Sex-specific dendritic spine and microglia pathology in depression

摘要 重度抑郁症（MDD）是导致残疾的主要原因，影响超过3亿人 国际吧众所周知，MDD的发病率存在性别差异，女性的发病率是男性的两倍。 诊断为男性。此外，MDD的影响在男性和女性之间存在差异， 病理学、严重程度和症状数量。例如，女性有三倍的可能性 非典型抑郁症，以嗜睡和体重增加为特征。这些显著的差异， 抑郁症男性和女性之间的精神病学使我们假设MDD在分子水平上不同， 男女之间的水平。我们最近评估了MDD的性别特异性分子病理学， 人类死后大脑分析我们第一次证明，抑郁症不仅在男性中不同， 女性，但其特征在于相反的分子病理学。最强烈的相反效果出现在 前扣带皮层（ACC; Brodmann区25），一个始终与MDD病理学有关的脑区。 我们对MDD患者的分析发现，突触功能标志物减少， 小胶质细胞和炎症，与锥体细胞树突棘突触减少的报告一致， 抑郁症患者的反应性小胶质细胞增多MDD男性的分子变化与 反应性小胶质细胞参与过度病理性突触清除的模型。令人惊讶的是，我们 对患有MDD的女性的分析发现，突触功能的标记物增加， 免疫功能和小胶质细胞，这与抑郁症男性正好相反。然而，没有任何研究 研究了锥体细胞树突棘和小胶质细胞的变化，特别是在抑郁症的妇女，留下了一个 抑郁症文献中的主要空白。总之，这些研究表明，锥体细胞和小胶质细胞是 在MDD中受影响，但在男性和女性中相反。值得注意的是，对啮齿动物的研究报告称， 在男性中，压力增加了反应性小胶质细胞，降低了前额叶皮层树突的复杂性， 在女性中恰恰相反。因此，啮齿类动物提供了一个很好的模型系统来探测分子 在人类MDD中观察到的性别特异性病理学的潜在机制。在这里，我们将评估金字塔 细胞树突棘和反应性小胶质细胞在男性和女性的ACC与MDD，解决了一个主要的差距 在文献中（目标1）。接下来，我们将评估锥体细胞和小胶质细胞特异性转录变化， 发生在抑郁的男性和女性（目标2）。最后，我们将确定观察到的功能相关性。 使用小鼠模型的性别特异性MDD脊柱和小胶质细胞病理学（目的3）。这些研究对以下方面至关重要： 了解性别和细胞类型特异性MDD病理，并确定这些性别差异是否驱动MDD 症状此外，他们还将评估性别特异性治疗是否能缓解抑郁症相关症状 并为未来的性别特异性治疗开发提供关键见解。

Abstract Major depressive disorder (MDD) is a leading cause of disability, affecting more than 300 million people worldwide. There is a well-known sex difference in incidence of MDD, with women being twice as likely to be diagnosed as men. Additionally, the impact of MDD varies between men and women, with sex differences in symptomatology, severity, and number of symptoms. For instance, women are three times more likely to have atypical depression, characterized by hypersomnia and weight gain. These marked differences in symptomatology between depressed men and women led us to hypothesize that MDD differs at the molecular level between men and women. We recently assessed the sex-specific molecular pathology of MDD using human postmortem brain analysis. We showed, for the first time, that depression is not only distinct in men and women, but is characterized by opposite molecular pathology. The strongest opposite effects were in the anterior cingulate cortex (ACC; Brodmann area 25), a brain region consistently implicated in MDD pathology. Our analysis of men with MDD found reductions in markers of synaptic function and increases in markers of microglia and inflammation, consistent with reports of decreased pyramidal cell dendritic spine synapses and increased reactive microglia in depressed men. The molecular changes in MDD males are consistent with a model in which reactive microglia participate in excessive pathologic synapse removal. Surprisingly, our analysis of women with MDD found increased markers of synaptic function coupled with decreased markers of immune function and microglia, which is exactly the opposite of depressed men. However, no study has examined pyramidal cell dendritic spine and microglia changes specifically in depressed women, leaving a major gap in the depression literature. Together, these studies suggest pyramidal cells and microglia are affected in MDD, but in opposite directions in men and women. Notably, studies in rodents report that chronic stress increases reactive microglia and decreases prefrontal cortex dendritic complexity in males, but does exactly the opposite in females. Thus, rodents provide an excellent model system to probe molecular mechanisms underlying the sex-specific pathology observed in human MDD. Here, we will assess pyramidal cell dendritic spines and reactive microglia in the ACC of men and women with MDD, addressing a major gap in the literature (Aim 1). Next, we will assess pyramidal cell- and microglia-specific transcriptional changes that occur in depressed men and women (Aim 2). Finally, we will determine the functional relevance of observed sex-specific MDD spine and microglia pathology using mouse models (Aim 3). These studies are essential for understanding sex- and cell type-specific MDD pathology and determining if these sex differences drive MDD symptoms. In addition, they will assess whether sex-specific treatments alleviate depression-related symptoms and provide key insights for future sex-specific treatment development.