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: 9795535
• 负责人: Marianne L Seney
• 金额: $ 39.13万
• 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/9795535
• 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; 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; 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）是残疾的主要原因，影响超过3亿人 全世界。 MDD的发生率有众所周知的性别差异，女性的可能性是 被诊断为男人。此外，男性和女性的MDD影响有所不同，性别差异 症状，严重程度和症状数量。例如，女性的可能性是 非典型抑郁症，其特征是高血压和体重增加。这些明显的差异 抑郁的男性和女性之间的症状学使我们假设MDD在分子上有所不同 男女之间的水平。我们最近使用了使用MDD的性别特异性分子病理 人类验尸大脑分析。我们首次表明抑郁症不仅在男性中与众不同，而且 妇女，但具有相反的分子病理学。最强烈的相反影响是 前扣带回皮层（ACC; Brodmann区域25），这是一个与MDD病理相关的大脑区域。 我们对MDD男性的分析发现，突触功能标记的降低和标记的增加 小胶质细胞和炎症，与锥体细胞树突状脊柱突触减少的报道一致 抑郁症男性的反应性小胶质细胞增加。 MDD雄性的分子变化与A一致 反应性小胶质细胞参与过度的病理突触去除的模型。令人惊讶的是，我们的 对患有MDD的女性的分析发现，突触功能的标记增加了，加上降低的标记 免疫功能和小胶质细胞，这与抑郁的男性完全相反。但是，没有研究 检查的锥体细胞树突状脊柱和小胶质细胞在抑郁妇中特异性变化，留下 抑郁文献中的主要差距。总之，这些研究表明锥体细胞和小胶质细胞是 在MDD中受到影响，但男性和女人的方向相反。值得注意的是，啮齿动物的研究报告了慢性 压力增加了反应性小胶质细胞，并降低了男性的前额叶皮层树突状复杂性，但DO 在女性中恰恰相反。因此，啮齿动物为探测分子提供了出色的模型系统 在人MDD中观察到的性别特异性病理的基础机制。在这里，我们将评估金字塔 男性和女性MDD的ACC中的细胞树突状刺和反应性小胶质细胞，解决了主要差距 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性的转录变化 发生在沮丧的男人和女人中（目标2）。最后，我们将确定观察到的功能相关性 使用小鼠模型的性别特异性MDD脊柱和小胶质细胞病理（AIM 3）。这些研究对于 了解性别和细胞类型特异性的MDD病理学，并确定这些性别差异是否驱动MDD 症状。此外，他们将评估特定于性别的治疗是否减轻了与抑郁症相关的症状 并为未来的性别治疗发展提供关键见解。