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它们的行为。到 为了达到这一目的，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，这些表达变化及其上游调节因子的破坏是 与神经系统疾病有关。在这里，我建议利用温度依赖性神经元 和行为可塑性。优雅，生物学相关的现象，容易操纵， 可量化的，以询问基因表达变化和基因调控机制 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 行为在C.优雅我们已经确定，调节单一的热感觉的生理学 神经元对AFD有助于行为可塑性。我们已经鉴定了受体型鸟苷酸环化酶， 可能的热敏基因在AFD中起作用，并表明它们在温度水平上受到调节。 转录。在这个建议中，我使用这个单细胞可塑性范例作为一种途径，进行详细的 基因调控系统驱动神经可塑性的分析，并将它们与动物行为联系起来。 首先，我描述了实验，以确定全基因组的基因，差异表达的AFD和 介导可塑性的动态进展。然后，我概述了一个策略，以揭示分子调控 在温度诱导的可塑性过程中控制热敏rGC表达的原理。我 建议的计画将详细描述在活体内驱动神经元可塑性的基因调控路径 并将它们与行为联系起来。这项工作将定义环境输入，刺激- 诱导的基因表达和神经元可塑性，使神经元输出的准确转换 和行为。此外，基因调控途径的表征， 控制神经元可塑性可能有助于解释它们如何在神经系统疾病的背景下失败。

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.