Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Brain Behav Immun. 2024 Jan;115:169-178. doi: 10.1016/j.bbi.2023.10.006. Epub 2023 Oct 12.
Chronic stress is a major risk factor for Major Depressive Disorder (MDD), and it has been shown to impact the immune system and cause microglia activation in the medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. The aim of this study is to further investigate cellular and molecular mechanisms underlying persistent depression behavior in sex specific manner, which is observed clinically. Here, we report that both male and female mice exhibited depression-like behavior following exposure to chronic stress. However, only female mice showed persistent depression-like behavior, which was associated with microglia activation in mPFC, characterized by distinctive alterations in the phenotype of microglia. Given these findings, to further investigate the underlying molecular mechanisms associated with persistent depression-like behavior and microglia activation in female mice, we used translating-ribosome affinity purification (TRAP). We find that Toll like receptor 4 (TLR4) signaling is casually related to persistent depression-like behavior in female mice. This is supported by the evidence that the fact that genetic ablation of TLR4 expression in microglia significantly reduced the persistent depression-like behavior to baseline levels in female mice. This study tentatively supports the hypothesis that the TLR4 signaling in microglia may be responsible for the sex differences in persistent depression-like behavior in female.
慢性应激是导致重度抑郁症（MDD）的一个主要风险因素，它已被证明会影响免疫系统，并导致参与抑郁症发病机制的中前额皮质（mPFC）中的小胶质细胞激活。本研究旨在进一步探讨临床上观察到的性别特异性持续性抑郁行为的细胞和分子机制。在这里，我们报告说，暴露于慢性应激后，雄性和雌性小鼠都表现出类似抑郁的行为。然而，只有雌性小鼠表现出持续性类似抑郁的行为，这与 mPFC 中的小胶质细胞激活有关，其特征是小胶质细胞表型的独特改变。鉴于这些发现，为了进一步研究与雌性小鼠持续性类似抑郁行为和小胶质细胞激活相关的潜在分子机制，我们使用了翻译核糖体亲和纯化（TRAP）。我们发现 Toll 样受体 4（TLR4）信号与雌性小鼠的持续性类似抑郁行为有关。这一事实提供了证据，即小胶质细胞中 TLR4 表达的基因缺失显著降低了雌性小鼠持续性类似抑郁行为的基线水平。这项研究初步支持了这样一种假说，即小胶质细胞中的 TLR4 信号可能是导致雌性持续性类似抑郁行为性别差异的原因。
