Neuronal and theoretical analysis of spatial orientation

描述(申请人提供)：本研究的长期目标是了解神经系统是如何控制行为的。这一目标意义重大，因为精神疾病是一种行为疾病。挑战在于了解健康的神经系统是如何产生正常行为的，以便了解患病的神经系统是如何产生异常行为的。这一研究问题将在理解一个简单有机体--线虫--秀丽线虫的遗传和神经基础的背景下进行。线虫基因组的完整序列的存在，加上对线虫大脑302个神经元突触连接的完整描述，使其非常适合拟议的研究。目前的建议集中在线虫的几种行为之一：趋化性，即动物根据化学梯度确定其运动方向的能力。放在琼脂表面的虫子会做出正弦的游泳运动，偶尔会被短暂的跳动打断。众所周知，线虫的定向涉及一个简单的规则--向下倾斜时更频繁地转弯，而向上倾斜时较少转向。控制游泳和转身之间切换的神经元已经被发现，但还不知道它们如何在趋化作用中发挥作用。这项拟议的研究利用遗传学、电生理学、钙成像、行为分析和数学建模的非凡组合来解决这个问题。有三个具体目标。具体目标1是通过测试切换神经元的数学模型来阐明在游泳和转身之间切换的神经元机制，特定目标2是通过用激光杀死各种神经元并测试定向缺陷来识别组成从化学感觉神经元到切换网络的通路的中间神经元。具体目标3是通过记录具有可能的味道基因突变的蠕虫的化学感觉神经元的活动，来研究线虫中的味觉感受器神经元是如何编码和传递化学感觉信息的。具体目标3将促进对味觉传导机制的更好理解，并可能导致影响大约200万美国人的化学感觉障碍的新疗法。

DESCRIPTION (provided by applicant): The long-term objective of this research is to understand how the nervous system controls behavior. This objective is significant because mental illness is a disease of behavior. The challenge is to understand how the healthy nervous system produces normal behavior in order to understand how the diseased nervous system produces abnormal behavior. This research question will be pursued in the context of understanding the genetic and neuronal basis of behavior in a simple organism: the round worm Caenorhabditis elegans. The existence of the complete sequence of the C. elegans genome, together with the complete description of the synaptic connectivity of the 302 neurons of the C. elegans brain, makes it well-suited to the proposed studies. The present proposal focuses on one of several behaviors in C. elegans: chemotaxis, the ability of an animal to orient its locomotion with respect to a chemical gradient. A worm placed on an agar surface makes sinusoidal swimming movements that are occasionally interrupted by a brief tum. Orientation in C. elegans is known to involve a simple rule--turn more frequently when going down the gradient and turn less frequently when going up the gradient. Neurons that control the switch between swimming and turning have been identified, but it is not yet known how they function in chemotaxis. The proposed research addresses this question using a remarkable combination of genetics, electrophysiology, calcium imaging, behavioral analysis, and mathematical modeling. There are three specific aims. Specific Aim 1 is to elucidate the neuronal mechanism for switching between swimming and turning by testing a mathematical model of the switching neurons, Specific Aim 2 is to identify the interneurons that comprise the pathways from chemosensory neurons to the switching network by killing various neurons with a laser and testing for defects in orientation. Specific Aim 3 is to investigate how taste receptor neurons in C. elegans encode and transduce chemosensory information by recording the activity of chemosensory neurons in worms that have mutations in likely taste genes. Specific Aim 3 will promote a better understanding of taste transduction mechanisms and could lead to new treatments for chemosensory disorders affecting an estimated two million Americans.