Department of Biological Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Genetics. 2023 Apr 6;223(4). doi: 10.1093/genetics/iyad017.
Organisms rely on chemical cues in their environment to indicate the presence or absence of food, reproductive partners, predators, or other harmful stimuli. In the nematode Caenorhabditis elegans, the bilaterally symmetric pair of ASH sensory neurons serves as the primary nociceptors. ASH activation by aversive stimuli leads to backward locomotion and stimulus avoidance. We previously reported a role for guanylyl cyclases in dampening nociceptive sensitivity that requires an innexin-based gap junction network to pass cGMP between neurons. Here, we report that animals lacking function of the gap junction component INX-20 are hypersensitive in their behavioral response to both soluble and volatile chemical stimuli that signal through G protein-coupled receptor pathways in ASH. We find that expressing inx-20 in the ADL and AFD sensory neurons is sufficient to dampen ASH sensitivity, which is supported by new expression analysis of endogenous INX-20 tagged with mCherry via the CRISPR-Cas9 system. Although ADL does not form gap junctions directly with ASH, it does so via gap junctions with the interneuron RMG and the sensory neuron ASK. Ablating either ADL or RMG and ASK also resulted in nociceptive hypersensitivity, suggesting an important role for RMG/ASK downstream of ADL in the ASH modulatory circuit. This work adds to our growing understanding of the repertoire of ways by which ASH activity is regulated via its connectivity to other neurons and identifies a previously unknown role for ADL and RMG in the modulation of aversive behavior.
生物体依赖环境中的化学线索来指示食物、繁殖伴侣、捕食者或其他有害刺激的存在或缺失。在秀丽隐杆线虫中，双侧对称的 ASH 感觉神经元作为主要的伤害感受器。有害刺激激活 ASH 会导致向后运动和刺激回避。我们之前报道过鸟苷酸环化酶在抑制伤害感受敏感性中的作用，这种作用需要一个连接蛋白为基础的间隙连接网络来在神经元之间传递 cGMP。在这里，我们报告说，缺乏间隙连接成分 INX-20 的动物对通过 G 蛋白偶联受体途径在 ASH 中信号的可溶性和挥发性化学刺激的行为反应过度敏感。我们发现，在 ADL 和 AFD 感觉神经元中表达 inx-20 足以抑制 ASH 的敏感性，这得到了通过 CRISPR-Cas9 系统用 mCherry 标记的内源性 INX-20 的新表达分析的支持。尽管 ADL 与 ASH 之间没有直接形成间隙连接，但它通过与中间神经元 RMG 和感觉神经元 ASK 的间隙连接来形成。敲除 ADL 或 RMG 和 ASK 也导致伤害感受过度敏感，这表明 ADL 下游的 RMG/ASK 在 ASH 调节回路中起着重要作用。这项工作增加了我们对 ASH 活性通过与其他神经元的连接进行调节的方式的理解，并确定了 ADL 和 RMG 在调节厌恶行为中的一个以前未知的作用。
