[
International Worm Meeting,
2021]
Neuromodulators (monoamines and neuropeptides) shape nervous system function by regulating neuronal depolarization and synaptic strengths. We are studying neuromodulation in the context of nociception, to better understand pain perception and pain treatment strategies. The ASH neuron is a major nociceptor in C. elegans. ASH senses 1-octanol and drives an aversive response, modulated by the monoamines serotonin (5-HT, potentiating) and octopamine (OA, inhibitory). To better understand neuromodulation, we are focusing on 1-octanol stimulated Ca2+ dynamics in ASH, and the quantitative relationship between Ca2+ signals and depolarization amplitudes. We showed that 5-HT potentiates ASH depolarization, but surprisingly, inhibits ASH Ca2+ transient amplitudes. These effects, like the 5-HT stimulation of behavior, depend on the SER-5 receptor in ASH. This paradoxical finding is explained by existence of a Ca2+-dependent inhibitory feedback loop: Ca2+ inhibits ASH depolarization through SLO-1 IKCa channels, and 5-HT inhibits EGL-19 L-type Ca2+ channels in ASH (via SER-5), thus disinhibiting the neuron. We are currently investigating modulation of 1-octanol responses by OA. OA inhibits 1-octanol behavioral responses, and antagonizes 5-HT potentiation, dependent on the OCTR-1 receptor in ASH. OA also inhibits ASH Ca2+ transients, representing another paradox: how can OA and 5-HT have opposite effects on ASH-dependent aversive behaviors, but the same effect on ASH Ca2+ transients? Our results show that 5-HT and OA utilize distinct signaling pathways in ASH (Galphaq for 5-HT and Galphao for OA), and that OA does not inhibit EGL-19. We are currently testing the hypothesis that OA hyperpolarizes ASH through Galphao-dependent activation of IRK K+ channels. These results further emphasize that neuronal Ca2+ transients, as key reporters of neuronal depolarization, are also critical signaling intermediates in and of themselves, with multiple upstream inputs and downstream consequences.