In C. elegans, nutritional status is translated by both monoaminergic and peptidergic signaling in the modulation of behavior. To characterize these interactions we have examined aversive responses to dilute octanol mediated by glutamatergeric ASH sensory neurons. Previously we demonstrated that food or 5-HT dramatically decreased the time taken to initiate aversive responses and this stimulation required the expression of the neuropeptide encoding gene,
nlp-3, in the ASHs (Harris et al., 2009). Surprisingly, the selective overexpression of
nlp-3 not only in the ASHs, but also a number of other
nlp-3 expressing neurons also increased aversive responses off food. Conversely,
nlp-3 RNAi knockdown in the ASHs or other
nlp-3 expressing neurons abolished the food or 5-HT sensitization of aversive responses, suggesting that
nlp-3 encoded peptides may be humorally released to sensitize the aversive circuit.
nlp-3 encodes three distinct neuropeptides (NLP-3A,B,C) and the injection of NLP-3C directly into wild type animals rapidly and transiently stimulated aversive responses, suggesting that the responses to NLP-3C were not developmentally mediated. In contrast, the injection of NLP-3A or NLP-3B alone had no effect, and, more importantly, the injection of NLP-3A with NLP-3C abolished NLP-3C mediated stimulation, suggesting that neuropeptides encoded by the same gene might play different and potentially antagonistic roles in signaling. As predicted, the overexpression of
nlp-3 or the injection of NLP-3C into
npr-17 null animals had no effect on ASH-mediated aversive responses, supporting the identification of NPR-17 as the NLP-3C receptor. Together, these data suggest that a humoral pool of both tonically and acutely released
nlp-3 encoded peptides sensitize the ASH-mediated locomotory circuit. These studies are continuing to functionally characterize the neuron-specific roles of NPR-17 signaling and how the tonic release of
nlp-3 encoded peptides modulates the 5-HT sensitization of the ASH-mediated aversive circuit. Given the similarities between nematode and mammalian receptors, these studies may provide useful insights into serotonergic/peptidergic interactions in mammals. Supported by NIH grant AI-145147.