Dissecting The Neural Circuitry And Molecular Mechanisms Underlying Nociception Modulation In C. Elegans

Animals must make a correct choice to response to the environment and adapt to it when live in a complex environment. Sensory modulation is essential for animal sensations, behaviors and survival, but the modulation of nociception and avoidance behavior is poorly understood. Study on how an organism response to a harmful stimulus is important for understanding of the nociception modulation.Due to numerous advantages, such as a short life span, transparent body, well-understood nervous system, easy genetic manipulations and so on, we chose Caenorhabditis elegans as a model organism to study the molecular mechanism and neural circuit of the nociception. The C. elegans has 12 pairs of amphid sensory neurons which have a clear division of responsibilities. The polymodal sensory neurons ASHs are the primary neurons that can detect nociceptive and aversive stimuli including water solution containing heavy metals and quinine, some noxious odors, temperature, touch to the nose, high or low osmolarity and so on. There are a large number of studies on the molecular mechanisms and neural circuits of the ASH neurons mediating the nociception and avoidance behavior. The ASIs are key sensory neurons for the entry into dauer by integrating high population density, low food availability, the level of CO2, sex pheromone and so on. Besides, it also participate in the sensory modulation of high temperature and aversive stimuli. The AWC olfactory neurons are important in the sensitivity to attractive odours and temperature, and AWCON has a potential to direct both attraction and repulsion, which needs a receptor-like guanylate cyclase GCY-28 that acts in adult worms and localizes to AWCON axons. It is recently reported that AWCON can response to high salt acts as an interneuron.Here, using a reverse genetic screen as well as behavior assays, in vivo calcuim imaging, general genetic manipulation and cell-specific gene knockdown methods, we investigate the molecular mechanism and neural circuit of ASHs and ASIs mediating nociception and avoidance behaviors, and how the AWC olfactory neurons modulate nociception by receiving signaling from the ASIs. We found that the sensory neuron ASIs modulate the ASHs copper ions reception and copper ions-aversive behaviors by cross-inhibition with ASHs. In this neural circuit, ASHs respond to the nociceptive Cu2+ stimulus quickly and robustly, which allows ASHs to predominate over and inhibit ASIs at the initial stage. ASI sensory neurons are secondary copper ions sensory neurons, because they have a weaker copper ions response. Meanwhile, ASIs inhibit ASHs during the application of copper ions solution. The molecular mechanism and neural circuit under cross-inhibition is that the ASIs release neuropeptides to promote the serotoninergic neuron ADFs that release 5-HT that act on the SER-5 receptor to inhibit ASHs activity. At the same time, the ASHs activate the octopaminergic neuron RICs through gap junction, the RICs release octopamine act on the SER-3 receptor to inhibit the activity of ASIs. The peripheral modulations of nociception and avoidance behaviors are direct and faster than the central nervous system modulation. The ASIs modulation of ASH-mediated nociception determined by this work suppresses the super sensation and super behavioral responses. Besides, we found that ASIs inhibit super sensation and super behavioral responses through AWCs. In this pathway, ASIs relsease neuropeptides acting on the insulin receptor DAF-2 activate AWCON, and AWCON acts as an interneuron that release glutamate and neuropeptides to inhibit super sensation to copper solution, this super sensation inhibition may be mediated by the downstream interneurons AIBs or others.The ASIs are very important for nociception and avoidance behavior, it may decrease the sensitivity to nociceptive stimuli through two different pathways. The first pathway is that ASIs promote release of 5-HT from ADFs to inhibit the activity of ASHs, and decrease of the ASHs activity may decreases the activity of AIBs to inhibit the super sensation behavior. The other pathway is that ASIs facilitate release of glutamate and neuropeptides from AWCON to inhibit the super sensation behavior.