PACAP a mediator of inflammation following trauma exposure and mild traumatic brain injury: Differential effects in males and females.

Individual differences in systemic responses to trauma exposure, posttraumatic stress disorder (PTSD), and/or mild traumatic brain injury (mTBI) may help account for differential risk of adverse sequalae in females and heterogeneity in pathophysiology, symptoms, and treatment responses. Accordingly, this study investigated sex differences in the association between neuroendocrine (pituitary adenylate cyclase-activating polypeptide [PACAP]) and inflammatory markers following lifespan trauma exposure, PTSD, and mTBI in 71 trauma-exposed veteran and non-veteran males (n = 41) and females (n = 30). Two mediation models were proposed and evaluated, informed by an existing theoretical model. Both mediation models examined elevated PACAP as a key variable that may be associated with elevated inflammatory cytokine interleukin-6 (IL-6). The first model evaluated this effect following psychological trauma exposure and the second following mTBI. Trauma exposure and mTBI accounted for a large proportion of sex differences in PACAP and inflammation independent of the effects of time since the events (M = 8-11 years), PTSD symptom severity and diagnostic status, suggesting potentially long-term impacts of trauma exposure and mTBI on systemic pathophysiological responses regardless of PTSD symptom variations. Specifically, PACAP mediated the relationship between cumulative trauma exposure and IL-6 as well as mTBI history and IL-6, with a stronger mediating effect of PACAP on mTBI (β = 0.352) than trauma exposure (β = 0.149). Sex differences were observed in which males with mTBI histories had significantly elevated PACAP levels (Hedges' g = 0.79) and females with mTBI histories had significantly elevated IL-6 levels (Hedges' g = 1.03). PACAP was uniquely associated with trauma exposure in females (β = 0.56) and mTBI in males (β = 0.35). Conversely, IL-6 was uniquely associated with mTBI in females (β = 0.47-0.61) and trauma exposure in males (β = 0.42-0.54). For both sexes, childhood emotional neglect was uniquely associated with PACAP and inflammation later in life. This study presents preliminary evidence of the association between PACAP and inflammation following both trauma exposure and mTBI, which was differentially related in males and females. Although further study is needed, findings have the potential to help explicate heterogeneous presentations and differential risk of trauma-related pathology and mTBI that could lead to more targeted and effective treatments.