Exploring the Role of OSM-9 in Odor Aversive Learning and Long-term Memory

项目摘要/摘要 对环境线索的适应对生存至关重要。例如，学习将某些 具有食物可获得性的气味对于线虫破译营养细菌和病原细菌至关重要。 虽然我们知道长时程增强(LTP)和长期抑郁(LTD)是学习和长期抑郁的基础 记忆巩固这一术语，我们缺乏对记忆形成的分子机制的了解 在神经电路中进行编码。瞬时受体电位香草型(TRPV)通道已被 与促进LTP和LTD1有关。此外，TRPV1的上调已被证明是 挽救阿尔茨海默病小鼠模型中神经可塑性和学习能力的丧失2.有趣的是，我们的实验室已经证明 它的经典功能是OSM-9，一个类似TRPV的通道，而不是作为主要的感觉受体 在嗅觉适应所需的几个核事件的下游。这项研究的目的是探索 OSM-9促进活体动物长期记忆形成的机制。拟议的目标将 验证OSM-9表达通过非细胞自主方式介导嗅觉适应的假设 在学习和长期记忆巩固过程中促进钙内流，但在发育过程中不促进。 为了帮助描述OSM-9在长期记忆巩固的每个阶段中的作用，我们首先 探讨内源性OSM-9在受过先天相关训练的蠕虫中的表达模式 诱人的气味，丁酮，训练后和训练后恢复后都会饿死。(目标1A)届时我们会 利用生长素诱导降解(AID)系统降解内源性OSM-9并询问在哪些神经元 以及在什么阶段OSM-9的表达对适应起作用。(目标1B和1C)进一步研究OSM-9 在学习和记忆后，在嗅觉回路中产生激活或减弱的反应，我们首先 询问已知的嗅觉回路中的钙活动模式是如何在学习和 16小时恢复。(目标2A)然后，我们将通过可视化钙离子来询问这些活动变化是否需要OSM-9 受过训练的野生型和耗尽OSM-9的蠕虫中表达OSM-9的神经元的活性。(目标2B) 综上所述，这一建议将有助于解决OSM-9在神经可塑性中的作用，并可能指导其 用作阿尔茨海默氏症、精神分裂症、帕金森氏症、嗅觉障碍、癫痫、夏科-玛丽-牙齿病的可药物靶点 疾病和其他由色氨酸通道功能障碍引起的神经和感觉障碍。3，4

Project Summary/Abstract Adaptation to environmental cues is essential to survival. For example, learning to associate certain scents with food availability is critical to C. elegans deciphering nutritious bacteria from pathogenic bacteria. While we know that long-term potentiation (LTP) and long-term depression (LTD) underlie learning and long- term memory consolidation, we lack an understanding of the molecular mechanism by which memory is encoded within a neural circuit. Transient receptor potential vanilloid-type (TRPV) channels have been implicated in promoting both LTP and LTD.1 Furthermore, the upregulation of TRPV1 has been shown to rescue loss of neural plasticity and learning in Alzheimer's mouse models.2 Interestingly, our lab has shown that instead of acting as a primary sensory receptor, its classic function, OSM-9, a TRPV-like channel, is downstream of several nuclear events required for olfactory adaptation. The goal of this study is to probe the mechanism by which OSM-9 promotes long-term memory formation in live animals. The proposed aims will test the hypothesis that OSM-9 expression mediates olfactory adaptation non-cell autonomously by promoting Ca2+ influx during both learning and long-term memory consolidation, but not during development. To help delineate the role of OSM-9 in each stage of long-term memory consolidation, we will first probe endogenous OSM-9 expression patterns in worms who have been trained to associate an innately attractive odor, butanone, with starvation both after training and post-training recovery. (Aim 1A) We will then utilize the auxin-inducible degradation (AID) system to degrade endogenous OSM-9 and ask in what neurons and at what stages OSM-9 expression is functional for adaptation. (Aim 1B and 1C) To further study if OSM-9 produces an activating or attenuating response in the olfactory circuit after learning and memory, we will first ask how patterns of Ca2+ activity evolve in the known olfactory circuit in response to odor after learning and 16-hr recovery. (Aim 2A) We will then ask if OSM-9 is required for these changes in activity by visualizing Ca2+ activity in OSM-9 expressing neurons in trained wild-type and OSM-9 depleted worms. (Aim 2B) Taken together, this proposal will help resolve the role of OSM-9 in neural plasticity and may guide its use as a druggable target in Alzheimer's, schizophrenia, Parkinson's, anosmia, epilepsy, Charcot-Marie-Tooth disease, and other neurological and sense disorders caused by TRP channel dysfunction.3,4