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

探索 OSM-9 在气味厌恶学习和长期记忆中的作用

• 批准号: 10390222
• 负责人: Mashel Fatema Saifuddin
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390222
• 关键词: Exploring; Role; OSM; Odor; Aversive

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

项目总结/摘要 对环境线索的适应对生存至关重要。例如，学习将某些 气味与食物供应的关系对C.从病原菌中分辨出营养菌的线虫。 虽然我们知道长时程增强（LTP）和长时程抑郁（LTD）是学习和长时程的基础， 长期记忆巩固，我们缺乏对记忆的分子机制的理解， 编码在神经回路中瞬时受体电位香草酸型（TRPV）通道已被广泛应用于临床。 参与促进LTP和LTD。1此外，TRPV 1的上调已被证明 在阿尔茨海默氏症小鼠模型中挽救神经可塑性和学习能力的丧失。2有趣的是，我们的实验室已经表明， 它的经典功能，OSM-9，一种TRPV样通道， 嗅觉适应所需的几个核事件的下游。本研究的目的是探讨 OSM-9促进活体动物长期记忆形成的机制。拟议的目标将 测试OSM-9表达介导嗅觉适应非细胞自主的假设， 在学习和长期记忆巩固过程中促进Ca 2+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，我们将首先 在经过训练的蠕虫中探索内源性OSM-9表达模式， 吸引人的气味，丁酮，与饥饿后的培训和培训后恢复。(Aim（1）我们将 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中 以及在什么阶段OSM-9表达对于适应是有功能的。(Aim 1B和1C）进一步研究OSM-9是否 在学习和记忆后，在嗅觉回路中产生激活或衰减反应，我们将首先 询问学习后已知嗅觉回路中的Ca 2+活性模式如何对气味做出反应， 16小时恢复期。(Aim 2A）然后，我们将通过可视化Ca 2+来询问OSM-9是否是这些活性变化所必需的。 在训练的野生型和OSM-9耗尽的蠕虫中表达OSM-9的神经元中的活性。(Aim第2B段） 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，并可能指导其研究。 用作阿尔茨海默氏症、精神分裂症、帕金森氏症、嗅觉丧失、癫痫、腓骨肌萎缩症 疾病以及由TRP通道功能障碍引起的其他神经和感觉障碍。