Microglia-Mediated Astrocyte Activation in Chronic Pain

Project Abstract

While acute pain is an important biological signal in response to injured tissue, chronic pain occurs when the pain signaling outlasts the initial injury and has deleterious effects on health and quality of life. Chronic pain represents an enormous public health burden with few therapeutic options. After a pain causing peripheral injury, spinal cord microglia, the resident immune cells of the CNS, become acutely activated. This is followed by astrocyte activation, which is long-lasting and contributes to the chronic pain state. Preventing activation of astrocytes represents a key therapeutic target. Microglia manipulation may provide a tool to prevent or alter astrocyte activation, which in turn may prevent pain from becoming chronic. Previous research from our lab has shown that depletion of microglia at the time of transition from acute pain to chronic pain prevents chronic pain. I hypothesize that at the acute-to-chronic transition microglia are necessary and sufficient to activate astrocytes and that microglia effects in chronic pain are entirely dependent on astrocyte activation. In Aim 1, I will characterize astrocyte activation in a mouse model of pain-producing peripheral injury after selective depletion of microglia at the acute-to-chronic pain transition. I will further use DREADDs to exogenously activate microglia in uninjured mice to determine the effect of microglia activation on astrocyte state. In Aim 2 I will determine which signals from microglia are important for astrocyte activation in the induction of chronic pain using cell-cell interaction analyses of single nuclei RNA-Sequencing data from astrocytes and microglia. Using the interdisciplinary experiments in this research proposal, I will uncover the relative roles and contributions of microglia and astrocytes to chronic pain and generate new targets for pain therapeutics.