Cholinergic Modulation of Olfaction

描述(申请人提供)：胆碱能信号中断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知识，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，该系统在不同水平上合成信息，将细胞机制与行为影响联系起来。嗅觉障碍是大多数形式的神经退行性疾病的核心。胆碱能信号的中断被认为是导致嗅觉功能障碍的机制之一。嗅觉系统的简单性使嗅觉只有两个突触就能识别气味，这使它成为研究胆碱能调节嗅觉信号的机制的理想系统。以大鼠嗅球为起点，本研究将探讨大鼠嗅球胆碱能信号转导通路的定位及其对主细胞兴奋性和行为的影响。伽马氨基丁酸(GABA)是一种基本的递质系统，被认为是影响暴徒气味信息处理的因素。在第一个具体目标中，我们将利用电生理学和成像研究，研究毒胆碱型乙酰胆碱受体(MAChRs)在大鼠主嗅球(MOB)中的信号转导位置和机制。我们将集中于mAChRs对GABA释放的调节、作用轨迹以及mAChRs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，我们将针对烟碱型乙酰胆碱受体(NAChRs)对MOB中GABA能信号的影响。我们将研究这些受体的基因座，这些受体用于钙信号传递的机制，以及它们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，即在胆碱能信号中存在发育转换。利用电生理学研究，我们将描述这种转换背后的机制。然后，我们将使用行为实验来阐明这种机制转换对发育过程中嗅觉的胆碱能调节意味着什么。来自这些研究的信息将成为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