CHOLINERGIC & GABAERGIC MECHANISM SEPTOHIPPOCAMPAL PATHWAY

胆碱能

• 批准号: 6694434
• 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/6694434
• 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（改编自申请人摘要）： 认知障碍在美国是一个严重的健康问题， 不仅伴随着正常衰老和痴呆症（如阿尔茨海默氏症）， 还有几种精神疾病，比如精神分裂症。基础和临床 研究早已认识到胆碱能机制对于 维持认知功能和治疗，增加突触 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，对抗胆碱能紧张的治疗，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健忘综合征， 强调毒蕈碱机制的重要性。基础研究表明， 内侧隔/斜角带（MSDB）中的毒蕈碱机制，通过 隔海马通路，有助于产生的认知缺陷， 全身麻醉/范围因此，将毒蕈碱激动剂输注到MSDB中， 缓解健忘症，而局部输注Atr/Scop模拟了 综合征在我们的初步实验中， 记录技术在大鼠脑切片，我们已经发现，Atr/Scop，当 应用于间隔切片，在绝大多数情况下停止自发放电活动 MSDB神经元，包括非胆碱能（推测为GABA能）神经元 投射到海马状突起。相反，一系列AChEI，包括 临床上使用的他克林，产生了放电活动的显著增加， 的MSDB神经元，这是由Atr/Scop阻断。 因此，在目前的研究中，我们假设1）有一个主音 MSDB中ACh的释放（Atr/Scop和AChEI可能会发现），以及 通过毒蕈碱受体释放的ACh提供了一种主要的兴奋性驱动， 隔海马GABA能神经元; 2）释放ACh，通过毒蕈碱 受体，提供了一个主要的兴奋驱动隔海马GABA 神经元; 3）由于自发放电，ACh的紧张性释放发生 隔海马胆碱能神经元（也支配MSDB）的活性 GABA能神经元通过轴突侧支）; 4）MSDB胆碱能神经元的损失 (as可发生在正常衰老和阿尔茨海默氏症中）降低 隔海马GABA神经元。据推测， 胆碱能和γ-氨基丁酸能传递到肉食动物将有助于 学习和记忆的缺陷。上述假设将通过以下方式进行检验： 最先进的电生理记录方法， 逆行激活和/或逆行标记的隔海马神经元 使用红外视频显微镜技术可视化。胆碱能神经元 选择性损伤美迪格免疫毒素，1921 gG-皂草素。在 此外，将采用双标记和三标记技术来鉴定 隔海马胆碱能和GABA能神经元。希望广大 拟议的研究将提供新的见解的作用 隔海马GABA能通路在认知功能中的作用