Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory.

Marieke R Gilmartin,Nicole C Ferrara

doi:10.3389/fncel.2021.663418

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that regulates neuronal physiology and transcription through Gs/Gq-coupled receptors. Its actions within hypothalamic, limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition. Recently, elevated PACAP levels and genetic disruption of PAC1 receptor signaling in humans has been linked to maladaptive threat learning and pathological stress and fear in post-traumatic stress disorder (PTSD). PACAP is positioned to integrate stress and memory in PTSD for which memory of the traumatic experience is central to the disorder. However, PACAP’s role in memory has received comparatively less attention than its role in stress. In this review, we consider the evidence for PACAP-PAC1 receptor signaling in learning and plasticity, discuss emerging data on sex differences in PACAP signaling, and raise key questions for further study toward elucidating the contribution of PACAP to adaptive and maladaptive fear learning.

Highlights

The salient experiences of our daily life create memories that form the narrative of our self
These studies demonstrate a role for forebrain Pituitary adenylate cyclase-activating polypeptide (PACAP) in contextual fear learning and suggest that PAC1 receptor (PAC1R) signaling may be preferentially engaged by aversive events
One candidate mechanism is the regulation of GluN2B-containing NMDARs, which promote recurrent activity in cortical circuits (Wang et al, 2013) and which are needed for trace cued, but not contextual fear learning in the prefrontal cortex and hippocampus (Gao et al, 2010; Gilmartin et al, 2013a)

Summary

Frontiers in Cellular Neuroscience

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that regulates neuronal physiology and transcription through Gs/Gqcoupled receptors. Limbic, and mnemonic systems underlie its roles in stress regulation, affective processing, neuroprotection, and cognition. Elevated PACAP levels and genetic disruption of PAC1 receptor signaling in humans has been linked to maladaptive threat learning and pathological stress and fear in post-traumatic stress disorder (PTSD). PACAP is positioned to integrate stress and memory in PTSD for which memory of the traumatic experience is central to the disorder. We consider the evidence for PACAP-PAC1 receptor signaling in learning and plasticity, discuss emerging data on sex differences in PACAP signaling, and raise key questions for further study toward elucidating the contribution of PACAP to adaptive and maladaptive fear learning

INTRODUCTION

PACAP in Learning and Memory

DISTRIBUTED MEMORY SYSTEMS

CELLULAR AND SYNAPTIC PHYSIOLOGY

SEX DIFFERENCES

OPEN QUESTIONS

CONCLUDING REMARKS