Mesolimbic neuropeptide W coordinates stress responses under novel environments

Abstract

Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stressinduced inhibition was attenuated in the CeAL neurons of NPW −/− mice. Moreover, the response of NPW −/− mice to either formalininduced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW −/− mice in a habituated environment was indistinguishable from that of wildtype mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments.L imbic structures, including the amygdala and bed nucleus of the stria terminalis (BST), where different modalities of environmental stimuli can converge and interact, are critical for the response to stress (1). The basolateral amygdala (BLA) receives sensory information from the thalamus and cortex and transfers that information to the central amygdala (CeA), an output center for the amygdaloid complex. Subsequently, the CeA relays this information through axonal projections to nuclei in diverse areas, such as the hypothalamus, brainstem, and pons (2, 3). These circuits are essential for mediating fear and anxiety, especially for fear conditioning using auditory or visual conditioned stimuli (4, 5). Indeed, in a recent report, optogenetic manipulation of the BLA-CeA pathway was found to modulate the expression of anxiety in the mouse (6).The lateral BST (BSTL) and CeA (CeAL) are two major components of the central extended amygdala, a continuum of telencephalic structures of the forebrain (7,8). Both the BSTL and CeAL contain numerous GABAergic as well as peptidergic neurons, such as those producing enkephalin, corticotropin-releasing factor, and somatostatin (9-13); these GABAergic neurons form dense local inhibitory circuits within these nuclei. The GABAergic microcircuit in the CeAL is thought to play pivotal roles in mediating fear and anxiety, as recently dissected at the cellular level by studies that combined optogenetics and electrophysiology (14-17). A subpopulation of GABAergic neurons in the CeAL, which is inhibited by a conditioned stimulus (CS), is differentiated by the expression PKCδ (14). These PKCδ + GABAergic neurons were shown to provide feed-forward disinhibition on output neurons in the medial CeA (CeAM), resulting in a conditioned freezi...

The role of neuropeptide W in energy homeostasis

“…It has been reported that the inhibitory effect of central NPW on food intake is attenuated by an antagonist of the corticotropin‐releasing hormone (CRH), a hormone that plays an important role in the stress response and inhibition of food intake . This is consistent with another report demonstrating that NPW‐knockout mice have abnormal behaviour responses to pain and predator stress in a novel environment . Similarly, central administration of NPW induces stress‐associated hormone changes and stress responses including increased body temperature, consumption of oxygen, production of heat, arterial blood pressure and heart rate .…”

“…GPR7‐knockout male but not female mice develop adult‐onset obesity, with increased food intake and decreased energy expenditure . However, NPW‐knockout male and female mice show normal body weight and food intake . In the NPW‐knockout mice, there could be compensation, for the lack of NPW, via other appetite‐regulating pathways, such as leptin‐ or NPB‐mediated pathways.…”

“…35,36 This is consistent with another report demonstrating that NPW-knockout mice have abnormal behaviour responses to pain and predator stress in a novel environment. 37 Similarly, central administration of NPW induces stress-associated hormone changes 29 and stress responses including increased body temperature, consumption of oxygen, production of heat, arterial blood pressure and heart rate. 30,38,39 On the other hand, stress may also influence the direct effects of NPW on food intake regulation in the hypothalamus.…”

“…32 However, NPW-knockout male and female mice show normal body weight and food intake. 37 In the NPW-knockout mice, there could be compensation, for the lack of NPW, via other appetite-regulating pathways, such as leptin-or NPBmediated pathways. NPB-knockout male mice also develop an adult-onset obesity which certainly suggests a role for NPB in energy homeostasis.…”

Distribution and Function of Neuropeptides W/B Signaling System

“…In the mouse brain, in situ hybridization method was used to analyze NPW mRNA distribution, which was detected in the hippocampus, periaqueductal gray, ventral tegmental area, EW, and dorsal part of dorsal raphe nucleus ( Tanaka et al, 2003 ; Kelly et al, 2005 ). Immunohistochemistry revealed presence of NPW peptide in the axon terminals within central amygdala nucleus and bed nucleus of the stria terminalis ( Motoike et al, 2016 ).…”