MeCP2 regulates cell-type-specific functions of depressive-like symptoms in the nucleus accumbens.

Methyl-CpG binding protein 2 (MeCP2) is a chromatin-associated transcriptional regulator that modulates neuronal gene programs in response to environmental stimuli. Although MeCP2 has been implicated in stress responses and depression, its cell-type-specific functions within defined limbic circuits remain incompletely understood. Here, using a chronic restraint stress (CRS) model, we show that CRS selectively reduces MeCP2 protein in dopamine D2 receptor (D2R)-expressing medium spiny neurons in the nucleus accumbens (NAc). D2R-restricted MeCP2 knockdown was sufficient to increase immobility in the forced swim test, whereas Cre-dependent restoration of MeCP2 in NAc D2R neurons attenuated CRS-associated behavioral alterations across affective coping, anxiety-like behavior and reward sensitivity. Ex vivo multielectrode array recordings combined with optogenetic stimulation revealed that CRS-associated suppression of NAc activity was normalized toward control levels by MeCP2 restoration. To profile molecular correlates, we performed cell-type-resolved GeoMx digital spatial transcriptomics in virally labeled NAc D2R neurons and found that MeCP2 overexpression was associated with attenuation of CRS-linked transcriptional perturbations, prominently involving synaptic and neuronal communication-related programs. In parallel, we detected CRS-responsive molecular signatures in the ventral pallidum that shifted with NAc D2R-restricted MeCP2 restoration, although these downstream profiles are not projection-resolved. Collectively, our findings identify a D2R neuron-biased role for MeCP2 in the NAc and support the view that restoring MeCP2 in this cell population is associated with mitigation of CRS-induced depression-like phenotypes and accompanying circuit/transcriptomic signatures. Chronic restraint stress (CRS) reduces MeCP2 protein in nucleus accumbens (NAc) D2 receptor (D2R)-expressing neurons, suppressing activity- and synapse-related programs and promoting depressive-like behaviors. Cell-type-specific restoration of MeCP2 in NAc D2R neurons normalizes neuronal activity and attenuates behavioral deficits, accompanied by coordinated transcriptional shifts involving synaptic organization, glutamatergic signaling, potassium channel activity and cytoskeletal regulation. CRS-responsive molecular signatures in the ventral pallidum (VP) show partial normalization in association with MeCP2 upregulation (VP bulk ROIs). Together, these findings implicate MeCP2-dependent regulation of NAc D2R neuron state in stress-related outcomes.