CHOLINERGIC & GABAERGIC MECHANISM SEPTOHIPPOCAMPAL PATHWAY

描述(改编自申请人的摘要)： 认知障碍在美国是一个严重的健康问题；它 不仅伴随着阿尔茨海默氏症等非正常衰老和痴呆症， 还有几种精神疾病，比如精神分裂症。基础和临床 研究很早就认识到胆碱能机制对 认知功能的维持和增加突触的治疗 使用乙酰胆碱酯酶抑制剂(AChELs)的乙酰胆碱(ACh)水平是 目前最广泛用于治疗阿尔茨海默病的药物。在……里面 相反，反对胆碱能紧张的治疗，如全身输液 M胆碱能受体拮抗剂阿托品和东莨菪碱 (ATR/SCOP)，在人和大鼠身上都会引起遗忘综合征， 强调毒鼠强机制的重要性。基础研究表明， 内侧隔/斜角带(MSDB)的毒鼠碱机制，通过 隔-海马区通路，导致认知功能障碍 系统ATR/范围。因此，向MSDB中注入M受体激动剂 减轻遗忘综合征，而局部输注ATR/SCOP模拟 综合症。在我们的初步实验中，使用电生理学 在大鼠脑片上的记录技术，我们发现ATR/SCOP，当 应用于隔区脑片，可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 投射到海马体。相比之下，大量的AChEI，包括 临床上使用的他克林，产生的放电活动显著增加 MSDB神经元的表达被ATR/SCOP阻断。 因此，在本研究中，我们假设1)有一种补药 在MSDB中释放ACH(Carl被ATR/Scope和AChEis揭开面纱)和 通过M受体释放的ACh提供一种主要的兴奋性驱动力 至隔-海马区GABA能神经元；2)经M胆碱释放的ACh 受体，为隔-海马区GABA提供主要的兴奋性驱动 3)ACh的紧张性释放是由自发放电引起的。 隔海马胆碱能神经元(也支配MSDB)的活动 4)MSDB胆碱能神经元的缺失 (就像在正常衰老和阿尔茨海默氏症中可能发生的那样)会降低脑组织中 隔-海马区GABA神经元。据推测，由此产生的变化在 胆碱能和氨基丁酸能传递到海马体将有助于 学习和记忆方面的缺陷。上述假设将使用以下工具进行测试 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进行可视化。胆碱能神经元 将选择性地损害我们的红毛虫毒素，1921gG-Saporin。在……里面 此外，将使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。希望这一天 拟议中的研究将为 认知功能中的隔-海马GABA能通路。

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.