CHOLINERGIC & GABAERGIC MECHANISM SEPTOHIPPOCAMPAL PATHWAY

胆碱能

• 批准号: 6629276
• 负责人: Meenakshi Alreja
• 金额: $ 17.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629276
• 关键词: GABA receptor; acetylcholine; brain imaging /visualization /scanning; brain mapping; central neural pathway /tract; cholinesterase inhibitors; cognition; electrophysiology; gamma aminobutyrate; hippocampus; histology; infrared microscopy; laboratory rat; muscarinic receptor; neural transmission; neuronal transport; neurotransmitter transport; tissue /cell culture; video microscopy

DESCRIPTION(Adapted from applicant's abstract): Cognitive impainnent is a serious health Concern in the United States; it accompanies not only nonmal aging and dementing disorders such as Alzheimer's, but also several mental illnesses, such as schizophrenia. Basic and clinical studies have long recognized the importance of cholinergic mechanisms for the maintenance of cognitive functioning and treatments which increase synaptic acetylcholine (ACh) levels, using acetylcholinesterase inhibitors (AChEls), are currently the most extensively used for the therapy of Alzheimer's disease. In contrast, treatments which oppose cholinergic tone, such as systemic infusions of the muscarinic cholinergic receptor antagonists, atropine and scopolamine (Atr/Scop), produce an amnesic syndrome both in humans and in rats and emphasize the importance of muscarinic mechanisms. Basic studies suggest that muscarinic mechanisms in the medial septum/diagonal band (MSDB), via the septohippocampal pathway, contribute to the cognitive deficits produced by systemic Atr/Scop. Thus, infusions of muscarinic agonists into the MSDB alleviate the amnesic syndrome, whereas local infusions of Atr/Scop mimic the syndrome. In our preliminary shidies, conducted using electrophysiological recording techniques in rat brain slices, we have found that Atr/Scop, when applied to septal slices, stop spontaneous firing activity in a vast majority of MSDB neurons, including, non-cholinergic (presumably, GABAergic) neurons that project to the hippocampus. In contrast, a wide array of AChEIs, including the clinically used tacrine, produce a profound increase in the firing activity of MSDB neurons, which is blocked by Atr/Scop. Therefore, in the present study, we hypothesize 1) that there is a tonic release of ACh in the MSDB (which carl be unmasked by Atr/Scop and AChEIs) and the released ACh, via muscarinic receptors, provides a major excitatory drive to the septohippocampal GABAergic neurons; 2) the released ACh, via muscarinic receptors, provides a major excitatory drive to the septohippocampal GABA neurons; 3) the tonic release of ACh occurs due to the spontaneous firing activity of septohippocampal cholinergic neurons (which also innervate MSDB GABAergic neurons via axon collaterals); 4) a loss of MSDB cholinergic neurons (as can occur in normal aging and in Alzbeimer's) decreases the activity of septohippocampal GABA neurons. It is speculated that the resultant changes in cholinergic and GABergic transmission to the hippocarnpus will contribute to deficits in learning and memory. The above hypothesis will be tested using state-of-the-art electrophysiological recording methods in antidromically-activated and/or retrogradely labeled septohippocampal neurons visualized using the technique of infrared videomicroscopy. Cholinergic neurons will be selectively lesioned US aboutDig the irnrnunotoxin, 1921gG-saporin. In addition, double and triple-labeling techniques will be employed to identify septohippocampal cholinergic and GABAergic neurons. It is hoped that the proposed research will provide fresh insights into the role of the septohippocampal GABAergic pathway in cognitive functioning.

描述（改编自申请人的摘要）： 在美国，认知障碍是一个严重的健康问题；它 不仅伴随着非正常衰老和痴呆症，例如阿尔茨海默氏症， 还有一些精神疾病，例如精神分裂症。基础和临床 研究早已认识到胆碱能机制对于 维持认知功能和增加突触的治疗 使用乙酰胆碱酯酶抑制剂 (AChEls) 测定乙酰胆碱 (ACh) 水平 目前最广泛用于治疗阿尔茨海默病。在 相反，对抗胆碱能张力的治疗，例如全身输注 毒蕈碱胆碱能受体拮抗剂阿托品和东莨菪碱 (Atr/Scop)，在人类和大鼠中产生遗忘综合症， 强调毒蕈碱机制的重要性。基础研究表明 内侧隔膜/对角带（MSDB）中的毒蕈碱机制，通过 隔海马通路，导致认知缺陷 系统性 Atr/Scop。因此，将毒蕈碱激动剂输注至 MSDB 缓解遗忘综合症，而 Atr/Scop 的局部输注则模仿 综合症。在我们的初步实验中，使用电生理学进行 在大鼠脑切片中的记录技术中，我们发现 Atr/Scop，当 应用于隔膜切片，阻止绝大多数的自发放电活动 MSDB 神经元，包括非胆碱能（可能是 GABA 能）神经元 那个项目到海马体。相比之下，多种 AChEI，包括 临床上使用的他克林可显着增加放电活动 MSDB 神经元，被 Atr/Scop 阻断。 因此，在本研究中，我们假设1）存在补品 MSDB 中 ACh 的释放（可通过 Atr/Scop 和 AChEI 揭示）和 通过毒蕈碱受体释放的乙酰胆碱提供了主要的兴奋性驱动 至隔海马 GABA 能神经元； 2) 通过毒蕈碱释放的乙酰胆碱 受体，为隔海马 GABA 提供主要的兴奋性驱动 神经元； 3）由于自发放电而发生乙酰胆碱的强直性释放 隔海马胆碱能神经元的活动（也支配 MSDB） 通过轴突侧支的 GABA 能神经元）； 4) MSDB胆碱能神经元丧失 （如正常衰老和阿尔兹贝默病中可能发生的那样）降低 隔海马 GABA 神经元。据推测，由此产生的变化 胆碱能和 GABergic 传输到海马将有助于 学习和记忆力缺陷。上述假设将使用以下方法进行检验 最先进的电生理记录方法 逆向激活和/或逆行标记的间隔海马神经元 使用红外视频显微镜技术进行可视化。胆碱能神经元 将选择性损伤美国约Dig免疫毒素，1921gG-皂素。在 此外，将采用双重和三重标记技术来识别 隔海马胆碱能和 GABA 能神经元。希望 拟议的研究将为了解该组织的作用提供新的见解 认知功能中的隔海马 GABA 能通路。