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, ¿FosB, 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 ¿FosB
expression to alter MC dynamics and promote vulnerability to psychiatric diseases associated with
neuroinflammation in the brain. To delineate the mechanisms by which ¿FosB 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 ¿FosB 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 ¿FosB 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.