Cholinergic Modulation of Olfaction

描述（由申请人提供）：胆碱能信号的破坏被认为是许多神经退行性疾病的主要因素。然而，由于我们缺乏对胆碱能系统如何调节各种大脑系统的了解，对抗这些干扰的药物设计一直受到阻碍。缺乏的是对胆碱能系统的系统研究，该系统综合了不同层次的信息，将细胞机制与行为效应联系起来。嗅觉功能障碍是大多数神经退行性疾病的核心。胆碱能信号的破坏被认为是嗅觉功能障碍的一种机制。嗅觉系统的简单性，气味感知距离气味识别只有两个突触，使其成为研究嗅觉信号的胆碱能调节机制的理想系统。以大鼠嗅球为出发点，我们将研究嗅球中胆碱能信号的传导途径，并研究其位点及其对主要细胞兴奋性和行为的影响。一个基本的传递系统，被认为是塑造嗅觉信息的处理在MOB是γ -氨基丁酸（GABA）。在第一个具体目标中，我们将使用电生理学和影像学研究来研究毒蕈碱乙酰胆碱受体（mAChRs）在大鼠主嗅球（MOB）中的信号转导位置和机制。我们将重点讨论machr对GABA释放的调控，其作用位点以及对二尖瓣细胞（MOB的主要神经元）放电的影响。在第二个特定目标中，我们将针对烟碱乙酰胆碱受体（nAChRs）对MOB中gaba能信号传导的影响。我们将研究这些受体的位点，这些受体钙信号传导的机制及其在二尖瓣细胞兴奋性中的作用。在第三个具体目标中，我们将扩展我们最初的发现，即在胆碱能信号传导中存在发育开关。利用电生理学研究，我们将描述这种开关的机制。然后，我们将使用行为实验来阐明这种机制开关在发育过程中对嗅觉的胆碱能调节意味着什么。来自这些研究的信息将形成旨在对抗神经退行性疾病的合理药物设计的基础

DESCRIPTION (provided by applicant): Disruption of cholinergic signaling is thought to be a major factor in many neurodegenerative disorders. However, design of drugs to combat these disruptions has been hampered by our lack of knowledge of how various brain systems are modulated by the cholinergic system. What is lacking is a systematic study of cholinergic system that synthesizes information at various levels to link cellular mechanisms to behavioral effects. Olfactory dysfunction is central to most forms of neurodegenerative disorders. Disruption of cholinergic signaling is thought to be a mechanism underlying olfactory dysfunction. The simplicity of the olfactory system where odor perception is only two synapses away from odor recognition, make this an ideal system to examine mechanisms underlying cholinergic modulation of olfactory signaling. Using the rat olfactory bulb as a starting point, in this proposal we will examine pathways transducing cholinergic signaling in the bulb their loci and their effects on the excitabiltiy of principals cells as well as on behavior will be examined. A fundamental transmitter system that is thought to shape processing of odorant information in the MOB is gamma-amino-butyric acid (GABA). In the first specific aim, we will examine, using electrophyiological and imaging studies, the location and mechanisms of signal transduction by muscarinic acetylcholine receptors (mAChRs) in the rat main olfactory bulb (MOB). We will focus on the regulation of GABA release by mAChRs, the locus of action and the effects of mAChRs on the firing of mitral cells the principal neurons of the MOB. In the second specific aim we will target the effects of nicotinic acetylcholine receptors (nAChRs) on GABAergic signaling in the MOB. We will examine the loci of these receptors, mechanisms employed by these receptors for calcium signaling and their role in mitral cell excitability. In the third specific aim we will extend our initial finding that there is a developmental switch in cholinergic signaling. Using electrophysiological studies we will characterize the mechanisms underlying this switch. We will then, using behavioral experimetns elucidate what this mechanistic switch implies for cholinergic modulation of olfaction during development. Information from these studies will form the bases for rational drug design aimed at combatting neurodegenerative diseases