Chronic Stress Induces Coordinated Cortical Microcircuit Cell–Type Transcriptomic Changes Consistent With Altered Information Processing

Information processing in cortical cell microcircuits involves regulation of excitatory pyramidal (PYR) cells by inhibitory somatostatin- (SST), parvalbumin-, and vasoactive intestinal peptide-expressing interneurons. Human postmortem and rodent studies show impaired PYR cell dendritic morphology and decreased SST cell markers in major depressive disorder or after chronic stress. However, knowledge of coordinated changes across microcircuit cell types is virtually absent.We investigated the transcriptomic effects of unpredictable chronic mild stress (UCMS) on distinct microcircuit cell types in the medial prefrontal cortex (cingulate regions 24a, 24b, and 32) in mice. C57BL/6 mice, exposed to UCMS or control housing for 5 weeks, were assessed for anxiety- and depressive-like behaviors. Microcircuit cell types were laser microdissected and processed for RNA sequencing.UCMS induced predicted elevations in behavioral emotionality in mice. DESeq2 analysis revealed unique differentially expressed genes in each cell type after UCMS. Presynaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed downregulated postsynaptic gene signatures. Across the cortical microcircuit, we observed a shift from a distributed transcriptomic coordination across cell types in control mice toward UCMS-induced increased coordination between PYR, SST, and parvalbumin cells and a hub-like role for PYR cells. Finally, we identified a microcircuit-wide coexpression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviors.These findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cells regulating the cortical excitation-inhibition balance, suggesting increased coordinated regulation of PYR cells by SST and parvalbumin cells.