Dissecting neural mechanisms integrating multiple inputs in C.elegans

剖析线虫中整合多种输入的神经机制

• 批准号: 9921491
• 负责人: Sreekanth H. Chalasani
• 金额: $ 48.1万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921491
• 关键词: Acids; Adult; Affect; Agonist; Animals; Automobile Driving; Behavior; Behavioral; Biochemical; Brain; Caenorhabditis elegans; Cell Adhesion Molecules; Cells; Chemicals; Complementary DNA; Complex; Copper; Data; Defect; Development; Diagnostic; Disease; Drug Targeting; Exhibits; Foundations; Fragile X Syndrome; Genes; Genetic; Goals; Human; Image; Imaging Device; Ligands; Light; Link; Maps; Measures; Mediating; Methods; Modeling; Molecular; Molecular Target; Mutate; Mutation; Nematoda; Nervous system structure; Neurons; Neuropeptide Y Receptor; Nipecotic Acids; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Schizophrenia; Sensory; Signal Pathway; Signal Transduction; Site; Solid; Stimulus; Synapses; Therapeutic Intervention; Time; Transgenic Animals; analog; autism spectrum disorder; avoidance behavior; base; behavioral response; cell type; cellular targeting; gamma-Aminobutyric Acid; genetic analysis; genetic approach; high resolution imaging; human disease; imaging platform; inhibitor/antagonist; insight; molecular drug target; mutant; neural circuit; neuroligin 1; neuromechanism; new therapeutic target; presynaptic; protein function; receptor; response; reuptake; sensory stimulus; small molecule; small molecule libraries; social; synaptic function; tool; young adult

Summary Atypical sensory-based behaviors are a common feature of a number of human conditions, including autism spectrum disorder, schizophrenia, fragile X, etc. Despite this, little is known about how the genes associated with these conditions affect sensory behavior. A complete understanding of this process requires a thorough characterization of the underlying neural circuitry, along with the ability to measure and perturb the activity of these circuits. The nematode, Caenorhabditis elegans, provides a unique opportunity to analyze genes, cells, and circuits regulating complex behaviors, as its nervous system consists of just 302 neurons interconnected via identified synapses that utilize highly conserved synaptic machineries. The Chalasani lab has shown that C. elegans homologs of the human autism-associated genes (neurexin (NRX) and neuroligin (NLG)) affect sensitivity to specific sensory stimuli, and that mutations in these genes result in hyposensitivity to a repellent copper stimulus. They propose to identify the specific C. elegans synapses where these two synaptic proteins function to modify sensory behaviors. Additionally, they plan to identify the developmental time window in which these genes are required to generate a typically behaving young adult (Aim 1). Moreover, they have shown that sensory defects associated with neuroligin mutants (nlg-1) are rescued by mutations in the gene npr-1, a gene that when mutated alone results in a “social” aggregation behavior. They propose to identify the neural mechanisms that underlie this interaction and reveal components of the NPR-1 signaling pathway that act to suppress nlg-1 behavioral defects (Aim 2). Finally, they have identified Nipecotic acid and CGP-13501 as candidate small molecules that suppress nlg-1 behavioral deficits. They plan to map the cellular and molecular targets of these drugs in C. elegans, analyzing the genetic pathways modifying NRX-1/NLG-1 signaling in this model (Aim 3). These studies will reveal mechanisms by which NRX-NLG signaling modifies sensory behavior at the level of genes, synapses, circuits, and whole animals, providing a solid foundation for further analyses in vertebrate models. As both NLG and NRX have been implicated in autism spectrum disorder, results may shed light on molecular and circuit mechanisms underlying human disorders that have been linked to abnormalities in sensory processing.

总结 非典型的基于感觉的行为是包括自闭症在内的许多人类疾病的共同特征 尽管如此，人们对与遗传相关的基因是如何与遗传相关的知之甚少。 这些条件影响感觉行为。要完全理解这一过程， 沿着测量和干扰神经元活动的能力， 这些电路。线虫，秀丽隐杆线虫，提供了一个独特的机会，分析基因，细胞， 和控制复杂行为的电路，因为它的神经系统只有302个神经元， 识别出利用高度保守的突触机制的突触。查拉萨尼实验室已经证明，C。 人类孤独症相关基因（neurexin（NRX）和neuroligin（NLG））的线虫同源物影响 对特定感觉刺激的敏感性，这些基因的突变导致对驱避剂的敏感性降低 铜刺激他们建议确定具体的C。这两种突触蛋白 改变感官行为的功能。此外，他们计划确定发展的时间窗口， 这些基因是产生具有典型行为的年轻成年人所必需的（Aim 1）。此外，他们还表明， 与神经连接蛋白突变体（NLG-1）相关的感觉缺陷可通过基因NPR-1（一种基因 当单独突变时会导致“社会”聚集行为。他们建议识别神经 这种相互作用的基础机制，并揭示了NPR-1信号通路的组成部分， 抑制nlg-1行为缺陷（目标2）。最后，他们已经鉴定了尼泊甲酸和CGP-13501， 抑制NLG-1行为缺陷的候选小分子。他们计划绘制出 这些药物在C. elegans，分析在这种情况下修饰NRX-1/NLG-1信号传导的遗传途径。 模型（目标3）。这些研究将揭示NRX-NLG信号调节感觉行为的机制 在基因，突触，电路和整个动物的水平上，为进一步分析提供了坚实的基础， 脊椎动物模型由于NLG和NRX都与自闭症谱系障碍有关，结果可能会 光的分子和电路机制的人类疾病，已链接到异常， 感觉处理