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

www.nature.com/emm ARTICLE OPEN MeCP2 regulates cell-type-specific functions of depressive-like symptoms in the nucleus accumbens 1234567890();,: © The Author(s) 2026 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 Credependent 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01721-3 Graphical Abstract 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. A full list of authors and their affiliations appears at the end of the paper. Received: 26 July 2025 Revised: 27 January 2026 Accepted: 24 February 2026 J. Bae et al. 2 INTRODUCTION Major depressive disorder is associated with persistent alterations in stress reactivity, affective behavior and neural circuit dynamics. Identifying the molecular regulators that determine stress susceptibility versus resilience remains a critical gap in the field. Methyl-CpG binding protein 2 (MeCP2) is a chromatin-associated transcriptional regulator that integrates neuronal activity with gene expression programs1–6. Although MeCP2 is best known for its developmental role and association with Rett syndrome, emerging evidence indicates that it also modulates adult stress adaptation and emotional regulation4,6,7. For example, changes in MeCP2 expression and phosphorylation have been reported following chronic stress, antidepressant treatment and ketamine exposure7,8, and peripheral MeCP2 reductions have been observed in individuals experiencing depressive symptoms4. However, despite these observations, the mechanisms by which MeCP2 contributes to affective behavioral regulation—particularly under chronic stress conditions—remain poorly understood. Notably, whether MeCP2 acts in a cell-type-specific manner within defined limbic circuits to shape stress susceptibility versus resilience has not been directly addressed. The nucleus accumbens (NAc) is a key node in limbic circuitry that integrates motivational, emotional and stress-related signals9–11. Neurons in the NAc are predominantly composed of dopamine D1 receptor-expressing (D1R) and dopamine D2 receptor-expressing (D2R) populations, which exert dissociable and often opposing influences on behavior12,13. D1R MSNs are generally linked to behavioral activation and positive valence, whereas D2R MSNs are associated with aversion, withdrawal states and stress-induced behavioral change. Dysregulated signaling within these neuronal populations has been repeatedly implicated in stress-related behavioral dysfunction and circuit maladaptation9,14,15. Here, we used a chronic restraint stress (CRS) model to examine whether MeCP2 is associated with stress-related behavioral and circuit changes in a cell-type-specific manner. We found that CRS was accompanied by reduced MeCP2 protein levels in D2R neurons, but not D1R neurons, in the NAc. Viral restoration of MeCP2 expression specifically in D2R neurons attenuated CRS-associated behavioral alterations, including increased immobility in the forced swim test (FST) and elevated anxiety-like behavior in the elevated plus maze (EPM). In addition, we included a reward-related readout (sucrose preference test, SPT) in the MeCP2 restoration experiment to assess reward sensitivity (anhedonia-related behavior). To further characterize the neurobiological correlates of these effects, we performed multielectrode array (MEA) recordings and spatial transcriptomics, which revealed activity patterns and transcriptional profiles that shifted toward baseline in the recovery condition and were consistent with attenuation of CRS-associated transcriptional changes in NAc D2R neurons. Parallel transcriptional changes were also observed in the ventral pallidum (VP). Together, these findings indicate that MeCP2 in NAc D2R neurons plays a central role in stress-related behavioral and molecular adaptations, and that cell-type-targeted restoration of MeCP2 is sufficient to attenuate multiple CRS-associated phenotypes. In parallel, MeCP2 restoration is accompanied by coordinated molecular changes in downstream regions, including the VP. While the present study does not resolve projection-specific mechanisms or a single causal pathway linking these effects, the data support a model in which MeCP2-dependent regulation in NAc D2R neurons is contributes to broader circuit-level and transcriptomic adaptations under chronic stress. MATERIALS AND METHODS Animals We used 7–9-week-old male C57BL/6J (DBL), B6.FVB (Cg)-Tg (Drd2-cre) ER44Gsat/Mmcd (#032108-UCD, MMRRC) or B6. Cg-Tg (Drd1-cre) 262Gsat/ Mmcd (#030989-UCD, MMRRC) mice for experimental procedures. All transgenic mi (...truncated)