The perception of odor blends and mixtures: Modulation, Inhibition and Enhancement of Olfactory Receptors alters perception of complex blends

对气味混合物和混合物的感知：嗅觉受体的调节、抑制和增强改变了对复杂混合物的感知

• 批准号: 10301349
• 负责人: Stuart J Firestein
• 金额: $ 33.91万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301349
• 关键词: Acetates; Acetophenones; Adopted; Afferent Neurons; Agonist; Allosteric Site; Area; Behavioral; Binding; Biological; Brain; Calcium; Cells; Characteristics; Chemical Structure; Chemicals; Chemistry; Classification; Code; Collection; Complex; Data; Development; Discrimination; Drug Industry; Epithelial; Event; Family; Funding; G-Protein-Coupled Receptors; Grant; Human; Image; In Situ; Individual; Investigation; Lead; Light; Medical; Microscopic; Microscopy; Molecular; Monitor; Nature; Neurons; Odors; Olfactory Pathways; Optics; Organic Chemistry; Pattern; Perception; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Psychophysics; Receptor Inhibition; Resolution; Sensory; Sensory Receptors; Signal Transduction; Smell Perception; Stimulus; Structure; System; Techniques; Testing; Tissues; Work; antagonist; base; citral; drug development; experimental study; grasp; high throughput screening; hormone regulation; insight; neurotransmission; novel; olfactory receptor; olfactory stimulus; patch clamp; programs; receptor; receptor function; response; sensory system; side effect; signal processing; virtual

Project Summary/Abstract This is a continuation of an existing program funded by an RO1 that seeks to understand fundamental questions about the nature of the olfactory stimulus and its discrimination by primary sensory receptors, in order to better grasp the nature of the signal being forwarded to the brain. We supplement the standard organic chemistry approach to odor classification with one that includes a biological perspective based in principles of medicinal chemistry pioneered in the pharmaceutical industry and drug development. This allows us to not only consider physical chemical characteristics of molecules but also how they interact with the many olfactory receptors. This work, like much of olfactory cellular studies, utilized monomolecular stimuli to probe receptor function. However the olfactory system is usually confronted with complex stimulus blends of between tens and hundreds of components. To better understand the complexity of mixture discrimination we have begun utilizing a novel microscopic technique, SCAPE – that allows us to visualize large numbers of individual neurons in an intact tissue with single cell temporal and spatial resolution. Preliminary data from that work showed a remarkable and unexpected degree of inhibition and enhancement of responses by one component of the mixture on other components of the mixture. This raises a fundamental issue in olfactory discrimination as there appears to be considerable interaction between stimuli at the primary receptor, raising crucial questions about how the brain perceives and manages signals that differ depending on the presence of particular odors in a blend. It appears that many, if not all, odors can act as either an agonist or antagonist at different receptors. Thus depending on whether or not an antagonist to odor X, for example, exists in the blend, the signal from odor X will appear different to the brain. This level of complexity is unusual in sensory systems where signal processing of this sort occurs in the brain not the primary receptors. Understanding higher brain processing olfactory signals will require a greater understanding of the initial events at primary receptors. The olfactory code is more than the additive contributions of the olfactory receptors.

项目概要/摘要 这是由 RO1 资助的现有计划的延续，旨在了解基本原理 关于嗅觉刺激的性质及其对初级感觉受体的辨别的问题， 为了更好地掌握转发到大脑的信号的性质。我们补充标准 气味分类的有机化学方法，其中包括基于生物视角的方法 药物化学原理在制药工业和药物开发中处于领先地位。这允许 我们不仅要考虑分子的物理化学特性，还要考虑它们如何与许多物质相互作用 嗅觉受体。与许多嗅觉细胞研究一样，这项工作利用单分子刺激来探测 受体功能。然而，嗅觉系统通常面临着复杂的刺激混合物 数十到数百个组件。为了更好地理解混合判别的复杂性，我们 已经开始利用一种新颖的显微技术 SCAPE——它使我们能够可视化大量的 完整组织中的单个神经元具有单细胞时间和空间分辨率。初步数据来自 一项研究显示出一种显着且出乎意料的抑制作用和增强反应的程度 混合物的组分对混合物的其他组分的影响。这就提出了嗅觉的一个根本问题 歧视，因为主要受体的刺激之间似乎存在相当大的相互作用， 关于大脑如何感知和管理因存在而异的信号的关键问题 混合物中的特殊气味。看来许多（如果不是全部）气味可以充当激动剂或拮抗剂 不同的受体。因此，例如，取决于气味 X 的拮抗剂是否存在于 混合后，气味 X 发出的信号对大脑来说会有所不同。这种复杂程度在感官上是不寻常的 这种信号处理发生在大脑而不是主要受体的系统。理解 大脑处理嗅觉信号的能力更强，需要对小学时的初始事件有更深入的了解 受体。嗅觉密码不仅仅是嗅觉受体的附加贡献。