Sex-specific dendritic spine and microglia pathology in depression

抑郁症中的性别特异性树突棘和小胶质细胞病理学

• 批准号: 10406879
• 负责人: Marianne L Seney
• 金额: $ 38.81万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-19 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406879
• 关键词: Address; Affect; Anterior; Atypical depressive disorder; Autopsy; Behavior; Biological Models; Brain; Brain Pathology; Brain region; Brodmann' s area; Calcium Signaling; Chronic stress; Coupled; Dendritic Spines; Depressed mood; Diagnosis; Disease; Excision; Exhibits; Female; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Germ Cells; Glutamate Receptor; HLA-DR Antigens; Human; Hypersomnias; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Markers; Incidence; Inflammation; Interferon-alpha; Label; Literature; Major Depressive Disorder; Mental Depression; Microglia; Minocycline; Modeling; Molecular; Molecular Probes; Moods; Mus; Pathologic; Pathology; Patients; Pattern; Persons; Phagocytosis; Prefrontal Cortex; Pyramidal Cells; Reporting; Resolution; Rodent; Severities; Sex Differences; Spinal Diseases; Stains; Stress; Symptoms; Synapses; Synaptic Transmission; Testing; Time; Vertebral column; Weight Gain; Woman; cell type; cingulate cortex; cohort; density; depressive symptoms; disability; effective therapy; immune function; insight; male; men; molecular pathology; mouse model; sex; symptomatology; synaptic function; therapy development; transcriptome sequencing; transcriptomics

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.

抽象的 重度抑郁症 (MDD) 是导致残疾的主要原因，影响超过 3 亿人 全世界。众所周知，MDD 的发病率存在性别差异，女性患 MDD 的可能性是女性的两倍 诊断为男性。此外，MDD 对男性和女性的影响也不同，其中性别差异 症状、严重程度和症状数量。例如，女性患此病的可能性是女性的三倍 非典型抑郁症，以嗜睡和体重增加为特征。这些显着差异 抑郁症男性和女性之间的症状学使我们假设 MDD 在分子水平上有所不同 男女之间的水平。我们最近使用以下方法评估了 MDD 的性别特异性分子病理学： 人类死后大脑分析。我们首次表明，抑郁症不仅在男性中存在明显差异， 女性，但具有相反的分子病理学特征。最强烈的相反影响是 前扣带皮层（ACC；布罗德曼区 25），一个始终与 MDD 病理有关的大脑区域。 我们对患有 MDD 的男性的分析发现，突触功能标记物减少，而突触功能标记物增加。 小胶质细胞和炎症，与锥体细胞树突棘突触减少的报道一致 抑郁男性的反应性小胶质细胞增加。 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去除的模型。令人惊讶的是，我们的 对患有 MDD 的女性的分析发现，突触功能标记物增加，同时突触功能标记物减少 免疫功能和小胶质细胞，这与抑郁症男性正好相反。然而，没有研究 研究了抑郁症女性中锥体细胞树突棘和小胶质细胞的变化， 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 MDD 会受到影响，但男性和女性的方向相反。值得注意的是，对啮齿动物的研究报告称，慢性 压力会增加男性的反应性小胶质细胞并降低前额皮质树突的复杂性，但 女性则恰恰相反。因此，啮齿动物提供了一个极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 患有 MDD 的男性和女性 ACC 中的细胞树突棘和反应性小胶质细胞，解决了重大空白 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的转录变化 发生在抑郁的男性和女性中（目标 2）。最后，我们将确定观察到的功能相关性 使用小鼠模型进行性别特异性 MDD 脊柱和小胶质细胞病理学（目标 3）。这些研究对于 了解性别和细胞类型特异性 MDD 病理学并确定这些性别差异是否导致 MDD 症状。此外，他们还将评估针对特定性别的治疗是否可以缓解抑郁相关症状 并为未来针对性别的治疗开发提供重要见解。