Mast cells as Immune modulators of behavior and brain cellular composition

Abstract

Abstract Mast cells (MC) are involved in peripheral disease such as allergy/anaphylaxis, but they are also present in brain where they can modulate behavior. MC deficient KitW–sh/W–sh (sash) mice have been reported to show increased anxiety-like behaviors compared to wild type (WT) mice, but these studies did not consider potential interactions with sex and/or stress, which is relevant considering that MCs are sexually dimorphic and stress-sensitive. Here, wild type (WT) and sash male and female mice were exposed to control handling or mild environmental stress and then phenotyped for behaviors relevant to human mood disorders. Stress did not alter anxiety or motivated behaviors in WT. Compared to WT, sash showed increased anxiety, which was independent of sex or stress. A measure of depressive-like behavior in rodents is preference for sucrose water over regular water. In females, sash showed reduced sucrose preference compared to WT, which was exacerbated by stress. In males, control sash and WT showed similar sucrose preference, but stress induced sucrose anhedonia only in sash. To explore the underlying mechanisms, we studied the Nucleus Accumbens, a brain area involved in anxiety and motivation. We found that sash have a reduced number of astrocytes and a two-fold higher number of cells expressing FosB, a transcription factor induced by stress and involved in synaptic plasticity and behavior. Together, these data implicate MCs as key immune modulators of brain cellular composition and activity. Our ongoing investigations aim at deeply understanding the role that MCs play on mood and cognition, which could provide significant insights into the mechanisms underlying human psychiatric disease and inform new therapeutic targets.