NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking

Abstract

Summary paragraphBinge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies including alcohol abuse, and anxiety1–4. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin–releasing factor (CRF). The central actions of NPY and CRF play opposing functional roles in the regulation of emotional and reward–seeking behaviors; therefore, dysfunctional interactions between these peptidergic systems could play a role in the development of these pathologies. Here, we used converging physiological, pharmacological, and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a novel, Gi-mediated, PKA-dependent postsynaptic mechanism. Further, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of novel therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.

Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

“…For example, Pleil et al (2015) found an effect of chronic alcohol drinking on the BNST that was conserved between mice and monkeys. Importantly, recent neuroimaging studies have shown that the connectivity of the BNST in humans is in large part similar to that of rodents and non-human primates, with the addition of connections between the BNST and more rostral cortical areas such as the orbitofrontal cortex (Avery et al, 2014, Krüger et al, 2015.…”

“…In fact, in another study chemogenetically inhibiting CRF neurons using the designer receptor exclusively activated by designer drugs (DREADD) system caused a reduction in anxiety-like behavior (Pleil et al, 2015). CRF neurons in the BNST are thought to make both local connections as well as project out of the nucleus to regions involved in emotion processing including the periventricular nucleus of the hypothalamus (PVN), ventral tegmental area (VTA), periaqueductal gray (PAG), dorsal potion of the dorsal raphe (DRD) and locus coeruleus (LC) (Dabrowska et al, 2011;Dabrowska & Rainnie, 2014;Meloni et al, 2006;Rodaros et al, 2007;Silberman et al, 2013;Van Bockstaele et al, 1999).…”

“…Whereas PKC-δ + neurons in the CeA L represent -fear off‖ neurons (Haubensak et al, 2010), perhaps Type II PKC-δ + cells represent -anxiety off‖ neurons in the BNST ( Figure 1D). In addition to inhibition via local GABAergic connections, CRF action and CRF neurons themselves are opposed by NPY (Ide et al, 2013;Kash and Winder, 2006;Pleil et al, 2015). In fact, NPY in the BNST has been shown to block CRF-induced-place aversion (Ide et al, 2013).…”

The role of Neuropeptide Y in fear conditioning and extinction

“…Specifically, activation of Gi/o-coupled Y1 receptors reduces NMDA receptor-mediated excitatory postsynaptic currents and increases GABA A receptormediated inhibitory postsynaptic currents by reducing the activity of exchange protein activated by cAMP (Epac) and Protein Kinase A (PKA), respectively (Molosh et al, 2013). It is worth highlighting that the Y1 receptor was also found to increase GABA A receptormediated inhibition in the BNST (Pleil et al, 2015), as this provides a fine example of the similarities in Y receptor function in different brain regions. Thus, these studies provide evidence that NPY likely exerts its potent fear-reducing effects when injected into the BLA by reducing the activity of BLA pyramidal neurons.…”

“…Although many studies have found that NPY typically reduces synaptic transmission, it is interesting to note that NPY can also enhance inhibitory transmission. Pleil et al (2015) demonstrated that the Y1 receptor agonist, Leu 31 Pro 34 NPY increases the frequency of miniature inhibitory postsynaptic currents in BNST neurons probably by increasing the surface expression of postsynaptic GABA A receptors (Pleil et al, 2015).…”