Prevention of Stress-Impaired Fear Extinction Through Neuropeptide S Action in the Lateral Amygdala

Abstract

Stressful and traumatic events can create aversive memories, which are a predisposing factor for anxiety disorders. The amygdala is critical for transforming such stressful events into anxiety, and the recently discovered neuropeptide S transmitter system represents a promising candidate apt to control these interactions. Here we test the hypothesis that neuropeptide S can regulate stress-induced hyperexcitability in the amygdala, and thereby can interact with stress-induced alterations of fear memory. Mice underwent acute immobilization stress (IS), and neuropeptide S and a receptor antagonist were locally injected into the lateral amygdala (LA) during stress exposure. Ten days later, anxiety-like behavior, fear acquisition, fear memory retrieval, and extinction were tested. Furthermore, patch-clamp recordings were performed in amygdala slices prepared ex vivo to identify synaptic substrates of stress-induced alterations in fear responsiveness. (1) IS increased anxiety-like behavior, and enhanced conditioned fear responses during extinction 10 days after stress, (2) neuropeptide S in the amygdala prevented, while an antagonist aggravated, these stress-induced changes of aversive behaviors, (3) excitatory synaptic activity in LA projection neurons was increased on fear conditioning and returned to preconditioning values on fear extinction, and (4) stress resulted in sustained high levels of excitatory synaptic activity during fear extinction, whereas neuropeptide S supported the return of synaptic activity during fear extinction to levels typical of non-stressed animals. Together these results suggest that the neuropeptide S system is capable of interfering with mechanisms in the amygdala that transform stressful events into anxiety and impaired fear extinction.

Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object recognition memory consolidation

“…Our data is consistent with the finding that NPSR mRNA is widely distributed in the BLA in mice . In addition, local infusion of NPS into lateral/basolateral amygdala is demonstrated to facilitate extinction of conditioned fear memory, and NPS in the lateral amygdala prevents stress-induced impairment of fear extinction (Chauveau et al, 2012;Juengling et al, 2008). Present findings and previous reports suggest that amygdala is crucial for the regulatory effects of NPS on aversive and non-aversive memories.…”

Neuroleptics Affect Neuropeptide S and NPSR mRNA Levels in the Rat Brain

“…It is also suggested that in the rat medial amygdala, NPS stimulates GABAergic inhibitory neurons, reducing fear-related activities (Jungling et al 2008). Moreover, the NPS signaling may be involved in the regulation of HPA axis, because it acts as a part of a negative feedback loop in response to various stress stimuli (Chauveau et al 2012).…”

Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

“…Coronal slices were prepared and whole-cell patch clamp recordings were obtained from principal neurons (PNs) in the lateral amygdala (LA) (Sah et al, 2003), as described previously (Sosulina et al, 2006; for details, see Supplementary Information). After assessing membrane properties, postsynaptic responses were recorded under current-or voltage-clamp conditions, as previously described (Chauveau et al, 2012; for details, see Supplementary Information). Extracellular stimuli (500 ms duration) were delivered every 20 s through a bipolar stainless-steel electrode, placed at thalamic or cortical afferents (Szinyei et al, 2000).…”