The Mechanism Of ASK And ASH Neurons In Modulating Nociception And Behavioral Adaptation In C.elegans

The perception and appropriate response of animals to aversive stimuli are crucial to their adaptation to the environment,which is mediated by altering the activity of neurons and neural circuits through a variety of neuroplasticity mechanisms.Existing studies are mostly limited to describing whether animals can sense specific aversive stimuli,but the dynamic plasticity of the aversive sensaion is poorly understood.Therefore,it is crucial to understand the dynamic function of the nervous system and uncover the mechanisms that drive neuroplasticity at various levels.Sensory neurons are at the initial chain of sensory pathways,providing more veridical and instantaneous information for animals to achieve rapid,more fine-tuned,and concentrated behavioral responses.In Caenorhabditis elegans（C.elegans）,paired ASH sensory neurons are the main nociceptor,whereas ADL（Amphid Dual Ciliated Ending L）,ASK（Amphid Single Cilium K）,ASE（Amphid Single Cilium E）,ASI（Amphid Single Cilium I）,and AWB（Amphid Wing Neuron B）play minor roles in the detection of certain chemical repellents.The polymodal sensory neuron ASH mediates the sensation of varieties of noxious stimuli,such as heavy metal ion,hyperosmotic and hypoosmotic stress,SDS,quinine and mechanical stimulation.ASK is a secondary nociceptive neuron,that mediate avoidance behavior from protons,detergents,alkaloids such as quinine.Nociception is tightly regulated by central and peripheral nervous systems.Peripheral modulations of sensation exist universally in various sensory modalities.Peripheral circuitry modulations of nociception include that nociceptive ASI neurons reciprocally inhibit nociceptive ASH in Cu²⁺sensation and secondary nociceptive ASK neurons inhibit ASH nociceptive signal transduction by providing cGMP through gap junctions.Is there a similar regulatory mechanism between ASK and ASH neurons in Cu²⁺sensation and adaptation?In this study,nematodes C.elegans were used as experimental materials,and behavioral screening,neuronal manipulation,genetic analyses,optogenetics,and calcium imaging were comprehensively applied to explore the molecular mechanisms and neural circuits that regulate Cu²⁺avoidance and adaptability.It was found that ASH and ASK neurons positive interact in Cu²⁺avoidance and adaptability.When the C.elegans were exposed to Cu²⁺stimulation,firstly,guanylate cyclase ODR-1（ODo Rant response abnormal-1）generates a second messenger cGMP in ASK neurons,which diffuses to ASH neurons through gap junctions containing INX-4（Innexin-4）and accelerates the calcium response of ASH neurons to Cu²⁺through the cGMP-EGL-4（EGg Laying defective-4）signaling pathway.Secondly,ASH neurons release glutamate and act on glutamate chloride-gated channel receptor GLC-3（Glutamate-gated Ch Loride channel-3）to inhibit AIA（Anterior Interneuron A）interneurons.AIA inhibits ASK through the FLP-1（FMRF-Like Peptide-1）/NPR-5（Neuro Peptide Receptor family-5）neuropeptide signaling pathway.The activation of ASH neurons eliminates the inhibition of AIA to ASK neurons,in other words,ASH neurons promote the activity of ASK neurons through the ASH/AIA/ASK disinhibition circuit.In summary,the positive interaction between ASK and ASH neurons is essential for the rapid rise of calcium dynamics of ASH neurons with Cu²⁺stimulation,and the rapid response ensures slow adaptation,which is of great significance for survival.In this study,we suggest that calcium dynamic characteristics of sensory neurons（intensity and speed of calcium response）are important for the regulation of sensation and behavioral adaptation,and reveal the neural circuits and molecular mechanisms mediating the dynamic plasticity of nociceptive and behavioral adaptation.