Neural circuits and synaptic mechanisms underlying behavior in C. elegans

描述（由申请人提供）：神经回路由一组神经元通过特定的突触连接组装而成，是神经系统的功能和结构单位。神经回路和突触功能异常导致多种类型的神经系统疾病。我们感兴趣的是绘制神经回路的功能成分，剖析神经回路处理信息的突触机制，了解基因如何调节这一过程，以及这最终如何产生和重塑行为输出。考虑到人类神经系统的巨大复杂性及其基因操作的不可接近性，具有相对简单神经系统的遗传模式生物，如秀丽隐杆线虫和果蝇，已被广泛用于研究这些问题。秀丽隐杆线虫由于其简单的神经系统特征和易于遗传操作，近年来已成为研究神经生物学各种现象的一种越来越受欢迎的遗传模型。值得注意的是，秀丽隐杆线虫是唯一已知其连接组（整个神经系统的接线图）的生物。此外，许多控制神经信号、处理和发育的基本原理在秀丽隐杆线虫中是保守的。大约三分之二的人类疾病基因在这种生物体中有同源物。然而，秀丽隐杆线虫的神经系统是如何在功能上组织起来产生行为的，这在很大程度上仍然是一个谜。我们最近开发了一种自动钙成像系统，可以记录自由行为动物的神经活动。我们还开发了一种多学科的方法，通过整合功能成像、光基因审讯、基因操作、激光消融、

DESCRIPTION (provided by applicant): Neural circuits are assembled from a group of neurons via specific synaptic connections, and are the functional and structural units of the nervous system. Abnormal neural circuit and synaptic function lead to many types of neurological disorders. We are interested in mapping the functional components of neural circuits, dissecting the synaptic mechanisms by which the circuits process information, and understanding how genes regulate this process and how this ultimately produces and reshapes behavioral output. Given the immense complexity of the human nervous system and its inaccessibility to genetic manipulation, genetic model organisms with a relatively simple nervous system, such as C. elegans and Drosophila, have been widely used to investigate these questions. C. elegans has recently emerged as an increasingly popular genetic model for studying various phenomena in neurobiology, due to its simple and well characterized nervous system and amenability to genetic manipulation. Notably, C. elegans represents the only organism whose connectome (wiring diagram of its entire nervous system) is known. Additionally, many basic principles governing neural signaling, processing and development are conserved in C. elegans. About two-third of human disease genes have homologs in this organism. However, it remains largely enigmatic how the C. elegans nervous system is functionally organized to generate behaviors. We have recently developed an automated calcium imaging system that allows recording of neural activity in freely-behaving animals. We have also developed a multidisciplinary approach to map the neural circuits underlying behavior by integrating functional imaging, optogenetic interrogation, genetic manipulation, laser ablation, and electrophysiology. Using this approach, we will map the functional components of motor circuits, investigate the synaptic mechanisms by which the circuits process information, and characterize how sensory cues regulate the circuit dynamics to modulate behavioral output. As the microcircuits and the synaptic mechanisms employed by worms to process information show striking similarities to those by mammals, our study will provide novel insights into the neural basis of behavior in higher organisms.