Distinct Molecular Patterns in R6/2 HD Mouse Brain: Insights from Spatiotemporal Transcriptomics

Huntington’s disease (HD) is a progressive neurodegenerative disease marked by widespread cellular disruption. To understand disease mechanisms by investigating transcriptional differences, we and others have utilized bulk and single cell transcriptomics which provide cell type information but limited spatial information. We therefore utilized 10x Genomics Visium spatial transcriptomics integrated with matched single nuclei-RNA-seq in the HD R6/2 mouse brain (postnatal day 0, 4- and 12-week) to examine disease trajectories across regions in a rapidly progressing model. Our data suggests regional, temporal and cell type specific regulatory pathways that establish distinct gene expression changes in brain. Synaptic dysfunction is observed broadly throughout the brain. We observed early dysregulation of the transcription factor Tcf-4 that may drive cortical changes. Mitochondrial deficits are the earliest changes, beginning at P0 in striatum prior to overt symptom onset together with increased expression of striatal identity genes that then become progressively downregulated. Finally, we identified a time-dependent dysregulation of neuropeptide Y signaling and potential interaction with the cAMP/PKA pathway, which may be involved in early imbalance between Drd1 and Drd2 neuron vulnerability.