SUMMARY Stress- and infection-driven neuroimmune activation in the brain plays a central role in sickness, allergies, and psychiatric diseases like anxiety and depression. Mast cells (MCs) are innate immune cells rapidly activated upon exposure to immune challenges and stress, and they release preformed mediators such as histamine, serotonin, enzymes, and cytokines that regulate inflammation and physiology in the brain, making them well positioned affect brain function and drive behavioral and physiological responses to stress and sickness. Although we know that MC development and function are largely driven by changes in gene transcription, the genetic and transcriptional mechanisms by which MCs are regulated remain poorly understood, and the means to target MCs to treat infection and stress-related diseases remain largely unavailable. We have uncovered a novel transcription factor that limits MC activation and modulation, ΔFosB, and our preliminary data show that mice lacking the FosB gene specifically in MCs are more vulnerable to sickness in response to acute immune activation but show elevated mood and reduced anxiety overall. Thus, we hypothesize that: 1) acute MC activity is limited by FosB gene expression as a mechanism to prevent sickness; and 2) chronic stress or immune activation drives ΔFosB expression to alter MC dynamics and promote vulnerability to psychiatric diseases associated with neuroinflammation in the brain. To delineate the mechanisms by which ΔFosB regulates MC gene expression and function, we will complete the following aims: 1) Determine the role of FosB gene expression in MC function using traditional immunohistochemistry combined with a completely novel ex vivo and in vivo Ca2+ imaging technique; 2) Characterize the role of MC ΔFosB in physiology and behavior using our novel mouse line lacking FosB gene expression specifically in MCs and testing both physiological response to immune challenge and behavioral response to stress; 3) Determine the downstream gene targets of ΔFosB in MCs using RNAseq and CUT & RUN in cultured MCs and an innovative TRAP approach to uncover gene targets in MCs in vivo. Together, these aims will demonstrate a novel mechanism of MC regulation relevant to physiology and disease, introduce and validate new tools critical for the study of MC activity in the living mouse, and uncover new genetic and transcriptional targets in MCs that could be pharmacologically leveraged to treat conditions ranging from allergic reactions to deadly infections to depression and other mood disorders.