Neuropeptide S-Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala

Abstract

Summary A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice. An NPS receptor antagonist exerts functionally opposing responses, indicating that endogenous NPS is involved in anxiety behavior and extinction. Cellularly, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala via presynaptic NPS receptors on connected principal neurons. These results identify mechanisms of NPS in the brain, a key role of intercalated neurons in the amygdala for fear extinction, and a potential pharmacological avenue for treating anxiety disorders.

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

“…Therefore, it can be concluded that the increase in NPS signaling may critically affect the regulation of anxiety behavior, chronic pain, and restlessness. 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).…”

“…One of the proposed mechanisms of NPS anxiolytic activity is its influence on memory processes. Peptide administration into the mouse amygdala results in conditioned fear elimination, but it has no effect before the conditioning process (Jungling et al 2008).…”

Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic

“…The NPSR1 T allele was furthermore found to be associated with decreased prefrontal control in an emotional stroop task paradigm (Tupak et al, 2012) as well as increased amygdala activity in healthy participants (Dannlowski et al, 2011) and decreased activity in the prefrontal cortex and the ACC in patients with PD during emotional processing. The NPS system is of particular interest regarding the suggested excitatory/inhibitory dysbalance involving GABA and glutamate neurotransmission in anxiety and PD, since NPS precursor is co-expressed with glutamate in brainstem nuclei (Xu et al, 2007), NPS has been shown to alleviate neuropathological, neurochemical and behavioral changes produced by N-methyl-D-aspartate (NMDA) receptor antagonists in the murine model (Okamura et al, 2010), and an increased glutamatergic synaptic transmission to intercalated GABAergic neurons in the amygdala has been identified to accompany the effects of NPS administration on anxiety-like behavior in mice (Jungling et al, 2008).…”

Neuropeptide S receptor gene: Fear-specific modulations of prefrontal activation

“…By binding to the NPSR, NPS elicits increases in intracellular calcium and cyclic adenosine monophosphate (Reinscheid et al, 2005). Central NPS administration had anxiolytic effects on rodent behavior in a number of tests including the open field, light-dark box, elevated plus/zero maze, four-plate test, and marble-burying test (Jüngling et al, 2008;Leonard et al, 2008;Xu et al, 2004). Ionescu et al (2012) recently developed a method to apply NPS intranasally with similar effects in the light-dark box test, particularly in mouse strains with high innate anxiety behavior.…”