Gene regulatory mechanisms underlying temperature-dependent neuronal plasticity

为了生存，动物必须在遇到新的环境条件时改变自己的行为。至 做到这一点，神经系统整合复杂的外部刺激，并适当地调整其活动。 最终，单个神经元水平的可塑性使这些变化成为可能，在许多情况下，神经元和 行为可塑性是持久的。基因表达的变化已被证明是许多形式的基础 长期可塑性和这些表达变化的干扰及其上游调节因子是 与神经系统疾病有关。在这里，我建议利用依赖温度的神经元 和线虫的行为可塑性，这是一种与生物相关的现象，容易操纵，以及 可量化的，以询问基因表达的变化和基因调控机制 体内潜在的可塑性。我们的实验室和其他实验室已经表征了温度偏好的可塑性 线虫的行为。我们已经确定了单一热敏感官的生理调节 神经元对AFD有助于行为可塑性。我们已经鉴定出受体类型的鸟苷酸环化酶是 可能作用于AFD的温度敏感基因，并表明它们在温度水平上受到温度的调节 抄写。在这个提议中，我使用单细胞可塑性范式作为一种途径来进行详细的 分析驱动神经元可塑性的基因调控系统，并将其与动物行为联系起来。 首先，我描述了在全基因组范围内识别AFD和AFD中差异表达的基因的实验 调节可塑性的动态发展。然后，我概述了一种发现分子调控的策略 温敏性视网膜节细胞在温度诱导可塑性过程中表达的调控原理。我的 拟议的项目将详细描述体内驱动神经元可塑性的基因调控途径。 并将它们与行为联系起来。这项工作将定义环境投入、刺激- 诱导基因表达和神经元可塑性，使神经元输出能够准确转换 和行为。此外，对动态和精确的基因调控途径的表征 控制神经元的可塑性可能有助于解释它们如何在神经疾病的背景下失败。

In order to survive, animals must modify their behavior as they encounter new environmental conditions. To achieve this, the nervous system integrates complex external stimuli and modifies its activity appropriately. Ultimately, plasticity at the level of single neurons enables these changes, and in many cases neuronal and behavioral plasticity is long-lasting. Changes in gene expression have been shown to underlie many forms of long-term plasticity, and disruption of these expression changes and their upstream regulators are associated with neurological disease. Here I propose to take advantage of temperature-dependent neuronal and behavioral plasticity in C. elegans, phenomena that are biologically relevant, easily manipulated, and quantifiable, in order to interrogate the gene expression changes and gene regulatory mechanisms underlying plasticity in vivo. Our lab and others have characterized plasticity of temperature preference behavior in C. elegans. We have established that modulation of the physiology of the single thermosensory neuron pair AFD contributes to behavioral plasticity. We have identified receptor-type guanylyl cyclases as likely thermosensory genes acting in AFD and shown that they are regulated by temperature at the level of transcription. In this proposal I use this single cell plasticity paradigm as an avenue to conduct detailed analyses of gene regulatory systems driving neuronal plasticity and to connect them to animal behavior. First, I describe experiments to identify genome-wide the genes that are differentially expressed in AFD and mediate the dynamic progression of plasticity. Then, I outline a strategy to uncover the molecular regulatory principles that control expression of thermosensory rGCs during temperature-induced plasticity. My proposed project will describe in great detail the gene regulatory pathways driving neuronal plasticity in vivo and link them to behavior. This work will define the relationships among an environmental input, stimulus- induced gene expression, and neuronal plasticity that enables accurate transformation of neuronal output and behavior. Additionally, characterization of gene regulatory pathways that dynamically and precisely control neuronal plasticity may help to explain how they can fail in the context of neurological disease.