Resting-state fMRI reveals longitudinal alterations in brain network connectivity in the zQ175DN mouse model of Huntington's disease

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Huntington's disease is an autosomal, dominantly inherited neurodegenerative disease caused by an expansion of the CAG repeats in exon 1 of the huntingtin gene. Neuronal degeneration and dysfunction that precedes regional atrophy result in the impairment of striatal and cortical circuits that affect the brain's large-scale network functionality. However, the evolution of these disease-driven, large-scale connectivity alterations is still poorly understood.Here we used resting-state fMRI to investigate functional connectivity changes in a mouse model of Huntington's disease in several relevant brain networks and how they are affected at different ages that follow a disease-like phenotypic progression. Towards this, we used the heterozygous (HET) form of the zQ175DN Huntington's disease mouse model that recapitulates aspects of human disease pathology. Seed- and Region-based analyses were performed at different ages, on 3-, 6-, 10-, and 12-month-old HET and age-matched wild-type mice.Our results demonstrate decreased connectivity starting at 6 months of age, most prominently in regions such as the retrosplenial and cingulate cortices, pertaining to the default mode-like network and auditory and visual cortices, part of the associative cortical network. At 12 months, we observe a shift towards decreased connectivity in regions such as the somatosensory cortices, pertaining to the lateral cortical network, and the caudate putamen, a constituent of the subcortical network. Moreover, we assessed the impact of distinct Huntington's Disease-like pathology of the zQ175DN HET mice on age-dependent connectivity between different brain regions and networks where we demonstrate that connectivity strength follows a non-linear, inverted U-shape pattern, a well-known phenomenon of development and normal aging. Conversely, the neuropathologically driven alteration of connectivity, especially in the default mode and associative cortical networks, showed diminished age-dependent evolution of functional connectivity.These findings reveal that in this Huntington's disease model, altered connectivity starts with cortical network aberrations which precede striatal connectivity changes, that appear only at a later age. Taken together, these results suggest that the age-dependent cortical network dysfunction seen in rodents could represent a relevant pathological process in Huntington's disease progression.