Nicotinic Receptors in Glia-Neuron Interactions

神经胶质-神经元相互作用中的烟碱受体

• 批准号: 7586926
• 负责人: SUKUMAR VIJAYARAGHAVAN
• 金额: $ 22.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586926
• 关键词: Accounting; Acetylcholine; Action Potentials; Acute; Address; Affect; Astrocytes; Attention; Axon; Brain; Brain region; Calcium; Calcium Oscillations; Calcium Signaling; Cell physiology; Cells; Choline; Cholinergic Agents; Cholinergic Fibers; Chromosome Pairing; Chronic; Complex; Development; Disruption; Drug Design; Electrophysiology (science); Event; Glial Fibrillary Acidic Protein; Glutamates; Green Fluorescent Proteins; Health; Health Care Costs; Hippocampus (Brain); Homeostasis; Image; Imaging Techniques; In Situ; Intervention; Knowledge; Label; Link; Mediating; Methods; Mus; Neuroglia; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Numbers; Pharmaceutical Preparations; Physiological; Plant Roots; Play; Process; Public Health; Role; Signal Transduction; Signaling Molecule; Slice; Smoking; Societies; Source; Supporting Cell; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Transferase; Transgenic Mice; addiction; base; cholinergic; drug of abuse; hedonic; mossy fiber; postsynaptic; presynaptic; promoter; receptor; response; tau Proteins; transmission process

DESCRIPTION (provided by applicant): Nicotine addiction is a major health problem in our society and accounts for millions in health care costs. A fundamental prerequisite for understanding the actions of nicotine is to elucidate the physiological role for nicotinic acetylcholine receptors (nAChRs) in the brain. Recently, it has been shown that nAChRs are expressed in astrocytes. This proposal will examine the role of astrocytic nAChRs on synaptic signaling in the CA3 region of the mouse hippocampus and how these receptors contribute to glia-neuron interactions in the brain. The proposal will address two issues. First, we will characterize nicotinic signaling in astrocytes using acute hippocampal slices from mice expressing GFP linked to the glial fibrillary acidic protein (GFAP). Electrophysiological analyses will be carried out examining nicotinic currents on astrocytes. Calcium imaging will be used to elucidate the details of calcium signaling in these cells, including the contributions from various sources of calcium within astrocytes. nAChR-induced intra- and inter-cellular calcium waves will be examined. We will use transgenic mice that express tau-GFP driven by the cholineacetyl transferase (ChAT) promoter in order to label cholinergic axons. The ability of local stimulation of cholinergic fibers to induce nAChR currents and calcium signals in astrocytes will be examined. These studies will establish the existence of functional nAChRs in astrocytes and their ability to transduce signals in these cells in response to both nicotine and endogenous acetylcholine. The second part of the proposal will address a unique signaling resulting in an action potential- independent form of transmission at the mossy fiber-CA3 synapse in the hippocampus. We will examine the role of astrocytes in mediating or modulating this form of short-term plasticity by its action on the presynaptic mossy fiber terminals. A combination of electrophysiology and calcium imaging will be used in these studies. It is increasingly becoming apparent that addiction is a problem of hedonic homeostasis that involves multiple regions of the brain, not just the mesolimbic dopaminergic system. Understanding the totality of nAChR actions in the brain, in order to arrive at a rational drug design to combat smoking must include the understanding of these receptors on glia as well as neurons. This proposal makes a start in that direction. PUBLIC HEALTH RELEVANCE: Methods that have been developed to combat smoking have been inadequate mainly because of our lack of knowledge on how this drug affects brain functions. It is now being recognized that drugs of abuse like nicotine have far reaching consequences for the brain. They affect not just functions of nerve cells in the brain but also support cells known as glia. These support cells have been shown to play a very active role in determining how the nerve cells function. Here we study the effects of nicotine on astrocytes, a type of glial cells, and determine how nicotine, acting via these cells can affect the functioning of, and signaling by neurons. This study will open a new direction in understanding the consequences of smoking for the brain and aid in the development of better pharmacological interventions to assist people in breaking nicotine addiction.

描述（由申请人提供）：尼古丁成瘾是我们社会的一个主要健康问题，医疗保健费用高达数百万美元。了解尼古丁作用的一个基本前提是阐明尼古丁乙酰胆碱受体（nAChRs）在大脑中的生理作用。最近，有研究表明nachr在星形胶质细胞中表达。本研究将研究星形细胞nAChRs在小鼠海马CA3区突触信号传导中的作用，以及这些受体如何促进大脑中胶质-神经元的相互作用。该提案将解决两个问题。首先，我们将利用表达GFP与胶质纤维酸性蛋白（GFAP）相关的小鼠急性海马切片来表征星形胶质细胞中的尼古丁信号。电生理分析将用于检查星形胶质细胞上的尼古丁电流。钙成像将用于阐明这些细胞中钙信号的细节，包括星形胶质细胞内各种钙来源的贡献。将检查nachr诱导的细胞内和细胞间钙波。我们将使用表达由胆碱乙酰转移酶（ChAT）启动子驱动的tau-GFP的转基因小鼠来标记胆碱能轴突。局部刺激胆碱能纤维诱导星形胶质细胞内nAChR电流和钙信号的能力将被检查。这些研究将确定星形胶质细胞中功能性nachr的存在，以及它们在这些细胞中对尼古丁和内源性乙酰胆碱作出反应时转导信号的能力。该提案的第二部分将解决导致海马苔藓纤维- ca3突触中动作电位独立形式的传输的独特信号。我们将通过星形胶质细胞对突触前苔藓纤维终端的作用来研究星形胶质细胞在介导或调节这种短期可塑性中的作用。电生理学和钙成像的结合将在这些研究中使用。越来越明显的是，成瘾是一个涉及大脑多个区域的快乐内稳态问题，而不仅仅是中脑边缘多巴胺能系统。了解nAChR在大脑中的全部作用，为了获得一种合理的药物设计来对抗吸烟，必须包括了解神经胶质和神经元上的这些受体。这项建议在这个方向上开了个好头。与公共卫生相关：已经开发的对抗吸烟的方法还不够充分，主要是因为我们对这种药物如何影响大脑功能缺乏了解。现在人们认识到，像尼古丁这样的滥用药物会对大脑产生深远的影响。它们不仅影响大脑中神经细胞的功能，还支持被称为神经胶质的细胞。这些支持细胞已被证明在决定神经细胞如何运作方面起着非常积极的作用。本文研究了尼古丁对星形胶质细胞（一种神经胶质细胞）的影响，并确定尼古丁如何通过这些细胞影响神经元的功能和信号传导。这项研究将为了解吸烟对大脑的影响开辟一个新的方向，并有助于开发更好的药物干预措施，帮助人们戒除尼古丁成瘾。