Prefrontal Cortex PACAP Signaling: Organization and Role in Stress Regulation

MARTELLE, SUSAN E.; COTELLA, EVELIN M.; NAWREEN, NAWSHABA; CHEN, CARRIE; PACKARD, BENJAMIN A.; FITZGERALD, MAUREEN; HERMAN, JAMES P.

STRESS

TAYLOR & FRANCIS LTD

Lugar: Londres; Año: 2021

1025-3890

Pituitary adenylate cyclase-activating polypeptide (PACAP) is anexcitatory neuromodulatory peptide strongly implicated in nervous stress processing.Human polymorphism of the primary PACAP receptor (PAC1) is linked to psychiatricdisorders, including posttraumatic stress disorder (PTSD). Prefrontal cortex PACAPsignaling is associated with processing of traumatic stress and fear learning, suggestinga potential role in PTSD-related deficits. We used RNAscope to define the cellularlocation of PACAP and PAC1 in the infralimbic cortex (IL). Subsequent experimentsused a pharmacological approach to assess the impact of IL PACAP infusion onbehavioral and physiological stress response and fear memory. Adult male Sprague-Dawley rats were bilaterally microinjected with PACAP (1 ug) or vehicle into the IL, 30minutes prior to forced swim test (FST). Blood was sampled at 15, 30, 60, and 120minutes for analysis of hypothalamic pituitary adrenal (HPA) axis reactivity. Five daysafter, animals were tested in a 3-day passive avoidance paradigm with subsequenttesting of fear retention two weeks later. We observed that PACAP is highly expressedin putative pyramidal neurons (identified by VGlut1 expression), while PAC1 is enrichedin interneurons (identified by GAD). Pretreatment with PACAP increased active copingstyle in the FST, despite higher levels of ACTH and corticosterone. The treatment wasalso sufficient to cause an increase in anxiety-like behavior in a dark/light crossover testand enhanced retention of passive avoidance. Our data suggest that IL PACAP plays arole in driving stress responses and in processing of fear memories, likely mediated byinhibition of cortical drive.