Cholinergic Modulation of Olfaction

嗅觉的胆碱能调节

基本信息

批准号：
7410104
负责人：
SUKUMAR VIJAYARAGHAVAN
金额：
$ 31.54万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7410104
关键词：
Abbreviations Acetylcholine Action Potentials Adult Affect Area Behavior Behavioral Biological Models Brain Butyric Acid Butyric Acids Calcium Calcium Signaling Calcium-Sensing Receptors Carbamoylcholine Cells Cholinergic Agents Cholinergic Antagonists Cholinergic Receptors Chromosome Pairing Classification Dendrodendritic Synapse Development Discrimination Disease Disruption Drug Design Electrophysiology (science)Endoplasmic Reticulum Ensure Fire - disasters Functional disorder ITPR1 gene Image Imaging Techniques Inositol Interneurons Intraperitoneal Injections Knowledge Learning Lesion Link Location M cell Mechanics Memory Muscarinic Acetylcholine Receptor Neurodegenerative Disorders Neurons Nicotinic Receptors Odors Olfactory Cortex Olfactory Learning Olfactory Nerve Pathway interactions Perception Pharmaceutical Preparations Process Property Rattus Regulation Research Personnel Role Ryanodine Receptor Calcium Release Channel Shapes Signal Transduction Smell Perception Synapses System Techniques Testing Thapsigargin Therapeutic Intervention Thinking Work basal forebrain cholinergic neurons base cholinergic esterase inhibitor gamma-Aminobutyric Acid granule cell inorganic phosphate olfactory bulb preference programs pup receptor research study

项目摘要

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

描述（由申请人提供）：胆碱能信号传导的破坏被认为是许多神经退行性疾病的主要因素。然而，由于我们对胆碱能系统如何调节各种大脑系统缺乏了解，因此设计抗击这些干扰的药物受到了阻碍。缺乏的是对胆碱能系统的系统研究，该系统合成不同水平的信息以将细胞机制与行为效应联系起来。嗅觉功能障碍是大多数形式的神经退行性疾病的核心。胆碱能信号的破坏被认为是嗅觉功能障碍的潜在机制。嗅觉系统非常简单，气味感知与气味识别之间只有两个突触，这使得该系统成为检查嗅觉信号的胆碱能调节机制的理想系统。使用大鼠嗅球作为起点，在本提案中，我们将研究在嗅球中转导胆碱能信号传导的途径及其位点及其对主细胞兴奋性以及行为的影响。 γ-氨基丁酸（GABA）被认为是影响 MOB 中气味信息处理的基本传递系统。在第一个具体目标中，我们将使用电生理学和成像研究来检查大鼠主嗅球（MOB）中毒蕈碱乙酰胆碱受体（mAChR）信号转导的位置和机制。我们将重点关注 mAChR 对 GABA 释放的调节、作用位点以及 mAChR 对二尖瓣细胞（MOB 的主要神经元）放电的影响。在第二个具体目标中，我们将针对烟碱乙酰胆碱受体 (nAChR) 对 MOB 中 GABA 信号传导的影响。我们将检查这些受体的位点、这些受体用于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，我们将扩展我们的初步发现，即胆碱能信号传导存在发育转变。通过电生理学研究，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阐明这种机制转换对于发育过程中嗅觉的胆碱能调节意味着什么。这些研究的信息将为旨在对抗神经退行性疾病的合理药物设计奠定基础