Heterogeneous microglia activation mediates stress-induced changes in neural circuitry.

异质小胶质细胞激活介导应激引起的神经回路变化。

基本信息

批准号：
10741172
负责人：
Gek Ming Sia
金额：
$ 41.03万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-08 至 2025-09-07
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10741172
关键词：
ATAC-seq Affect Alleles Area Automobile Driving Biological Assay Brain Brain Diseases Candidate Disease Gene Cell Nucleus Cells Chromatin Chronic Chronic stress Complement Complement 3 Complement Activation Corticosterone DNA cassette Data Disease Progression Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Goals Immune Initiator Codon Knockout Mice Medial Mediating Microglia Modeling Morphology Multiple Sclerosis Mus Pathogenesis Pathway interactions Phagocytosis Play Prefrontal Cortex Production Protocols documentation Psychological Models Psychological Stress Reporter Reporter Genes Research Resources Role Schizophrenia Scientist Signal Pathway Signal Transduction Specificity Stress Symptoms Synapses TNFSF5 gene Testing Therapeutic Transposase Work associated symptom biological adaptation to stress candidate identification cell type cytokine design glial activation inducible Cre insight mouse model multiple omics nervous system disorder neural circuit novel public database restraint stress single nucleus RNA-sequencing stress symptom synaptic pruning transcriptome

项目摘要

Project Summary/Abstract Microglia play an important role in the symptoms caused by chronic stress. However, the mechanisms through which microglia cause stress-induced changes in neural circuitry remain unclear. Our preliminary data suggests that chronic stress causes heterogeneous activation of microglia in the medial prefrontal cortex, and that complement- and microglia-mediated synapse loss contribute to the symptoms of stress. The goal of the proposed research is to determine how chronic stress causes heterogeneous activation of microglia. We hypoth- esize that chronic stress activates layer-specific signaling pathways in specific cell types which locally increase complement activation and heterogeneously activate microglia. We will test this hypothesis with the following aims: 1) characterize the transcriptomes and active transcriptional pathways in all cells in the mPFC to identify candidate pathways and cells driving complement activation, and 2) generate a novel complement C3 conditional deletion/reporter/rescue mouse line to delete and restore C3 expression in specific cell types to examine their involvement in the stress response. These studies will provide new insights into how stress aggravates numerous neurological disorders, and may lead to new microglia-based therapeutics.

项目概要/摘要小胶质细胞在慢性应激引起的症状中发挥着重要作用。然而，这些机制小胶质细胞通过何种方式引起应激诱导的神经回路变化仍不清楚。我们的初步数据表明慢性压力会导致内侧前额叶皮层小胶质细胞的异质激活，并且补体和小胶质细胞介导的突触损失会导致应激症状。的目标拟议的研究旨在确定慢性压力如何导致小胶质细胞的异质激活。我们假设—— 认为慢性压力会激活特定细胞类型中的层特异性信号传导途径，这些信号传导途径会局部增加补体激活和异质激活小胶质细胞。我们将用以下方法检验这个假设目标：1) 表征 mPFC 中所有细胞的转录组和活性转录通路，以识别驱动补体激活的候选途径和细胞，2) 生成新的补体 C3 条件删除/报告/救援小鼠系删除并恢复特定细胞类型中的 C3 表达，以检查其参与应激反应。这些研究将为压力如何加剧许多人的健康问题提供新的见解。神经系统疾病，并可能导致新的基于小胶质细胞的疗法。