Background-Persistent anxiety-like symptoms may have an inflammatory-related pathophysiology. Our previous work using repeated social defeat (RSD) in mice showed that recruitment of peripheral myeloid cells to the brain is required for the development of anxiety. Here, we aimed to determine if 1) RSD promotes prolonged anxiety through redistribution of myeloid cells and 2) prior exposure to RSD sensitizes the neuroimmune axis to secondary subthreshold stress.

Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24 days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-induced social avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24 days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24 days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.

Recent evidence indicates that inflammatory insults in neonates significantly influenced white matter development and caused behavioral deficits that manifest in young adulthood. The mechanisms underlying these developmental and behavioral complications, however, are not well understood. We hypothesize that acute brain inflammation caused by neonatal infection reduces the bioavailability of iron required for oligodendrocyte maturation and white matter development. Here, we confirm that peripheral Escherichia coli infection in neonates at postnatal day 3 (P3) caused acute brain inflammation that was resolved within 72 h. Nonetheless, transient early life infection (ELI) profoundly influenced behavior, white matter development, and iron homeostasis in the brain. For instance, mice exposed to E. coli as neonates had increased locomotor activity and impaired motor coordination as juveniles (P35) and young adults (P60). In addition, these behavioral deficits were associated with marked hypomyelination and a reduction of oligodendrocytes in subcortical white matter and motor cortex. Moreover, ELI altered transcripts related to cellular sequestration of iron in the brain including hepcidin, ferroportin, and L-ferritin. For example, ELI increased hepcidin mRNA and decreased ferroportin mRNA and protein in the brain at P4, which preceded increased L-ferritin mRNA at P12. Consistent with the mRNA results, L-ferritin protein was robustly increased at P12 specifically in neurons of E. coli infected mice. We interpret these data to indicate that neonatal infection causes significant neuronal sequestration of iron at a time point before myelination. Together, these data indicate a possible role for aberrant neuronal iron storage in neonatal infection-induced disturbances in myelination and behavior.

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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.2

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