Olfactory memory acquisition consolidation and recall

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，它改变了它的 作为特定经验的函数的反应。这种可塑性的分子和细胞基础以及如何 理解刺激特有的可塑性变化很重要，因为它是两个正常过程的基础 例如学习和记忆，以及成瘾和抑郁的疾病状态。我们的目标是使用 对遗传易感线虫的嗅觉反应来确定是否有小RNA 调节通路方式指导刺激特异性神经元的可塑性。 重复刺激改变神经元反应性的一种方式是通过改变 由表观遗传“标记”引起的转录，如DNA甲基化和组蛋白修饰(回顾文献1)。在……里面 植物和果蝇，染色质“标记”已经被证明是由小的RNA2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 作为特定行为的结果，动态调控神经元的表观遗传变化尚未得到 检查过了。一个有吸引力但完全未经检验的假说是，小RNA可能提供指导和 指示神经元活动发生长期变化的表观遗传事件的特异性。作为迈向未来的第一步 为了验证这一假设，我们询问了RNA干扰(RNAi)所需的基因是否可能需要 解剖简单但遗传功能强大的模式生物秀丽线虫的神经元可塑性。 线虫天生就会被特殊的气味所吸引，这种气味是通过G蛋白偶联受体来感知的 然而，如果气味不伴随食物，它的吸引力就会减弱。我们称这为 对气味嗅觉适应反应的经验依赖性抑制。开启的关键《S女巫》 嗅觉适应是cGMP依赖的蛋白激酶(PKG)、EGL-4进入嗅核的过程。 气味刺激感觉嗅觉神经元AWC(Lee等人，提交)。在我们的初步研究中，发现一个 特定类别的小RNA与编码染色质相关蛋白HPL-2(组蛋白H3)的基因一起工作 赖氨酸9三甲基结合蛋白)在气味暴露时促进感觉神经元 适应。这两个因子都作用在EGL-4核进入的下游，并且这两个因子作用于相同的基因 适应的途径。因此，我们的研究提出了一种新颖而令人兴奋的可能性，即环境 刺激可以通过小的RNA引导染色质的变化。 我们建议通过确定小RNA和染色质是否是中心来检验这一假设 适应过程中的参与者，他们如何在适应中发挥作用，以及他们是否可以调节转录 对长时间的气味暴露作出反应的候选目标。 这项工作的意义在于，我们正在研究的那种大规模的表观遗传变化是 在成瘾和抑郁的模型中发现3，4。在抑郁的模型中，这些变化发生在 长期的gpr刺激的背景。这些变化是如何发生的，目前尚不清楚。理解分子 神经元刺激转化为染色质标记的途径的细节是理解的关键 这些疾病。

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 path way 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 to wards 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 “s witch” 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, 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 depression3,4. 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.