No fear no stress with neuropeptide S

Abstract

Amino acid and amine transmitters serve the general basic functions in many behaviours, whereas specific brain functions, recognized as an entity in our behavioural definitions are sometimes organized by groups of neurons using a particular peptide transmitter. These include neurons triggering the release of hormones, like those carrying the corticotropin releasing factor (CRF) in response to stress and those involved with complex behaviours like fear. Neuropeptide S (NPS), composed of 20 amino acids, is the endogenous ligand for the former orphan GPR154, now the neuropeptide S receptor (NPSR), which is highly conserved in vertebrates including man. NPS-neurons are found mainly in the brainstem, particularly also in the locus coeruleus, and they possess prominent projections to prefrontal cortex and the amygdala, regions involved in emotions and coping with fear. With reference to work done on both rats and mice, in spite of differences regarding locations, numbers and projections of NPS neurons they follow a similar pattern. NPS controls both afferent and efferent neurotransmission in the amygdala through mobilization of intracellular Ca2+ and the cyclic AMP–PKA pathway. Polymorphisms in the human NPS receptor gene have been associated with altered sleep behaviour and panic disorder (review by Pape et al. 2010). Central NPS injection in rodents results in arousal and anxiolysis (Xu et al. 2004), the former probably through activation of wake-on neurons in brainstem and hypothalamus, the latter through a reduction of fear expression and the facilitation of fear extinction (Juengling et al. 2008). The latter removes memories of stressful and traumatic events which can cause anxiety disorders. Chaveau et al. (2012) reported recently prevention by NPS and aggravation by an NPS antagonist of stress induced aversive behaviour in mice. Patch-clamp recordings in slices revealed a clear correlation between synaptic activity and states of fear and fear extinction in lateral amygdala projection neurons. NPS counteracts the stress-induced impairment of fear extinction. In an article in this issue ofThe Journal of Physiology, Juengling et al. (2012) have now investigated the source of stress-related NPS activation in transgenic mice, allowing the behavioural and electrophysiological characterization of vital NPS neurons through the expression of enhanced green-fluorescent protein (EGFP). The corticotropin-releasing factor (CRF) is an obvious candidate found in axonal varicosities near the NPS neurons. In addition to the CRF-containing neurons in the hypothalamus that activate the adrenal stress axis, there are a number of CRF sources including the amygdala and the inferior olive. CRF excites NPS neurons in the locus coeruleus region through the CRF1 receptor and two mechanisms at the membrane level: reduction of a potassium conductance and activation of a cation conductance involving PKA signalling which is frequently associated with synaptic plasticity (Fig. 1). Figure 1 A pathway for the modulation of fear and anxiety These data show a direct link between the CRF and NPS systems and suggest a mechanism for stress-related, CRF-mediated NPS activation, buffering stress responsiveness in target areas such as the amygdala. It will be most interesting to relate NPS receptor variants to stress responsiveness in humans.