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: 10552551
• 负责人: Mashel Fatema Saifuddin
• 金额: $ 4.21万
• 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/10552551
• 关键词: Adult; Affect; Afferent Neurons; Alzheimer' s Disease; Animals; Anosmia; Anxiety; Arabidopsis; Attenuated; Auxins; Behavior; Behavioral Assay; Binding; Brain imaging; Buffers; Butanones; Caenorhabditis elegans; Calcium; Cells; Charcot-Marie-Tooth Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Data; Development; Disease; Environment; Epilepsy; Esthesia; Excision; Exposure to; Food; Fright; Functional disorder; Genes; Goals; Guidelines; Image; Individual; Ions; Label; Lead; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Mediation; Memory; Molecular; Nervous System Physiology; Neurologic; Neuronal Plasticity; Neurons; Nociception; Nuclear Accidents; Nutritional; Odors; Olfactory Learning; Olfactory Pathways; Pain; Parkinson Disease; Pathway interactions; Pattern; Physiologic Thermoregulation; Process; Proteins; Recovery; Role; Schizophrenia; Sensory; Sensory Receptors; Signal Transduction; Starvation; Stimulus; Stress; Synaptic plasticity; System; TRP channel; TRPV1 gene; Testing; Training; Up-Regulation; Vanilloid; Visual; Work; behavioral plasticity; druggable target; egg; functional adaptation; innovation; long term memory; loss of function; memory consolidation; mouse model; mutant; nervous system disorder; neural circuit; neuromechanism; new technology; olfactory sensory neurons; pathogenic bacteria; promoter; receptor; response; single-cell RNA sequencing

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

项目概要/摘要 适应环境线索对于生存至关重要。例如，学习关联某些 气味与食物的可用性对于线虫从病原菌中辨别营养菌至关重要。 虽然我们知道长时程增强（LTP）和长时程抑制（LTD）是学习和长期学习的基础。 术语“记忆巩固”，我们对记忆巩固的分子机制缺乏了解。 编码在神经回路中。瞬时受体电位香草酸型（TRPV）通道 涉及促进 LTP 和 LTD.1 此外，TRPV1 的上调已被证明可以 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 OSM-9（TRPV 样通道）不是主要的感觉受体，而是 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 检验 OSM-9 表达自主介导非细胞嗅觉适应的假设 在学习和长期记忆巩固过程中促进 Ca2+ 流入，但在发育过程中则不然。 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 探索线虫中的内源性 OSM-9 表达模式，这些线虫经过训练可以将先天性联系起来 诱人的气味，丁酮，训练后和训练后恢复时的饥饿感。 （目标 1A）然后我们将 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 OSM-9 表达在什么阶段发挥适应功能。 （目标1B和1C）进一步研究OSM-9是否 学习记忆后在嗅觉回路中产生激活或减弱反应，我们首先 询问学习后 Ca2+ 活动模式如何在已知的嗅觉回路中演变以响应气味 16 小时恢复。 （目标 2A）然后我们将通过可视化 Ca2+ 来询问这些活性变化是否需要 OSM-9 在经过训练的野生型和 OSM-9 耗尽的蠕虫中表达 OSM-9 的神经元的活性。 （目标 2B） 总而言之，该提案将有助于解决 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、嗅觉丧失症、癫痫症、腓骨肌萎缩症的药物靶点 TRP 通道功能障碍引起的疾病以及其他神经和感觉障碍。3,4