Lateral septal PACAP signaling regulates stress and anxiety reactions

Abstract Severe and/or repeated stress exposure can lead to a number of maladaptive physiological and behavioral changes that contribute to psychiatric illnesses. Recent work indicates that the neuropeptide pituitary-adenylate-cyclase-activating-polypeptide (PACAP) plays an important role in stress-related psychopathologies relevant to depression and trauma-related disorders such as PTSD. However, the specific neural circuits that mediate PACAP effects on stress function are not fully understood. One candidate area is the lateral septum (LS), a limbic structure where PACAP and its cognate PAC1 receptors are abundantly expressed. Despite this neuroanatomical evidence, direct functional data supporting a role for septal PACAP/PAC1 receptor signaling in stress regulation are lacking. Using quantitative PCR, we show that forced swim stress increases PACAP mRNA expression in several limbic areas, including the LS, bed nucleus of the stria terminalis and basolateral amygdala, while chronic variable mild stress reduced PACAP expression in the LS only. Providing functional evidence of a PACAP/stress interaction, local administration of PACAP38 into the LS potentiated stress-induced ACTH release and altered stress-coping behavior by increasing passive (floating) and reducing active (struggling) coping during a forced swim challenge. Moreover, intraseptal PACAP38 administration significantly increased anxiety-like behavior in the elevated plus-maze and reduced grooming behavior in the sucrose splashtest, indicating anxiogenic and motivationally disruptive effects following enhanced PACAP signaling in the LS. Importantly, to assess the contribution of endogenous PACAP signaling, intra-LS administration of the PACAP receptor antagonist PACAP(6-38) produced a robust anxiolytic phenotype in the elevated plus-maze. Collectively, these findings provide the first direct evidence that PACAP/PAC1 receptor signaling in the LS modulates emotional and motivational processes in response to stress, identifying this system as a potential target for neuromodulatory interventions in stress-related psychiatric disorders.