CELLULAR AND TRANSCRIPTIONAL MECHANISMS INVOLVED IN LARGE-SCALE CIRCUIT REMODELING IN THE ADULT

A long-standing question in Neuroscience concerns the extent to which mature neural circuits, particularly in mammals, are capable of undergoing large-scale structural reorganization. Although extensive functional remapping has been reported in the adult human brain following both central and peripheral injuries, the cellular substrate underlying these functional changes is not clear. Here we aimed to study the contribution of different cell types to the structural remodeling of brain circuits throughout time. Using a mouse model of permanent whisker deprivation in the adulthood in combination with 3D histology methods (iDISCO, light-sheet imaging, ClearMap-derived tools), we mapped the longitudinal dynamics of neurons, astrocytes and microglia throughout the whole brain. We identified plastic cortical regions for further transcriptomic analysis. Our results show that adult circuit remodeling is a long-term process in which inflammatory and scaring mechanisms are prevalent in first order brainstem relays, while microglia and astrocyte morphology and distribution does not significantly change in other relays of the manipulated circuit. Long-range axonal markers suggest wide reorganization of cortical connectivity, where primary cortical regions related to the deprived sensory field (barrel field and nose) loss connectivity, while cortical regions related to secondary somatosensory processing or primary processing of another sensory modality (auditory) are reinforced. Together, our results highlight the multifactorial and spatially heterogeneous nature of adult circuit remodeling. Although these changes are subtle and unfold slowly, they may exert substantial functional consequences and provide critical insights for developing therapeutic strategies aimed at harnessing plasticity in the adult brain.