Dissecting neural mechanisms integrating multiple inputs in C. elegans

描述(申请人提供)：神经连接素结合其突触前配体Neuresin来改变大脑中的突触功能。神经连接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，人们对神经连接蛋白信号如何改变神经回路功能和动物行为知之甚少。要完全理解这一过程，需要对神经回路及其组件进行彻底的表征，以及测量和干扰它们的活动的能力。无脊椎动物电路及其明确的神经解剖学和定量 行为是破译复杂输出背后的神经连接素信号机制的理想工具。线虫，秀丽线虫，其神经系统只由302个神经元组成，这些神经元具有已识别的连接和高度保守的突触机制，为分析调控复杂行为的基因、细胞和电路提供了独特的机会。Chalasani实验室已经确定了AWC(嗅觉)和ASE(盐感)神经元之间一种新的基于神经肽的通讯。令人惊讶的是，与自闭症患者相关的人类神经连接素同源基因的线虫突变体在AWC和ASE感觉神经元之间的神经肽通讯调节的行为方面显示出严重的缺陷。此外，他们还表明，野生型人类神经素基因可以修复NLG-1的行为缺陷，而不是两个与自闭症相关的基因变体。这些结果表明，神经原信号在蠕虫和人类之间是保守的。他们建议识别构成新的AWC-ASE通信(目标1)的神经肽和受体。他们还将测试突触后NLG-1改变AWC和ASE神经元之间的神经肽信号的假设。此外，他们还将测试人类疾病相关基因变异体的蠕虫同源物和影响神经回路功能的神经尿毒素(目标2)。最后，他们将修改一个自动成像平台，以执行新的基于神经活动的遗传筛选，并识别NLG-1信号通路的组件(目标3)。这些研究将阐明神经回路如何整合突触、神经回路和整个生物体水平的信息，并确定与人类疾病相关的候选对象。

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.