The role of Neuropeptide Y in fear conditioning and extinction

Abstract

While anxiety disorders are the brain disorders with the highest prevalence and constitute a major burden for society, a considerable number of affected people are still treated insufficiently. Thus, in an attempt to identify potential new anxiolytic drug targets, neuropeptides have gained considerable attention in recent years. Compared to classical neurotransmitters they often have a regionally restricted distribution and may bind to several distinct receptor subtypes. Neuropeptide Y (NPY) is a highly conserved neuropeptide that is specifically concentrated in limbic brain areas and signals via at least 5 different G-protein-coupled receptors. It is involved in a variety of physiological processes including the modulation of emotional-affective behaviors. An anxiolytic and stress-reducing property of NPY is supported by many preclinical studies. Whether NPY may also interact with processing of learned fear and fear extinction is comparatively unknown. However, this has considerable relevance since pathological, inappropriate and generalized fear expression and impaired fear extinction are hallmarks of human post-traumatic stress disorder and a major reason for its treatment-resistance. Recent evidence from different laboratories emphasizes a fear-reducing role of NPY, predominantly mediated by exogenous NPY acting on Y1 receptors. Since a reduction of fear expression was also observed in Y1 receptor knockout mice, other Y receptors may be equally important. By acting on Y2 receptors, NPY promotes fear extinction and generates a long-term suppression of fear, two important preconditions that could support cognitive behavioral therapies in human patients. A similar effect has been demonstrated for the closely related pancreatic polypeptide (PP) when acting on Y4 receptors. Preliminary evidence suggests that NPY modulates fear in particular by activation of Y1 and Y2 receptors in the basolateral and central amygdala, respectively. In the basolateral amygdala, NPY signaling activates inhibitory G protein-coupled inwardly-rectifying potassium channels or suppresses hyperpolarization-induced I(h) currents in a Y1 receptor-dependent fashion, favoring a general suppression of neuronal activity. A more complex situation has been described for the central extended amygdala, where NPY reduces the frequency of inhibitory and excitatory postsynaptic currents. In particular the inhibition of long-range central amygdala output neurons may result in a Y2 receptor-dependent suppression of fear. The role of NPY in processes of learned fear and fear extinction is, however, only beginning to emerge, and multiple questions regarding the relevance of endogenous NPY and different receptor subtypes remain elusive. Y2 receptors may be of particular interest for future studies, since they are the most prominent Y receptor subtype in the human brain and thus among the most promising therapeutic drug targets when translating preclinical evidence to potential new therapies for human anxiety disorders.

Pancreatic polypeptide and its central Y4 receptors are essential for cued fear extinction and permanent suppression of fear

“…Importantly, also, NPY is crucially involved in both food intake (Loh et al , ) and modulation of emotional affective behaviour, including fear conditioning and extinction (Tasan et al , ). Thus, the NPY system may be at a central node for adapting emotional responses to the present homeostatic situation.…”

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

“…This entails one of the most important stress response systems mentioned above: the activation of the HPA axis, which is stimulated by immune and other stressors, but is attenuated by NPY [6,26]. Furthermore, NPY is implicated in the resilience to stressful or traumatic experiences, whereas a dysfunction of the HPA axis and lower circulating NPY levels can be observed in individuals that do not recover from stress easily [7]. Thus, PTSD patients present with lower plasma and cerebrospinal fluid levels of NPY when compared to healthy individuals [27,28].…”

“…However, such an effect of NPY has not yet been directly demonstrated. Nevertheless, NPY is known to promote stress buffering effects that might prevent affective disorders and are associated with reduced activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is also implicated in the response to immune stress [6,7].…”

How Metabolic State May Regulate Fear: Presence of Metabolic Receptors in the Fear Circuitry

“…In the hippocampus, NPY receptors (Npyr1/2) stood out prominently. The Y1 receptors (Npyr1) and Y2 receptors (Npyr2) are the predominant NPY receptors in the central nervous system (Tasan et al, 2016). While Y1 receptors are post-synaptic and anxiolytic, Y2 receptors are pre-synaptic and anxiogenic, most likely because Y2 receptors inhibit the release of anxiolytic NPY (Wu et al, 2011).…”