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

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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.