Critical Role of Neuropeptides B/W Receptor 1 Signaling in Social Behavior and Fear Memory

Abstract

Neuropeptide B/W receptor 1 (NPBWR1) is a G-protein coupled receptor, which was initially reported as an orphan receptor, and whose ligands were identified by this and other groups in 2002 and 2003. To examine the physiological roles of NPBWR1, we examined phenotype of Npbwr1 −/− mice. When presented with an intruder mouse, Npbwr1 −/− mice showed impulsive contact with the strange mice, produced more intense approaches toward them, and had longer contact and chasing time along with greater and sustained elevation of heart rate and blood pressure compared to wild type mice. Npbwr1 −/− mice also showed increased autonomic and neuroendocrine responses to physical stress, suggesting that impairment of NPBWR1 leads to stress vulnerability. We also observed that these mice show abnormality in the contextual fear conditioning test. These data suggest that NPBWR1 plays a critical role in limbic system function and stress responses. Histological and electrophysiological studies showed that NPBWR1 acts as an inhibitory regulator on a subpopulation of GABAergic neurons in the lateral division of the CeA and terminates stress responses. These findings suggest important roles of NPBWR1 in regulating amygdala function during physical and social stress.

Mesolimbic neuropeptide W coordinates stress responses under novel environments

“…We have observed the localization of NPW-and TH-immunoreactive fibers, as well as NPBWR1 expression, in the medial region of the CeAL (Figs. 1D and 2 A and B) (21). Although the cellular colocalization of NPBWR1 and D2R remains unconfirmed, considering that both NPBWR1 and D2R are Gicoupled inhibitory receptors, any activity of NPBWR1 + /D2R + neurons in the CeAL would be under potent inhibitory regulation by NPW/dopamine neurons.…”

“…This interpretation is supported by our previous finding that those CeAL neurons that were hyperpolarized by bath application of NPB or NPW in wholecell recordings send short axons within the CeAL or relatively long axons outside the CeAL. These axonal projections were shown by neurobiotin injection after recordings were completed (21). Importantly, therefore, a role of NPBWR1 neurons in conveying fearmediating signals would likely involve such projections.…”

“…Our present results now indicate that a subset of these dopaminergic projections, containing NPW, may play a critical role in the processing of, and adaptation to, novel environmental situations. Elsewhere, we have analyzed and described the behavioral phenotypes of mice with targeted disruption of the NPBWR1 gene (21). NPBWR1-null mice also showed a deficit in social interaction when they encountered a novel conspecific intruder, and they exhibited abnormal autonomic and neuroendocrine responses to physical stress.…”

“…A role for NPBWR1 has been characterized by the phenotypical analysis of NPBWR1-null mice, which demonstrate late-onset obesity with a hyperphagic phenotype (20). These mice also show abnormal social interaction and an aberrant autonomic response to physical stress (21). Recently, an SNP of the human NPBWR1 gene has been shown to influence the evaluation of facial expressions (22).…”

Potency of Animal Models in KANSEI Engineering

“…Neuropeptides have also been shown to affect social behavior by the analysis of knockout mice. Thus, mice lacking the gene for Neuropeptide B/W receptor 1 showed impulsive contact with the strange mice, increased autonomic and neuroendocrine responses to physical stress, and abnormality in the contextual fear conditioning test, suggesting a critical role of Neuropeptide B/W in regulating emotional functions of the limbic system during physical and social stress [16].…”