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

项目摘要/摘要 小胶质细胞在慢性应激引起的症状中起着重要作用。然而，这些机制 小胶质细胞是如何引起应激诱导的神经回路改变的，目前尚不清楚。我们的初步数据 提示慢性应激导致内侧前额叶皮质小胶质细胞异质性激活。 补体和小胶质细胞介导的突触丢失导致了应激症状。的目标是 拟议的研究是为了确定慢性应激如何导致小胶质细胞的异质性激活。我们假设- 确定慢性应激在特定细胞类型中激活特定细胞类型中特定信号通路，从而局部增加 补体激活和异质性激活小胶质细胞。我们将使用以下内容来验证这一假设 目的：1)鉴定mPFC中所有细胞中的转录本和活跃的转录通路 候选途径和细胞驱动补体激活，以及2)产生一种新的补体C3条件 删除/报告/拯救小鼠品系以删除和恢复特定细胞类型中的C3表达，以检查其 参与应激反应。这些研究将提供新的见解，了解压力是如何加剧 神经功能障碍，并可能导致基于小胶质细胞的新疗法。

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.