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Study of the functions of the Ras-MAPK pathway and the insulin pathway in neural plasticity of C. elegans

Ras-MAPK通路和胰岛素通路在秀丽隐杆线虫神经可塑性中的作用研究

基本信息

批准号：
15370071
负责人：
IINO Yuichi
金额：
$ 9.6万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

1)We reported before that the Ras-MAPK pathway acts in the olfactory neurons in C.elegans and is required for efficient odor responses (Hirotsu et al., 2000). In this study, we found that the Ras-MAPK pathway is also involved in olfactory adaptation and conducted detailed analyses on this role. We found that this form of olfactory adaptation, which we call "early adaptation", depends not only on sensory neurons, but also on a class of interneurons, AIY. AIY is a class of interneurons that receive synaptic inputs from sensory neurons including olfactory neurons AWA and AWC. Several mutants of the Ras-MAPK pathway showed defects in early adaptation. Moreover, we showed that Ras acts in AIY neurons, because expression of let-60 rasgene in AIY neurons rescues the defect of the let-60 mutants in early adaptation. By immunohistochemistry, we observed that MAPK is activated in olfactory neurons and in AIY interneurons by odor stimulation.2)We have previously established an assay system for associative learning. C.elegansis usually attracted to NaCl. However, after experiencing NaCl in the absence of food, they learn to avoid NaCl. Mutants for insulin INS-1, insulin receptor, and the downstream factors PI-3 kinase, PDK kinase and Akt kinase showed defects in associative learning. Through cell-specific expression experiments, we found that INS-1 acts in the interneuron AIA, and PI 3-kinase acts in ASE neurons, a pair of sensory neurons that sense NaCl. These results suggest that AIA neurons, which receive synaptic inputs from sensory neurons, send a retrograde signal via INS-1 to sensory neurons. ASE neurons consist of a bilaterally symmetrical pair of neurons. Of these, PI-3-kinase acts only in the right member.

1)我们之前报道过Ras-MAPK通路作用于秀丽隐杆线虫的嗅觉神经元，是有效的气味反应所必需的（Hirotsu et al., 2000）。在本研究中，我们发现Ras-MAPK通路也参与嗅觉适应，并对其作用进行了详细分析。我们发现这种形式的嗅觉适应，我们称之为“早期适应”，不仅依赖于感觉神经元，还依赖于一类中间神经元，AIY。AIY是一类接收来自感觉神经元（包括嗅觉神经元AWA和AWC）的突触输入的中间神经元。Ras-MAPK途径的几个突变体在早期适应中表现出缺陷。此外，我们发现Ras在AIY神经元中起作用，因为AIY神经元中let-60 Ras基因的表达挽救了let-60突变体早期适应的缺陷。通过免疫组化，我们观察到MAPK在气味刺激下在嗅觉神经元和AIY中间神经元中被激活。2)我们之前已经建立了一个联想学习的实验系统。秀丽隐杆线虫通常被NaCl吸引。然而，在没有食物的情况下经历了NaCl之后，他们学会了避免NaCl。胰岛素INS-1、胰岛素受体以及下游因子PI-3激酶、PDK激酶和Akt激酶的突变体在联想学习中表现出缺陷。通过细胞特异性表达实验，我们发现INS-1作用于中间神经元AIA， PI 3-激酶作用于一对感知NaCl的感觉神经元ASE神经元。这些结果表明，AIA神经元接受来自感觉神经元的突触输入，并通过INS-1向感觉神经元发送逆行信号。ASE神经元由双侧对称的一对神经元组成。其中，pi -3-激酶只作用于正确的分子。