Peripheral serotonergic neurons regulate anxiety-like behavior and intestinal barrier immunity

Abstract Serotonergic circuits in the central nervous system play important roles in regulating mood and behavior, yet the functions of peripheral serotonergic neurons (PSN) are less understood. Here, we engineered mice lacking the serotonin-producing enzyme Tph2 in peripheral neurons but with intact Tph2 in central neurons. We discovered that PSN contribute to gut motility and are important in the control of anxiety-like behavior. These animals also had reduced abundance of serotonin receptor 7 ( Htr7 )-positive dendritic cells (DC) and IgA + B cells in the small intestine and elevated susceptibility to oral Salmonella infection. Mechanistic studies suggest that PSN derived serotonin promotes gut homing/retention and activation of DC through Htr7 , thereby facilitating DC-mediated differentiation of IgA + B cells from IgD + precursors. Bioinformatic analyses of our single-cell RNA-seq data uncovered novel patterns of bidirectional communication between specific subsets of enteric neurons and DC. Our findings underscore the interplay between enteric neurons and innate immune defense. In brief Peripheral serotonergic circuits are hubs for control of specific behaviors, gut motility and innate immune defense. Highlights Peripheral serotonergic circuits control specific aspects of behavior. Peripheral serotonergic neurons regulate gut motility, immunity and host defense. Enteric serotonergic neurons remodel dendritic cell function to facilitate IgA B cell differentiation. Bidirectional communication between enteric neurons and innate immune cells.