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

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.

Grant Number: 1R21MH132078-01A1
NIH Institute/Center: NIH
Principal Investigator: MANZOOR BHAT