Cholinergic Modulation of Olfaction

嗅觉的胆碱能调节

• 批准号: 9062296
• 负责人: SUKUMAR VIJAYARAGHAVAN
• 金额: $ 33.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062296
• 关键词: Acetylcholine; Acute; Affect; Alzheimer' s Disease; Animals; Attention; Behavior; Brain; Calcium; Cells; Cholinergic Fibers; Cholinergic Receptors; DDX26 gene; Data; Diagonal Band of Broca; Discrimination; Disease; Drug Design; Early Diagnosis; Early Intervention; Electrophysiology (science); Etiology; Feedback; Foundations; Functional disorder; Genes; Genetic; Goals; Grant; Health; Human; Image; Individual; Knockout Mice; Learning; Limb structure; Link; Location; Mediating; Modeling; Molecular; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Neurodegenerative Disorders; Neurons; Nicotinic Receptors; Odors; Olfactory Nerve; Olfactory Pathways; Output; Parkinson Disease; Parkinsonian Disorders; Perceptual learning; Performance; Pharmacology; Play; Process; Rattus; Research; Role; Schizophrenia; Sensory; Short-Term Memory; Signal Transduction; Slice; Smell Perception; Staging; Stimulus; Symptoms; System; Testing; Time; Visual; Work; awake; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; gamma-Aminobutyric Acid; improved; mitral cell; mouse model; nerve supply; novel; olfactory bulb; optogenetics; research study; response; signal processing

DESCRIPTION (provided by applicant): Olfactory dysfunction is one of the earliest symptoms of neurodegenerative disorders like Alzheimer's disease and Parkinsonism. A dominant hypothesis is that these diseases have a primary cholinergic etiology. Understanding how this system modulates olfactory processing, therefore, sets the stage for early detection and intervention. Acetylcholine modulates olfactory perceptual learning and working memory. This modulation of olfaction results from the incoming cholinergic innervation from the basal forebrain and subsequent activation of two classes of cholinergic receptors - the muscarinic acetylcholine receptors and nicotinic acetylcholine receptors (nAChRs). In this proposal, we examine the role of nAChRs in modulating the excitability of mitral cells in the mouse main olfactory bulb. Using a synergistic approach incorporating olfactory slice electrophysiology and awake behaving recording we ask how interactions between various nAChR subtypes in the olfactory bulb result in the modulation of the glomerular output to incoming odor signals thereby affecting behavior. The proposal examines this question at multiple levels. In olfactory bulb slices we examine the nAChR modulation of the glomerular microcircuit using gene knockout mice, pharmacology, electrophysiology and calcium imaging. We test the model that nAChR modulation of glomerular output is due to efficient feedback inhibition from periglomerular (PG) cells. We also test a novel idea that effective inhibition of glomerular output is driven by amplification of GABA release due to PG-PG interactions. Using optogenetic approaches, we will examine how the glomerular circuit is modulated by ACh released from cholinergic fibers. Timing of transmitter release, relative to incoming odor input, will be examined both in slices, as well as with recordings from awake behaving animals. The research proposed here will greatly enhance our understanding of the principles governing cholinergic modulation in the brain to lay the foundation for rational drug design to treat neurodegenerative disorders.

描述（由申请人提供）：嗅觉功能障碍是阿尔茨海默病和帕金森病等神经退行性疾病的最早症状之一。一个主要的假设是这些疾病具有主要的胆碱能病因。因此，了解该系统如何调节嗅觉处理，为早期检测和干预奠定了基础。 乙酰胆碱调节嗅觉知觉学习和工作记忆。这种嗅觉调节是由基底前脑传入的胆碱能神经支配以及随后两类胆碱能受体——毒蕈碱乙酰胆碱受体和烟碱乙酰胆碱受体（nAChR）的激活引起的。在本提案中，我们研究了 nAChR 在调节小鼠主嗅球二尖瓣细胞兴奋性中的作用。使用结合嗅觉切片电生理学和清醒行为记录的协同方法，我们询问嗅球中各种 nAChR 亚型之间的相互作用如何导致肾小球输出对传入气味信号的调节，从而影响行为。该提案从多个层面探讨了这个问题。 在嗅球切片中，我们使用基因敲除小鼠、药理学、电生理学和钙成像检查肾小球微电路的 nAChR 调节。我们测试了以下模型：nAChR 对肾小球输出的调节是由于肾小球周围 (PG) 细胞的有效反馈抑制所致。我们还测试了一本小说 认为有效抑制肾小球输出是由 PG-PG 相互作用导致 GABA 释放放大驱动的。 使用光遗传学方法，我们将研究胆碱能纤维释放的乙酰胆碱如何调节肾小球回路。相对于传入的气味输入，发射器释放的时间将通过切片以及清醒行为动物的记录进行检查。 这里提出的研究将极大地增强我们对大脑胆碱能调节原理的理解，为治疗神经退行性疾病的合理药物设计奠定基础。