Cholinergic Modulation of Olfaction

描述(申请人提供)：嗅觉障碍是阿尔茨海默病和帕金森氏症等神经退行性疾病的最早症状之一。一种占主导地位的假说是，这些疾病的主要病因是胆碱能。因此，了解这个系统是如何调节嗅觉处理的，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。这种嗅觉的调节是由基底前脑传入的胆碱能神经支配以及随后激活两类胆碱能受体--M胆碱型乙酰胆碱受体和烟碱型乙酰胆碱受体(NAChRs)所致。在这项研究中，我们研究了nAChRs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制，从而影响行为。该提案从多个层面审查了这个问题。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对肾小球微电路的调制。我们测试了nAChR对肾小球输出的调制是由于来自球周(PG)细胞的有效反馈抑制。我们还测试了一部小说 有效地抑制肾小球输出的想法是由PG-PG相互作用导致的GABA释放的放大驱动的。利用光遗传学方法，我们将研究从胆碱能纤维释放的ACh是如何调节肾小球回路的。传送器释放的时间，相对于传入的气味输入，将被检查在切片上，以及清醒行为动物的录音中。本文提出的研究将极大地提高我们对大脑胆碱能调节原理的理解，为合理设计治疗神经退行性疾病的药物奠定基础。

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.