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

项目概要/摘要 小胶质细胞在慢性应激引起的症状中起重要作用。然而，机制 小胶质细胞通过何种途径引起神经回路中的应激诱导的变化仍不清楚。我们的初步数据 表明慢性压力会导致内侧前额叶皮层中小胶质细胞的异质激活， 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 拟议的研究是确定慢性压力如何导致小胶质细胞的异质激活。我们假设- 估计慢性应激激活特定细胞类型中的层特异性信号通路， 补体激活和非均匀激活小胶质细胞。我们将用以下方法来检验这一假设 目的：1）表征mPFC中所有细胞中的转录组和活性转录途径， 候选途径和驱动补体激活的细胞，和2）产生新的补体C3条件 删除/报告/拯救小鼠系，以删除和恢复特定细胞类型中的C3表达， 参与应激反应。这些研究将提供新的见解，压力如何使许多 神经系统疾病，并可能导致新的小胶质细胞为基础的疗法。

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.