Molecular and neuronal mechanisms of thermosensory behavior

描述(由申请人提供)：神经系统的一个主要作用是在过去的经验和当前条件的背景下感知和整合外部和内部线索，并将这些信息转化为行为输出。神经元网络产生的细胞内和细胞间信号通路是明确的，但适应行为还没有被很好地理解。线虫热敏行为的研究为探索小而硬连接的神经网络产生高度复杂和经验依赖的行为的途径提供了一个很好的系统。线虫在温度梯度上的行为是由其培养温度(T_C)的“记忆”决定的，因此动物在相对于T_c的特定温度范围内表现出特定的行为。TC记忆是塑料的，在新温度下饲养动物时可以重置。这一建议的总体目标是描述感觉转导、可塑性和热敏神经元之间的通信以经验和上下文依赖的方式产生健壮而灵活的行为的机制。研究的具体目的是：1)研究CaMKI/IV介导的基因表达调控在AFD热敏神经元建立TC记忆中的作用。TC记忆部分由AFD热敏神经元的反应阈值编码。这一目标将检验这样一种假设，即AFD表达的信号基因表达的活性调节变化设定了它们的反应阈值，并且这些变化是由CaMKI/IV级联反应介导的。2)探讨神经调节在确定ASI温敏神经元工作范围中的作用。虽然AFD是之前已知的唯一一种温敏神经元类型，但我们现在已经证明ASI感觉神经元也是温敏神经元，并表现出依赖于TC的工作范围。ASI的作用范围可由AFD通过肽能神经调节来设定。这一目标将利用高度定量的行为分析、活体成像和光遗传操作来描述AFD向ASI发送信号以协调其反应范围的机制。3)探讨AWC热敏神经元的热传导和可塑性机制。除了AFD和ASI，我们还发现AWC的嗅觉神经元也是温度敏感的。本研究的目的是明确AWC中热传导的分子机制，并探索AWC代表回路中饥饿诱导的行为可塑性的假设。我们实验室的工作发现，外围设备的热敏处理过程出人意料地复杂。拟议的实验将阐明多种类型的温敏神经元之间的协调和通信确保一致的行为输出的机制。鉴于信号通路、突触机制和电路功能在不同物种中的显著保守，这项工作将提供关于更复杂神经系统中感觉处理和可塑性的新信息。

DESCRIPTION (provided by applicant): A major role of the nervous system is to sense and integrate external and internal cues in the context of past experience and current conditions, and translate this information into behavioral outputs. The intracellular and intercellular signaling pathways by which neuronal networks generate defined, yet adaptive behaviors are not well understood. The study of thermosensory behaviors in C. elegans provides an excellent system in which to explore the pathways by which a small, hard-wired neuronal network generates highly complex and experience-dependent behaviors. The behavior of C. elegans on a thermal gradient is governed by a 'memory' of its cultivation temperature (Tc), such that animals exhibit defined behaviors in specific temperature ranges relative to Tc. Tc memory is plastic and can be reset upon cultivation of animals at a new temperature. The overall goal of this proposal is to describe the mechanisms by which sensory transduction, plasticity and communication among thermosensory neurons generate robust, yet flexible behaviors in an experience- and context-dependent manner. The Specific Aims are to: 1) Examine the role of CaMKI/IV-mediated regulation of gene expression in setting Tc memory in the AFD thermosensory neurons. Tc memory is in part encoded by the response threshold of the AFD thermosensory neurons. This aim will test the hypothesis that activity-regulated changes in the expression of AFD-expressed signaling genes sets their response threshold, and that these changes are mediated by a CaMKI/IV cascade. 2) Explore the role of neuromodulation in setting the operating range of the ASI thermosensory neurons. Although AFD was the only previously known thermosensory neuron type, we have now shown that the ASI sensory neurons are also thermosensory, and exhibit a Tc-dependent operating range. The operating range of ASI may be set by AFD via peptidergic neuromodulation. This aim will utilize highly quantitative behavioral assays, in vivo imaging, and optogenetic manipulations to describe the mechanisms by which AFD signals to ASI to coordinate their response ranges. 3) Investigate mechanisms of thermotransduction and plasticity in the AWC thermosensory neurons. In addition to AFD and ASI, we showed that the AWC olfactory neurons are also thermosensory. The goal of this aim is to define molecular mechanisms of thermotransduction in AWC, and to explore the hypothesis that AWC represents the locus of starvation-induced behavioral plasticity in the circuit. Work from our lab has uncovered unexpected complexity in thermosensory processing at the periphery. The proposed experiments will elucidate the mechanisms by which coordination and communication among multiple thermosensory neuron types ensures a coherent behavioral output. Given the remarkable conservation of signaling pathways, synaptic mechanisms and circuit functions across species, this work will provide new information about sensory processing and plasticity in more complex nervous systems.