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The function of gap junctions and chemical synapses in a simple neural circuit

间隙连接和化学突触在简单神经回路中的功能

基本信息

批准号：
10468692
负责人：
ZHAO-WEN WANG
金额：
$ 40.23万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

项目摘要

C. elegans locomotion neural circuit is an excellent model for decoding the circuit and gene bases of behaviors. Previous studies have produced a detailed wiring diagram of this circuit, and proposed that two pairs of premotor interneurons, AVA and AVB, play key roles in locomotion by activating A-type and B-type cholinergic motor neurons (A-MNs and B-MNs), respectively. However, how the various neurons interact at the synaptic level is largely unknown. Our recent success in voltage-clamping motor neurons and recording gap junction currents between neurons in worms makes it possible to look into properties of the circuit that are otherwise inaccessible. Our preliminary studies revealed several unexpected and novel properties of the locomotion circuit, including retrograde gap junction currents between the premotor interneurons and motor neurons, a putative degenerin/epithelial sodium channel (DEG/ENaC) serving as a stretch receptor in B-MNs, retrograde regulation of the backward circuit by GABAergic MNs (D-MNs), and electrical coupling between the left and right AVA interneurons. This proposal is to use a combination of electrophysiological, genetic, molecular, and behavioral approaches to test a new model with three specific aims. Aim 1 is to test the hypotheses that B-MNs activate AVB premotor interneurons through gap junctions, and that B-MN activity depends on a stretch receptor. We will determine molecular mechanisms of the gap junction rectification and the effects of deficient electrical coupling on AVB activity and locomotion behavior. We will identify the putative DEG/ENaC in B-MNs and determine its roles in B-MN activity and locomotion. Aim 2 is to investigate the mechanism of the rectifying coupling between AVA and A-MNs, and the physiological role of electrical coupling between the left and right AVA interneurons. We will determine whether the rectification is conferred by the N-terminal of UNC-7 innexin in AVA and whether disrupting the coupling between AVA interneurons alters locomotion behavior. Aim 3 is to test the hypotheses that D-MNs inhibit A-MNs retrogradely via AVA, and that AVB facilitates forward locomotion by inhibiting AVA. We will assess the effect of disrupting the novel D-MN inhibitory circuit on locomotion. We will identify the postsynaptic receptors mediating AVB inhibition on AVA, and analyze the effect that disrupting this receptor has on locomotion. This project may reshape our understanding of the C. elegans locomotion neural circuit, and help us approach the long-term goal of elucidating the circuit and gene bases of behaviors.

C. elegans运动神经回路是一个很好的模型，用于解码行为的回路和基因基础。以前的研究已经制作了这种电路的详细接线图，并提出了两对预电机中间神经元AVA和AVB通过激活A型和B型胆碱能运动在运动中起关键作用神经元（A-MN和B-MN）。然而，各种神经元如何在突触水平上相互作用，大部分未知。我们最近在电压钳位运动神经元和记录间隙连接电流方面的成功蠕虫神经元之间的相互作用使得研究电路的特性成为可能，否则这些特性是无法获得的。我们的初步研究揭示了运动回路的几个意想不到的新特性，包括运动前中间神经元和运动神经元之间的逆行间隙连接电流，一个假定的退变蛋白/上皮钠通道（DEG/ENaC）作为B-MN的牵张受体，逆行调节 GABA能MN（D-MN）的反向回路，以及左和右AVA之间的电耦合中间神经元这项建议是利用电生理学、遗传学、分子学和行为学的结合测试新模式的方法有三个具体目标。目的1是验证B-MN激活的假设， AVB前运动中间神经元通过缝隙连接，B-MN活动依赖于牵张受体。我们将确定差距结整流的分子机制和电耦合不足的影响对房室传导活动和运动行为的影响我们将确定B-MN中假定的DEG/ENaC，并确定其在B-MN活动和运动中的作用。目的2是研究整流耦合的机理， AVA和A-MN，以及左和右AVA中间神经元之间电耦合的生理作用。我们将确定AVA中的整流是否由N-7连接蛋白的N-末端赋予，以及AVA中的整流是否由N-7连接蛋白的N-末端赋予。破坏AVA中间神经元之间的耦合改变了运动行为。目的3是检验假设 D-MN通过AVA逆行抑制A-MN，AVB通过抑制AVA促进向前运动。我们将评估破坏新的D-MN抑制回路对运动的影响。我们将确定突触后受体介导AVB抑制AVA，并分析干扰该受体对AVA的影响。关于运动。这个项目可能会重塑我们对C。elegans运动神经回路，以及帮助我们实现阐明行为的电路和基因基础的长期目标。