Molecular and neuronal mechanisms of thermosensory behavior

描述（由申请人提供）：神经系统的主要作用是在过去经验和当前条件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。神经元网络产生已定义的适应性行为的细胞内和细胞间信号通路尚未得到很好的理解。秀丽隐杆线虫热感觉行为的研究提供了一个很好的系统，可以探索一个小的、硬连接的神经网络产生高度复杂和依赖经验的行为的途径。秀丽隐杆线虫在温度梯度上的行为受其培养温度（Tc）的“记忆”支配，因此动物在相对于Tc的特定温度范围内表现出明确的行为。这种记忆是可塑的，可以在动物在新的温度下培养时重置。本提案的总体目标是描述热感觉神经元之间的感觉转导，可塑性和通信以经验和上下文依赖的方式产生稳健但灵活的行为的机制。具体目的是：1)研究CaMKI/ iv介导的基因表达调控在AFD热感觉神经元Tc记忆中的作用。Tc记忆部分是由AFD热感觉神经元的反应阈值编码的。这一目的将验证一个假设，即在afd表达的信号基因的表达中，活性调节的变化设定了它们的反应阈值，这些变化是由CaMKI/IV级联介导的。2)探讨神经调节在调节ASI热感觉神经元工作范围中的作用。虽然AFD是以前唯一已知的热感觉神经元类型，但我们现在已经证明ASI感觉神经元也是热感觉神经元，并且表现出依赖于tc的工作范围。ASI的工作范围可由AFD通过多肽神经调节来设定。该目标将利用高度定量的行为分析，体内成像和光遗传学操作来描述AFD信号向ASI协调其反应范围的机制。3)探讨AWC热感觉神经元的热转导和可塑性机制。除了AFD和ASI，我们发现AWC嗅觉神经元也具有热感觉功能。本研究的目的是明确AWC中热转导的分子机制，并探讨AWC代表回路中饥饿诱导行为可塑性位点的假设。我们实验室的工作揭示了外围热感觉处理的意想不到的复杂性。提出的实验将阐明多种热感觉神经元之间的协调和沟通机制，以确保一致的行为输出。鉴于不同物种间信号通路、突触机制和回路功能的显著守恒，这项工作将为更复杂的神经系统的感觉加工和可塑性提供新的信息。

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. PUBLIC HEALTH RELEVANCE: All organisms must correctly process cues from their environment in order to generate a context-appropriate response. Deficits in sensory processing underlie many learning, developmental and behavioral disorders. Understanding the mechanisms by which the nervous system construes sensory signals may allow the formulation of behavioral and therapeutic strategies to address these devastating neurological disorders.