Olfactory Adaptation in C. Elegans

线虫的嗅觉适应

• 批准号: 8277953
• 负责人: Noelle D L 'Etoile
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277953
• 关键词: Adult; Affect; Afferent Neurons; Animal Model; Animals; Behavior; Benzaldehyde; Binding; Binding Proteins; Biochemical; Biochemistry; Brain; Butanones; Bypass; Caenorhabditis elegans; Cell Nucleus; Chromatin; Cyclic GMP-Dependent Protein Kinases; DNA Methylation; Data; Deposition; Developmental Process; Disease; Down-Regulation; Drosophila genus; Environment; Epigenetic Process; Event; Exposure to; Fission Yeast; Food; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Histone H3; Image; Intervention; Lead; Learning; Light; Location; Lysine; Memory; Mental Depression; Modeling; Molecular; Mutate; Nematoda; Nerve Degeneration; Neuronal Plasticity; Neurons; Nuclear; Odors; Opiates; Pathway interactions; Pharmaceutical Preparations; Phosphorylation Site; Phosphotransferases; Plants; Plastics; Process; Production; Proteins; RNA; RNA Binding; RNA Interference; Regulation; Regulatory Pathway; Repression; Role; Sensory; Signal Transduction Pathway; Small RNA; Sorting - Cell Movement; Specificity; Stimulus; Testing; Time; Translating; Work; addiction; base; experience; histone modification; member; novel; response

DESCRIPTION (provided by applicant): Though a neuron must be able to respond reliably to stimulation, it is equally important that it alters its response as a function of specific experiences. The molecular and cellular basis for this plasticity and how stimulus-specific changes in plasticity occurs is important to understand as it underlies both normal processes such as learning and memory as well as the disease states of addiction and depression. Our goal is to use the olfactory response of the genetically tractable nematode C. elegans to determine whether a small RNA regulatory pathway directs stimulus-specific neuronal plasticity. One means by which repeated stimulation alters neuronal responsiveness is via the changes in transcription elicited by epigenetic "marks" such as DNA methylation and histone modification (reviewed in1). In S. pombe, plants and Drosophila, chromatin "marks" have been shown to be directed by small RNAs2. These epigenetic changes are thought to regulate important developmental processes. Whether small RNAs can dynamically regulate epigenetic changes in neurons as a consequence of specific behaviors has not been examined. An attractive but completely untested hypothesis is that small RNAs might provide the guidance and specificity for epigenetic events that direct long-lasting changes in neuronal activity. As a first step towards testing this hypothesis, we asked whether genes required for RNA-interference (RNAi) might be required for neuronal plasticity in the anatomically simple but genetically powerful model organism, C. elegans. C. elegans is inherently attracted to specific odors which it senses using G-protein coupled receptors (GPCRs), however, its attraction is dampened if the odors are not accompanied by food. We term this experience-dependent dampening of the response to odor olfactory adaptation. The key "switch" that turns on olfactory adaptation is the entry of the cGMP-dependent protein kinase (PKG), EGL-4, into the nucleus of the odor-stimulated sensory olfactory neuron AWC (Lee et al., submitted). In our preliminary studies, we found that a specific class of small RNAs work with a gene encoding a chromatin associated protein, HPL-2, (a histone H3 lysine 9 tri-methyl binding protein), within the sensory neuron at the time of odor-exposure to promote adaptation. Both factors act downstream of EGL-4 nuclear entry and both factors act in the same genetic pathway for adaptation. Thus, our studies have raised the novel and exciting possibility that environmental stimuli can act via small RNAs to direct changes in chromatin. We propose to test this hypothesis by determining whether small RNAs and chromatin are central players in the adaptation process, how they function in adaptation and whether they can regulate transcription of candidate targets in response to prolonged odor-exposure. The significance of this work is that large scale epigenetic changes of the sort we are studying are found in models for addiction and depression (3,4). In the models of depression, these changes occur in the context of prolonged GPCR stimulation. How these changes occur, is unknown. Understanding the molecular details of the pathways by which neuronal stimulation is translated into chromatin marks is key to understanding these diseases.

描述（由申请人提供）：虽然神经元必须能够对刺激做出可靠的反应，但同样重要的是，它会根据特定的经历来改变其反应。这种可塑性的分子和细胞基础以及可塑性的刺激特异性变化如何发生非常重要，因为它是学习和记忆等正常过程以及成瘾和抑郁等疾病状态的基础。我们的目标是利用遗传上易驯化的线虫秀丽隐杆线虫的嗅觉反应来确定小RNA调节途径是否指导刺激特异性神经元可塑性。 重复刺激改变神经元反应性的一种方法是通过表观遗传“标记”（例如 DNA 甲基化和组蛋白修饰）引起的转录变化（综述于 1）。在粟酒裂殖酵母、植物和果蝇中，染色质“标记”已被证明是由小 RNA 引导的。这些表观遗传变化被认为调节重要的发育过程。小RNA是否可以动态调节神经元因特定行为而发生的表观遗传变化尚未得到检验。一个有吸引力但完全未经检验的假设是，小 RNA 可能为表观遗传事件提供指导和特异性，从而指导神经元活动的持久变化。作为检验这一假设的第一步，我们询问在解剖学简单但遗传强大的模式生物秀丽隐杆线虫中，RNA 干扰 (RNAi) 所需的基因是否可能是神经元可塑性所必需的。 线虫本质上会被它使用 G 蛋白偶联受体 (GPCR) 感知的特定气味所吸引，但是，如果气味不伴随食物，它的吸引力就会减弱。我们将这种对气味嗅觉适应反应的依赖于经验的抑制称为“经验依赖性抑制”。打开嗅觉适应的关键“开关”是 cGMP 依赖性蛋白激酶 (PKG)、EGL-4 进入气味刺激的感觉嗅觉神经元 AWC 的细胞核（Lee 等人提交）。在我们的初步研究中，我们发现，当感觉神经元接触气味时，一类特定的小RNA与编码染色质相关蛋白HPL-2（一种组蛋白H3赖氨酸9三甲基结合蛋白）的基因一起作用，以促进适应。这两个因子都作用于 EGL-4 核进入的下游，并且两个因子都作用于相同的适应遗传途径。因此，我们的研究提出了一种新颖且令人兴奋的可能性，即环境刺激可以通过小 RNA 来指导染色质的变化。 我们建议通过确定小RNA和染色质是否是适应过程的核心参与者、它们在适应过程中如何发挥作用以及它们是否可以调节候选目标的转录以响应长时间的气味暴露来检验这一假设。 这项工作的意义在于，在成瘾和抑郁模型中发现了我们正在研究的大规模表观遗传变化 (3,4)。在抑郁症模型中，这些变化发生在长期 GPCR 刺激的背景下。这些变化是如何发生的，目前尚不清楚。了解神经元刺激转化为染色质标记的途径的分子细节是了解这些疾病的关键。