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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Jinhee Bae,
  • Sung Hoon Kim,
  • Sun A Jung,
  • Nazarii Frankiv,
  • Hyunjeong Jin,
  • Eun Mi Hwang,
  • Young-Min Kim,
  • Sangjoon Lee,
  • Heh-In Im

摘要

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.