Neuronal and theoretical analysis of spatial orientation

描述（由申请人提供）：本研究的长期目标是了解神经系统如何控制行为。这个目标很重要，因为精神疾病是一种行为疾病。挑战在于理解健康的神经系统是如何产生正常行为的以便理解患病的神经系统是如何产生异常行为的。这个研究问题将在理解一种简单生物的行为的遗传和神经元基础的背景下进行：线虫。秀丽隐杆线虫基因组完整序列的存在，以及对秀丽隐杆线虫大脑302个神经元突触连通性的完整描述，使其非常适合所提出的研究。目前的建议集中在秀丽隐杆线虫的几种行为之一：趋化性，动物根据化学梯度定向运动的能力。放置在琼脂表面上的蠕虫作正弦游泳运动，偶尔被短暂的转动打断。众所周知，秀丽隐杆线虫的定向涉及一个简单的规则——在梯度下降时转向更频繁，在梯度上升时转向更少。控制游泳和转身之间转换的神经元已经被确定，但尚不清楚它们在趋化性中如何起作用。提出的研究使用遗传学，电生理学，钙成像，行为分析和数学建模的显着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弯之间切换的神经元机制，具体目标2是通过用激光杀死各种神经元并测试定向缺陷来确定包含从化学感觉神经元到切换网络的通路的中间神经元。特异性目的3是通过记录具有可能的味觉基因突变的蠕虫的化学感觉神经元的活动，研究秀丽隐杆线虫的味觉受体神经元如何编码和转导化学感觉信息。Specific Aim 3将促进对味觉传导机制的更好理解，并可能为影响约200万美国人的化学感觉障碍带来新的治疗方法。

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.