is a neurodegenerative disorder distinguishable by choreatic activity, behavioral and psychiatric impairments, and dementia. HD is an autosomal dominant genetic disease derived from a trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. This mutation leads to the misfolding and accumulation of the mutant HTT protein into aggregates, causing dysfunction and death of neurons in the striatum, a brain region responsible for movement and some forms of cognition. HD affects astrocytes, a type of non-neuronal cell in the brain that has roles in neuronal regulation, homeostasis, and inflammation. Despite knowing that this cell type is involved in HD, their exact roles in disease pathogenesis are still unclear. Previously, we showed that different subtypes of astrocytes in the striatum are different in number and spatial distribution. GFAP+ astrocytes preferentially accumulate in the dorsomedial (dm) striatum in the zQ175 HD mouse model and are associated with particular white matter (WM) fascicles. We sought to uncover which brain areas connect through the specific axonal bundles that interact with GFAP+ astrocytes. We delivered viral tracers through stereotaxic surgeries into the brains of HD mice and found that the secondary motor cortex (MOs) sends projections through the dm striatum. GFAP+ astrocytes are specifically found surrounding or within WM fascicles containing MOs projections and these fascicles are atrophic. We then looked for pathology in the MOs and found that GFAP+ astrocyte number increases in zQ175 mice compared to wildtype. The MOs is not well studied in HD but in general, the MOs is involved in early and choice-related activity, suggesting that this area is a driver of voluntary actions. Our data demonstrates that the MOs plays an important role in HD, and further investigation of the MOs may lead to a deeper understanding of cortical involvement in HD pathogenesis and symptomatology.