Cholinergic Modulation of Olfaction

描述（由申请人提供）：嗅觉功能障碍是神经退行性疾病（如阿尔茨海默病和帕金森症）的最早症状之一。一个占主导地位的假设是，这些疾病有一个主要的胆碱能病因。因此，了解这个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。嗅觉的这种调节是由来自基底前脑的传入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（nAChR）的激活引起的。在这个建议中，我们研究nAChRs在调节小鼠主嗅球中的二尖瓣细胞的兴奋性的作用。使用一种协同的方法，将嗅觉切片电生理学和清醒的行为记录，我们问如何在嗅球中的各种nAChR亚型之间的相互作用的结果在肾小球输出传入的气味信号的调制，从而影响行为。该提案从多个层面审查了这一问题。 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检查肾小球微回路的nAChR调制。我们测试的模型，nAChR调节肾小球输出是由于有效的反馈抑制肾小球周围（PG）细胞。我们还测试了一本小说 认为肾小球输出的有效抑制是由PG-PG相互作用引起的GABA释放放大驱动的。 利用光遗传学的方法，我们将研究如何肾小球电路的胆碱能纤维释放的乙酰胆碱调制。发射器释放的时间，相对于传入的气味输入，将在切片中进行检查，以及与清醒行为动物的记录。 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。

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.