Major-depressive-disorder-associated dysregulation of ZBTB7A in orbitofrontal cortex promotes astrocyte-mediated stress susceptibility.

ABSTRACT: Heightened activity in the orbitofrontal cortex (OFC), a brain region that contributes to motivation, emotion, and reward-related decision-making, is a key clinical feature of major depressive disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unclear. Here, we performed cell-type-specific profiling of human OFC and unexpectedly mapped MDD-linked epigenomic features (including genetic risk variants) to non-neuronal cells, revealing significant glial dysregulation in this region. Characterization of MDD-specific chromatin loci further identified ZBTB7A-a transcriptional regulator of astrocyte reactivity-as an important mediator of MDD-related alterations. In rodent models, we found that Zbtb7a induction in astrocytes is both necessary and suffi

SUBMITTER: Fulton SL 

PROVIDER: S-EPMC12210276 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature