Sex-specific Proteomic Adaptations in Microglia in Response to Nicotine Treatment and Withdrawal

Microglia, the resident immune cells of the brain, respond to environmental cues through morphological, transcriptional, and metabolic signaling adaptations. Throughout their life span microglia dynamically participate in many neural processes from synaptic development to functional and structural plasticity through complex patterns of neuroinflammatory signaling between microglia and other neural cells. Evidence indicates that microglia responses are important in drug-reward behaviors and contribute to addiction to various drugs including alcohol, cocaine, opioid, and nicotine. The conceptual premise of this project is that microglia are drivers of innate immune memory within critical neural circuits that mediate drug-associated behaviors. In support of this, there is evidence that although microglia are widely distributed throughout the adult brain, higher expression has been reported in reward centers such as the substantia nigra, basal ganglia, and hippocampus. In collaboration with ongoing research on sex-specific mechanisms of nicotine addiction and withdrawal at the Yale/NIDA Neuroproteomics Center, this project will identify proteomic changes in microglia of adult mice. Initial work will focus on the hippocampus as an important site for sex-specific neuroinflammatory signaling during nicotine addiction and withdrawal.