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: 8438368
• 负责人: Sreekanth H. Chalasani
• 金额: $ 47.74万
• 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 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438368
• 关键词: Afferent Neurons; Animal Behavior; Autistic Disorder; Behavior; Behavioral; Binding; Biological Neural Networks; Birth; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cells; Communication; Complementary DNA; Complex; Data; Defect; Diagnostic; Disease; Exhibits; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Screening; Genetic Variation; Goals; Homologous Gene; Human; Image; Impairment; Intervention; Invertebrates; Ligands; Manuals; Maps; Measures; Membrane Proteins; Modeling; Modification; Mus; Nematoda; Nervous system structure; Neuroanatomy; Neurons; Neuropeptide Receptor; Neuropeptides; Odors; Output; Pathway interactions; Patients; Pattern; Process; Property; Proteins; Role; Schizophrenia; Sensory; Side; Signal Pathway; Signal Transduction; Sodium Chloride; Stimulus; Synapses; Synaptic Transmission; Testing; Therapeutic Intervention; Validation; Variant; Vertebrates; Whole Organism; base; human disease; insight; mutant; neural circuit; neuromechanism; neurotransmission; novel; presynaptic; public health relevance; relating to nervous system; synaptic function; tool

DESCRIPTION (provided by applicant): Neuroligin binds its presynaptic ligand neurexin to modify synaptic functions in the brain. Disruption in the neuroligin signaling pathway is associated with devastating disorders like autism, schizophrenia, fragile X syndrome and others. However, little is known about how neuroligin signaling modifies neural circuit function and animal behavior. A complete understanding of this process requires thorough characterization of neural circuits and their components along with the ability to measure and more importantly perturb their activity. Invertebrate circuits with their well-defined neuroanatomy and quantitative behaviors are ideal to decipher the neuroligin signaling mechanisms underlying complex outputs. The nematode, Caenorhabditis elegans, with its nervous system comprising of just 302 neurons with identified connections and highly conserved synaptic machinery provides an unique opportunity to analyze genes, cells and circuits regulating complex behaviors. The Chalasani lab has identified a novel neuropeptide-based communication between the AWC (sensing odors) and ASE (sensing salt) neurons. Surprisingly, a C. elegans mutant for the homolog of human neuroligin that is associated with autism in patients shows severe defects in behaviors regulated by the neuropeptide communication between AWC and ASE sensory neurons. Moreover, they show that wild-type human neurolign cDNA, but not two autism-associated gene variants can rescue the nlg-1 behavioral defects. These results suggest that neurolign signaling is conserved between worms and humans. They propose to identify the neuropeptides and receptors that underlie the novel AWC-ASE communication (Aim 1). They will also test the hypothesis that post-synaptic NLG-1 modifies the neuropeptide signaling between AWC and ASE neurons. Moreover, they will test worm homologs of human disease-associated gene variants and neurexin in influencing neural circuit functions (Aim 2). Finally, they will modify an automated imaging platform to perform novel neural activity based genetic screens and identify components of the NLG-1 signaling pathway (Aim 3). These studies will clarify how neural circuits integrate information at the level of synapses, neural circuits and whole organisms and identify candidates relevant to human disease.

描述（由申请人提供）：神经胶蛋白与其突触前配体neurexin结合以改变大脑的突触功能。神经配素信号通路的中断与自闭症、精神分裂症、脆性X综合征等破坏性疾病有关。然而，很少有人知道神经连接素信号如何改变神经回路功能和动物行为。对这一过程的完整理解需要彻底表征神经回路及其组件，沿着测量能力，更重要的是干扰它们的活动。无脊椎动物回路及其明确的神经解剖学和定量 行为是理想的破译神经连接蛋白信号机制的基础复杂的输出。线虫，秀丽隐杆线虫，其神经系统仅由302个神经元组成，具有已识别的连接和高度保守的突触机制，为分析基因，细胞和调节复杂行为的电路提供了独特的机会。Chalasani实验室已经确定了AWC（感知气味）和ASE（感知盐）神经元之间的一种新的基于神经肽的通信。令人惊讶的是，C。与自闭症患者相关的人类神经配素同源物的elegans突变体在由AWC和ASE感觉神经元之间的神经肽通讯调节的行为中显示出严重的缺陷。此外，他们表明野生型人类neurolign cDNA，而不是两个自闭症相关基因变体可以挽救nlg-1行为缺陷。这些结果表明，neurolign信号是保守的蠕虫和人类之间。他们提出要确定的神经肽和受体的基础上的新AWC-ASE通信（目的1）。他们还将测试突触后NLG-1修饰AWC和ASE神经元之间的神经肽信号传导的假设。此外，他们还将测试人类疾病相关基因变体和neurexin的蠕虫同源物对神经回路功能的影响（目标2）。最后，他们将修改一个自动成像平台，以进行基于新神经活动的遗传筛选，并识别NLG-1信号通路的组成部分（Aim 3）。这些研究将阐明神经回路如何在突触、神经回路和整个生物体的水平上整合信息，并确定与人类疾病相关的候选者。