Serotonin modulates many key behaviors in C. elegans, including the stimulation of aversive responses to dilute octanol mediated by the ASH sensory neurons (Harris et al., 2009, J. Neuroscience 29, 1446-1456). The serotonergic stimulation of ASH-mediated aversive responses requires the expression of SER-5 in the ASHs, but the site of SER-5 action is unclear. For example, SER-5 signaling may increase the release of glutamate and/or neuropeptides from the the ASHs. Indeed, the ASHs express multiple peptide encoding genes, including
nlp-3 and
nlp-15, and the peptides encoded by these genes have multiple effects on ASH signaling. For example,
nlp-3 null animals exhibit wild-type basal responses to dilute octanol, but do not increase aversive responses in the presence of food or 5-HT. In contrast,
nlp-15 null animals exhibit elevated basal responses to dilute octanol in the absence of either food or 5-HT and these elevated basal responses are not inhibited by octopamine. As predicted, animals overexpressing
nlp-15 respond only weakly to dilute octanol and exhibit dramatically reduced basal responses. Interestingly, in these
nlp-15 overexpressors, aversive responses can be stimulated to near wild-type levels by food or 5-HT. Together, these results suggest that
nlp-15 inhibits ASH signaling by a mechanism that may not directly involve NT release from the ASHs. These observations have been confirmed by the ASH rescue and RNAi knockdown of
nlp-15 and
nlp-3. In addition, we have identified a number of other genes encoding peptides and peptide receptors that are also involved in modulating various aspects of ASH mediated signaling, highlighting the complexity of peptidergic modulation. These studies are continuing with the goal of identifying the receptors and downstream signaling pathways mediating the differential effects of
nlp-3 and
nlp-15 on signaling in the ASH sensory neurons.