Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice

Abstract

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have been implicated in stress regulation and learning and memory. Several bodies of research have shown the impact of the PACAP specific receptor PAC1 on fear memory, but the roles of other PACAP receptors in regulating fear stress responses remain to be elucidated. Here we aimed to investigate the effects of genetic deletion of VIPR2 encoding the VPAC2 receptor, which binds both VIP and PACAP, on fear-related memory and on dendritic morphology in the brain regions of the fear circuitry. Male VPAC2 receptor knockout (VPAC2-KO) and littermate wild-type control mice were subjected to Pavlovian fear conditioning paradigm. VPAC2-KO mice displayed normal acquisition of fear conditioning, contextual and cued fear memory, but impaired extinction of cued fear memory. Morphological analyses revealed reductions in cell body size and total branch number and length of apical and basal dendrites of prelimbic cortex neurons in VPAC2-KO mice. In addition, Sholl analysis indicated that the amount of dendritic material distal to the soma was decreased, while proximal dendritic material was increased. In the infralimbic cortex, the amount of apical dendritic material proximal to the soma was increased in VPAC2-KO mice, while other indices of axonal morphology did not differ. Finally, there were no differences in dendritic morphology in basolateral amygdala neurons between genotypes. These findings suggest that the VPAC2 receptor plays an important role in the fear extinction processes and the regulation of the dendritic morphology in the prelimbic and infralimbic cortices.

Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism

“…Overall, the results suggest that the activation of the VPAC2 receptor delays or limits the maturation in mouse cortical neurons. In a previous study, we also found that adult VPAC2 receptor knockout mice show abnormal dendritic morphology in the prelimbic and infralimbic cortices, but not basolateral amygdala (Ago et al, 2017). Loss of the VPAC2 receptor reorganized apical and basal dendritic arbors of prelimbic cortex neurons and apical, but not basal, dendritic arbors of infralimbic cortex neurons.…”

“…Recently, Tian et al (2019) have developed a conditional human VIPR2 CNV bacterial artificial chromosome (BAC) transgenic (hVIPR2-BAC tg) mouse model of VIPR2 CNV, and they reported that hVIPR2-BAC tg mice showed cognitive, sensorimotor gating, and social behavioral deficits and decrease in the complexity of dendritic arborization of the striatal spiny projection neurons. Additionally, VPAC2 receptor knockout mice have abnormal dendritic morphology of the prefrontal cortex neurons, but not basolateral amygdala neurons (Ago et al, 2017). These findings suggest that the VPAC2 receptor plays an important role in the regulation of the dendritic morphology and overactivation of the VPAC2 receptor might impair neural development in the brain.…”

“…The generation of VPAC2 receptor deficient mice using gene targeting has been previously reported (Harmar et al, 2002). VPAC2 receptor homozygous knockout mice and littermate wild-type mice (C57BL/6 strain) used here were obtained by crossing with VPAC2 receptor heterozygous mice (Ago et al, 2017). Mice were housed in clear cages in groups of 3-5 animals under controlled environmental conditions (22 ± 1 • C; 50 ± 10% relative humidity; a 12-h light-dark cycle, lights on at 0800 h; food and water ad libitum).…”

A 3’ UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction

“…VIP play diverse roles in the central nervous system, including the control of circadian rhythms, learning and memory, psychiatric illness, and responses to stress [30]. Vipr2 ( Vpac2 ) knockout mouse lacks circadian control [30] and also exhibits impaired extinction of cued fear memory and regulation of the dendritic morphology [31]. VIPR2 is located in the subtelomeric region of chromosome 7 and VIPR2 duplications were indicated in the etiology of autism [32].…”

Pituitary Adenylate Cyclase-Activating Polypeptide in Learning and Memory

“…Pituitary adenylate cyclase-activating polypeptide can also influence memory via modulation of intrinsic physiology (see Open Questions) and via developmental maturation of memory circuits (reviewed in Shen et al, 2013 ). For example, developmental knockout of VPAC2 which is sensitive to both VIP and PACAP prevented the formation of fear extinction memory in adulthood ( Ago et al, 2017 ). Importantly, VPAC2-KO mice had reduced cell size and dendritic branching in the prelimbic cortex, morphological changes similar to those observed after chronic corticosterone exposure and chronic stress, conditions which also produce fear extinction deficits ( Wellman, 2001 ; Radley et al, 2004 , 2006 ; Moench and Wellman, 2017 ; reviewed in Wellman et al, 2020 ).…”