Interleukin-1α in the ventral hippocampus increases stress vulnerability and inflammation-related processes.

Mechanisms of stress vulnerability remain elusive. Previous research demonstrated that inflammation-related processes in the brain play a role in stress vulnerability. Our previous research showed that inflammatory processes in the ventral hippocampus (vHPC) induced a stress vulnerable phenotype. To further understand neuroinflammatory processes in the vHPC in stressed rats, we determined that protein levels of the pro-inflammatory cytokine interleukin-1-α (IL-1α), but not interleukin-1β (IL-1β), were increased in the vHPC of rats vulnerable to the effects of repeated social defeat compared to rats resilient to its effects. Injections of IL-1α into the vHPC increased stress vulnerability as characterized by increases in passive coping during defeat and subsequent decreased social interactions. Conversely, injections of recombinant IL-1 receptor antagonist (IL1-RA) increased latencies to social defeat and decreased anxiety-like behaviors during social interaction, suggesting an reduction in stress vulnerability. Protein analyses revealed increased FosB expression in the vHPC of IL-1α-injected rats, and increased HPA activation following a social encounter. Further analysis of vHPC of IL1-α-injected rats showed increased density of microglia, increased expression of the pro-inflammatory cytokine HMGB1, and increases in a marker for vascular remodeling. Taken together, these data show increasing IL-1α during stress exposure is sufficient to produce a stress vulnerable phenotype potentially by increasing inflammation-related processes in the vHPC.LAY SUMMARYOur previous research demonstrated that inflammation-related processes in the brain play a role in inducing vulnerability to the effects of repeated social stress in rats. Here we demonstrate that a pro-inflammatory cytokine interleukin-1-α (IL-1α) induces inflammatory processes in the vHPC and behavioral vulnerability in stressed rats, whereas blocking IL receptors produces the opposite effects on behavioral vulnerability. Together, these results identify a substrate in the vHPC that produces vulnerability to stress by increasing inflammation-related processes in the vHPC.