Gap Junction-Mediated Regulation of Nociceptive Sensory Signaling

研究小神经电路的逻辑是了解更多知识的关键一步 复杂的电路，以及最终整个神经系统的计算和集成特性。 凭借紧凑的神经系统(只有302个神经元)和良好的行为特征， 小蛔虫线虫可作为研究电路级调控的良好动物模型。 神经功能。虽然化学突触允许神经元通过 神经递质的囊泡释放到细胞之间的突触缝隙中，缝隙连接允许直接 神经元之间的胞质通讯和电耦合。因此，缝隙连接通常是 被称为电突触。重要的是，神经系统中存在缝隙连接 允许建立比突触信号所产生的更复杂的电路 独自一人。我们已经确定了鸟苷酸环化酶在调节 伤害性感觉行为，并收集了神经元电路级调制的证据 第二信使cGMP通过缝隙连接的活动。作为重要的一步 我们的长期目标是了解细胞和细胞间机制如何相互作用 控制动物行为的神经回路，这个应用的总体目标是确定 精选鸟苷酸环化酶调节线虫伤害行为反应的机制。 在这里，我们建议使用遗传、行为和神经元成像方法的组合。 优雅的人建立cGMP的产生和通过缝隙连接的运动如何调节神经 系统功能。我们将：(1)使用活体成像来表征感官中cGMP和钙的动态变化 神经回路，(2)确定特定的鸟苷酸环化酶调节ASH的机制 伤害性感受器敏感性非细胞自主，以及(3)定义缝隙连接元件的网络(S 通过cGMP来调节ASH伤害性感受器的敏感性。总而言之，这些研究将 描绘了一种新的神经元交流方式和一种新的协调和 优化动物行为。这些信息是开发创新药理学所必需的 调节缝隙连接信号以达到治疗目标的方法。

Studying the logic of small neural circuits is an essential step toward understanding more complex circuits and, ultimately, the computational and integrative properties of whole nervous systems. With a compact nervous system (just 302 neurons) and a well-characterized behavioral repertoire, the small roundworm C. elegans serves as an excellent animal model to study circuit-level modulation of neuronal function. While chemical synapses allow neurons to communicate with each other through the vesicular release of neurotransmitters into synaptic clefts between the cells, gap junctions allow for direct cytoplasmic communication and electrical coupling between neurons. As such, gap junctions are often referred to as electrical synapses. Importantly, the presence of gap junctions in the nervous system allows for the establishment of even more complex circuits than can be generated by synaptic signaling alone. We have identified a non-cell-autonomous role for guanylyl cyclases in the regulation of nociceptive sensory behaviors, and have gathered evidence for circuit-level modulation of neuronal activity by movement of the second messenger cGMP through gap junctions. As an important step towards our long-term goal of understanding how cellular and intercellular mechanisms interact within neural circuits to control animal behavior, the overall objective of this application is to determine the mechanism by which select guanylyl cyclases modulate nociceptive behavioral responses in C. elegans. Herein we propose to use a combination of genetic, behavioral and neuronal imaging approaches in C. elegans to establish how cGMP generation and movement through gap junctions regulates nervous system function. We will: (1) use in vivo imaging to characterize cGMP and Ca2+ dynamics in a sensory neural circuit, (2) determine the mechanism by which specific guanylyl cyclases modulate ASH nociceptor sensitivity non-cell-autonomously, and (3) define the network(s) of gap junction components that coordinate to pass cGMP to modulate ASH nociceptor sensitivity. Together, these studies will delineate a new means of neuronal communication and a new mechanism for the coordination and optimization of animal behavior. This information is required to develop innovative pharmacological approaches to modulate gap junction signaling for therapeutic goals.