Repeated Social Defeat Stress Induces Neuroinflammation and Impairs Hippocampal Neurogenesis That Differentially Regulate Mood and Cognition

Repeated social defeat (RSD) is a murine stressor that models several key physiological, immunological, and behavioral alterations observed in humans exposed to psychosocial stress. RSD induces prolonged anxiety-like behavior associated with myeloid cell trafficking into the brain, including the hippocampus. Because the hippocampus (HPC) is a key area involved in neuroplasticity, behavior, and cognition, the goal of this study was to investigate if the stressinduced monocyte trafficking affected hippocampal neurogenesis and cognitive function. Here, we show that RSD increased inflammatory mediators (IL-1β, TNFα and IL-6), enhanced microglia activation and monocyte trafficking (CD45hi) specifically in the caudal hippocampus. RSD also impaired spatial memory recall in the Barnes maze independent of anxiety-like behavior. RSD did not affect the number of proliferating neural progenitor cells and developing neurons when examined 14 hours post-RSD. Nonetheless there was a significant reduction in the number of young neurons and mature neurons in the HPC 10 days and 28 days post-RSD, respectively. Consistent with region-specific neuroinflammation, reduction in the number of mature neurons was greater in the caudal hippocampus of the RSD mice compared to controls. The RSD-induced spatial deficits, which are rostral hippocampus-mediated, were resolved by 28 days. Social avoidance which is caudal hippocampus-mediated still persisted 28 days after stress. Thus, stress-induced neuroinflammation is associated with reduced neuroplasticity, and the stress-induced affective and cognitive deficits are differentially associated with hippocampal neurogenesis.