Neuronal and theoretical analysis of spatial orientation

描述(申请人提供)：这项研究的长期目标是提高我们对与动作选择相关的神经回路的结构和功能的基本理解。动作选择被定义为解决相互竞争的行为选择之间的冲突的任务，传统上在非人类灵长类动物中进行，这些灵长类动物不适用于一系列强大的实验技术，包括膜片钳记录和光遗传学。解决这一僵局的一个有希望的方法是，在基因上容易处理的更简单的生物体中，研究行动选择的神经元基础。这项拟议的研究调查了线虫Caorhabditis elegans的神经动作选择基础，这是一个仅有302个神经元的紧凑神经系统的实验系统，基本完整的解剖接线图，以及将分子、基因和神经元与行为联系起来的广泛的遗传、电生理和光遗传学技术。这项研究的重点是一种被称为趋趋性的空间定向行为，在这种行为中，头部有节奏的左右移动偏向于化学引诱剂浓度增加的方向。该项目是通过一种创新的微流体设备实现的，该设备为动物提供了携带不同浓度化学吸引剂的流体之间的二元选择，以及一种新型的跟踪系统，使人们能够成像自由移动的动物中单个识别的神经元的神经元活动。该项目将分三个阶段进行：(1)通过测量微流控装置中运动波动的时空传播及其被化学吸引剂的调节来开发趋趋性行为的定量描述。(2)通过神经元活动的光学记录、神经元消融和突触连接的电生理测量来识别趋动神经的神经元回路。(3)通过光刺激已鉴定的化学感觉神经元以模拟化学感觉输入来验证动作选择的数学模型。这项拟议的研究可能会识别出新的动作选择回路基序，这些基序可以用来产生关于高等生物体中调节动作选择的回路功能的假说。超过一半的人类疾病基因在线虫中有匹配的基因，包括已知损害运动和认知行为选择的疾病，如帕金森氏症、阿尔茨海默病和精神分裂症。因此，这项研究可能有助于追踪从遗传差异到精神障碍的因果联系。

DESCRIPTION (provided by applicant): The long-term objective of this research is to improve our basic understanding of the structure and function of neural circuits related to action selection. Defined as the task of resolving conflicts between competing behavioral alternatives, action selection has traditionally been carried out in non-human primates which are not amenable to a fleet of powerful experimental techniques including patch clamp recording and optogenetics. A promising approach to this impasse would be to investigate the neuronal basis of action selection in simpler organisms that are genetically tractable. The proposed research investigates the neuronal basis of action selection in the nematode Caeorhabditis elegans, an experimental system with a compact nervous system of only 302 neurons, an essentially complete anatomical wiring diagram, and a wide range of genetic, electrophysiological, and optogenetic techniques for linking molecules, genes, and neurons to behavior. This research focuses on a form of spatial orientation behavior known as klinotaxis in which rhythmic side-to-side movements of the head are biased in the direction of increasing concentration of a chemical attractant. The project is made possible by an innovative microfluidic device that presents the animal with a binary choice between fluid streams carrying different concentrations of chemoattractant, and a novel tracking system that allows one to image neuronal activity in single identified neurons in freely moving animals. The project will proceed in three phases: (1) Development of a quantitative description of klinotaxis behavior by measuring the spatiotemporal propagation of locomotory undulations and their modulation by chemoattractants in microfluidic devices. (2) Identification of the neuronal circuit for klinotaxis by optical recordings of neuronal activity, neuron- al ablations, and electrophysiological measurement of synaptic connectivity. (3) Validation of a mathematical model of action selection by photo-stimulation of identified chemosensory neurons to mimic chemosensory in- puts. The proposed research is likely to identify novel circuit motifs for action selection that can be used to generate hypotheses concerning the function of circuits regulating action selection in higher organisms. More than half of all human disease genes have a matching gene in C. elegans including diseases known to impair motor and cognitive action selection such as Parkinson's disease, Alzheimer's disease, and schizophrenia. The research is therefore likely to help trace causal connections from genetic differences to mental disorders.