Dissecting neural mechanisms integrating multiple inputs in C. elegans

描述（由申请人提供）：神经素结合其突触前配体神经素来改变大脑中的突触功能。神经胶质素信号通路的破坏与自闭症、精神分裂症、脆性X染色体综合征等毁灭性疾病有关。然而，人们对神经素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成部分进行彻底的描述，并具备测量和更重要的是干扰其活动的能力。无脊椎动物的电路有着明确的神经解剖学和定量

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.