Sex-specific dendritic spine and microglia pathology in depression

摘要 严重抑郁障碍(MDD)是导致残疾的主要原因，影响着3亿多人 全世界。众所周知，MDD的发病率存在性别差异，女性患MDD的可能性是男性的两倍 被诊断为男性。此外，MDD的影响在男性和女性之间有所不同，在 症状、严重程度和症状数量。例如，女性患癌症的可能性是女性的三倍 不典型的抑郁症，以多睡和体重增加为特征。这些显著的差异在 抑郁症男性和女性的症状学使我们假设MDD在分子上是不同的 男性和女性之间的水平。我们最近评估了MDD的性别特异性分子病理学 人类死后脑分析。我们第一次表明，抑郁症不仅在男性和 女性，但以相反的分子病理为特征。最强烈的相反影响是在 前扣带回皮质(ACC；Brodmann区25)，这是一个与MDD病理有关的脑区。 我们对男性MDD患者的分析发现，突触功能的标志物减少，而 小胶质细胞和炎症，与锥体细胞树突棘突触减少和 抑郁症患者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移除的模型。令人惊讶的是，我们的 对患有MDD的女性的分析发现，突触功能的标志物增加，而 免疫功能和小胶质细胞，这与抑郁男性正好相反。然而，没有研究表明 检查了抑郁女性特有的锥体细胞、树突棘和小胶质细胞的变化，留下了 在抑郁症文献中有很大差距。这些研究表明，锥体细胞和小胶质细胞 在MDD中受影响，但在男性和女性中方向相反。值得注意的是，对啮齿类动物的研究报告称，慢性 应激增加了男性的反应性小胶质细胞，降低了前额叶皮质树突的复杂性，但确实如此 而女性的情况正好相反。因此，啮齿动物为探索分子提供了一个很好的模型系统。 在人类MDD中观察到的性别特异性病理的潜在机制。在这里，我们将评估金字塔 男性和女性MDD患者ACC中的树突棘和反应性小胶质细胞，解决了一个主要差距 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的转录变化 发生于抑郁的男性和女性(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(目标3)。这些研究对以下方面是必不可少的 了解特定性别和细胞类型的MDD病理，并确定这些性别差异是否会导致MDD 症状。此外，他们还将评估针对性别的治疗是否能缓解抑郁症相关症状 并为未来针对性别的治疗发展提供关键见解。

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.