Sex differences in behavior and pro-inflammatory cytokine mRNA expression following stressor exposure and re-exposure

Stressful events promote a wide range of neurotransmitter and neuroendocrine changes, which likely serve in an adaptive capacity. However, with repeated stressor exposure, behavioral disturbances, such as anxiety and depression, may develop. Moreover, re-exposure to a stressor for some time following an initial aversive experience may instigate especially pronounced neurochemical variations that favor the emergence of depression and anxiety. These outcomes may stem from any number of neurobiological changes, but increasing attention has focused on the potential contribution of inflammatory factors, such as cytokines. Given the distinct differences in stressor responsiveness that have been reported between males and females, alongside a much higher rate of mood disorders in females, we sought to examine whether repeated exposure to stressors would differentially influence elevated plus-maze behavior in male and female CD-1 mice, and whether such changes would be paralleled by variations of pro-inflammatory mRNA cytokine expression within the prefrontal cortex (PFC) and the hippocampus. In males, the sensitization of interleukin (IL)-1β was evident in both brain regions in those mice that had initially been stressed and then 6 weeks later re-exposed to a stressor exhibiting higher IL-1β expression than did mice stressed on only a single occasion. Females demonstrated higher baseline expression of cytokine expression within the hippocampus, but neither a single exposure nor re-exposure stressor treatment produced significant cytokine elevations. In the PFC an acute stressor treatment increased IL-1R expression, but otherwise had little effect. In a plus-maze test, stressed male mice displayed markedly reduced latencies to the open arms that was evident in a test 6 weeks later irrespective of whether mice were re-exposed to a stressor, whereas in females this outcome was less evident. These studies are consistent with the perspective that female mice are relatively resilient toward stressor-induced cytokine elevations even though in humans females are generally more prone to developing mood disturbances.