Cholinergic Modulation of Olfaction

描述（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早期症状之一。一个主要的假设是这些疾病具有原发性胆碱能病因。因此，了解这个系统如何调节嗅觉处理，为早期发现和干预奠定了基础。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和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（nAChRs）的激活引起的。在本研究中，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。利用结合嗅觉切片电生理学和清醒行为记录的协同方法，我们探讨嗅球中不同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。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、电生理学和钙成像来研究nAChR对肾小球微回路的调节。我们测试了nAChR对肾小球输出量的调节是由于肾小球周围（PG）细胞的有效反馈抑制。我们还测试了一本小说

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.