Figure 2. Schematic illustrating the proposed relationship between pituitary adenylate cyclase-activating polypeptide (PACAP)-PAC1 receptor (PAC1R) signaling and fear/stress processes elicited by trauma exposure. (Left) The predominant gonadal hormone in females, estradiol (E,), and trauma both regulate the PACAP-PAC1R system in the female brain to drive normal fear and stress processes. (Right) Females, but not males, with high plasma PACAP38 levels and PAC1R polymorphisms may have altered PACAP-PAC1R signaling, which consequently drives pathological fear and stress processes associated with posttraumatic stress disorder (PTSD). This schematic diagram suggests that the responsiveness of the PACAP-PAC1R system to E, might be important in regulating PACAP-PAC1R activation of fearand stress-dependent pathways and phenotypes that underlie the sex-bias in PTSD prevalence. ERE, estrogen responsive element; E2, estradiol; Trauma, psychological trauma; PACAP, pituitary adenylate cyclase-activating polypeptide .