PACAP engages distinct signaling programs across cortical neuronal and non-neuronal cell types

Abstract

Neuropeptides form modulatory communication channels that tune neuronal circuits and their functions, often through selective targeting of distinct cell populations. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an important neuropeptidergic regulator of fear and stress. However, its receptors are surprisingly ubiquitous across most brain areas and cell types, making the physiological roles and functional mechanisms difficult to predict. Here, we investigate the cell type-specific effects of PACAP in the temporal association cortex (TeA), a brain region implicated in fear learning and memory. Adcyap1r1, encoding the PACAP receptor PAC1, was broadly expressed across the majority of neuronal and non-neuronal cells. Yet, PACAP engaged highly diverse molecular pathways across functionally distinct cell types that were differentially recruited during auditory fear learning and retrieval, providing a framework for how broad receptor expression can yield specific network modulation. Our data underscore the importance of dissecting cellularly resolved peptidergic signaling to understand functional mechanisms of neuropeptides.