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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

基本信息

批准号：
10618845
负责人：
Marianne L Seney
金额：
$ 38.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618845
关键词：
Address Affect Age Anterior Atypical depressive disorder Autopsy Behavior Biological Models Brain Brain Pathology Brain region Brodmann&apos s area Calcium Signaling Cd68 Chronic stress Coupled Dendritic Spines Depressed mood Diagnosis Disease Excision Exhibits Female Future Gene Expression Gene Expression Profile Genetic Transcription 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 Prevalence 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 inflammatory marker insight male men molecular pathology mouse model sex symptomatology synaptic function therapy development transcriptome sequencing transcriptomics

项目摘要

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.

摘要