Fulton Sasha L, Bendl Jaroslav, Di Salvo Giuseppina, Fullard John F, Al-Kachak Amni, Lepack Ashley E, Stewart Andrew F, Singh Sumnima, Poller Wolfram F, Bastle Ryan M, Hauberg Mads E, Fakira Amanda K, Patel Vishwendra, Chen Min, Durand-de Cuttoli Romain, Gameiro-Ros Isabel, Cathomas Flurin, Ramakrishnan Aarthi, Gleason Kelly, Shen Li, Tamminga Carol A, Milosevic Ana, Russo Scott J, Swirski Filip K, Slesinger Paul A, Abdus-Saboor Ishmail, Blitzer Robert D, Roussos Panos, Maze Ian
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Zuckerman Institute of Mind, Brain, and Behavior, Columbia University, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neuron. 2025 Jun 11. doi: 10.1016/j.neuron.2025.05.023.
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 sufficient to drive stress-mediated behavioral deficits, cell-type-specific transcriptional/epigenomic signatures, and aberrant OFC astrocyte-neuronal communication in male mice-an established MDD risk factor. These findings thus highlight essential roles for astrocytes in OFC-mediated stress susceptibility and identify ZBTB7A as a critical and therapeutically relevant regulator of MDD-related OFC dysfunction.
眶额皮质（OFC）活动增强是重度抑郁症（MDD）的一个关键临床特征，该脑区参与动机、情绪及与奖赏相关的决策过程。然而，这种功能障碍背后的细胞和分子基础仍不清楚。在此，我们对人类眶额皮质进行了细胞类型特异性分析，意外地将与MDD相关的表观基因组特征（包括遗传风险变异）映射到非神经元细胞上，揭示了该区域显著的胶质细胞失调。对MDD特异性染色质位点的表征进一步确定了ZBTB7A（一种星形胶质细胞反应性的转录调节因子）是MDD相关改变的重要介导因子。在啮齿动物模型中，我们发现星形胶质细胞中Zbtb7a的诱导对于驱动应激介导的行为缺陷、细胞类型特异性转录/表观基因组特征以及雄性小鼠中异常的眶额皮质星形胶质细胞 - 神经元通信（一种既定的MDD风险因素）而言，既是必要的也是充分的。因此，这些发现突出了星形胶质细胞在眶额皮质介导的应激易感性中的重要作用，并确定ZBTB7A是MDD相关眶额皮质功能障碍的关键且与治疗相关的调节因子。
