CHOLINERGIC REGULATION OF ENTORHINAL NETWORK FUNCTION

内嗅网络功能的胆碱能调节

• 批准号: 6539097
• 负责人: Michael E Hasselmo
• 金额: $ 25.31万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539097
• 关键词: acetylcholine; afferent nerve; behavioral /social science research tag; biofeedback; biological models; bioperiodicity; brain electrical activity; buffers; cerebellum; cholinergic receptors; entorhinal cortex; hippocampus; laboratory rat; memory; model design /development; neocortex; neurons; neuropharmacology; odors; olfactions; scopolamine; voltage /patch clamp

The proposed research combines modeling and physiology to explore how acetylcholine changes cellular and network dynamics in entorhinal cortex for different aspects of memory function. Physiological data suggests that high acetylcholine levels may set appropriate dynamics for sustained activity in entorhinal cortex, which might allow buffering of novel input patterns across short intervals in delayed match to sample tasks and might enhance formation of memory traces in the hippocampus, whereas low levels of acetylcholine may set appropriate dynamics for consolidation of additional memory traces. Research will focus on two hypotheses: Hypothesis number 1. Higher acetylcholine levels enhance buffering of novel activity patterns in entorhinal cortex, and thereby enhance memory encoding. Testing of this hypothesis includes modeling cholinergic effects on entorhinal non-stellate and stellate neurons to determine cellular mechanisms of sustained activity and network oscillations. These simulations will then be combined in network simulations of the entorhinal cortex focused on replication of network activity in vitro and in vivo. Physiological work will use pharmacological blockade to test the mechanisms for networks dynamics in slice preparations. In addition, experiments will test the effect of cholinergic receptor blockade on responses of entorhinal cortex neurons including sustained delay activity and match enhancement during performance of a delayed nonmatch to sample task in rats. Hypothesis number 2. Low acetylcholine levels in entorhinal cortex and hippocampus allows strong feedback appropriate for forming additional memory traces. Testing of this hypothesis will include analysis of network dynamics in entorhinal cortex underlying initiation and propagation of sharp wave and ripple activity in entorhinal cortex layer V, and studies of the cholinergic modulation of excitatory feedback connections in hippocampal region CA3 and entorhinal cortex. Acetylcholine levels change dramatically during different stages of waking and sleep. Blockade of acetylcholine receptors can cause amnesia and hallucinations. Disorders of this modulation may contribute to memory deficits in Alzheimer's disease, and Lewy Body dementia, disorders of REM sleep in depression, and the breakdown of slow wave sleep in development disorders such as Landau-Kleffner syndrome. Understanding of the cellular effects of acetylcholine involved in these processes could allow targeting of specific receptor effects in the treatment of disorders.

拟议的研究将建模和生理学结合起来，探索乙酰胆碱如何改变内嗅皮层的细胞和网络动力学，以实现记忆功能的不同方面。生理数据表明，高乙酰胆碱水平可能为内嗅皮层的持续活动设定适当的动态，这可能允许在与样本任务的延迟匹配中在短时间间隔内缓冲新的输入模式，并可能增强海马体中记忆痕迹的形成，而低水平的乙酰胆碱可能为巩固额外记忆痕迹设定适当的动态。 研究将集中在两个假设上：假设1。较高的乙酰胆碱水平增强了内嗅皮层中新活动模式的缓冲，从而增强了记忆编码。 对该假设的检验包括模拟胆碱能对内嗅非星状和星状神经元的影响，以确定持续活动和网络振荡的细胞机制。 然后，这些模拟将结合在内嗅皮层的网络模拟中，重点关注体外和体内网络活动的复制。 生理工作将使用药理学封锁来测试切片制剂中的网络动力学机制。 此外，实验将测试胆碱能受体阻断对内嗅皮层神经元反应的影响，包括在大鼠执行延迟不匹配样本任务期间的持续延迟活动和匹配增强。假设2。内嗅皮层和海马体中的乙酰胆碱水平较低，可以产生适合形成额外记忆痕迹的强烈反馈。 对该假设的检验将包括分析内嗅皮层 V 层尖波和波纹活动的启动和传播的网络动力学，以及海马区 CA3 和内嗅皮层兴奋性反馈连接的胆碱能调节的研究。乙酰胆碱水平在清醒和睡眠的不同阶段发生巨大变化。 乙酰胆碱受体的阻断会导致健忘症和幻觉。 这种调节障碍可能会导致阿尔茨海默病和路易体痴呆症中的记忆缺陷、抑郁症中的快速眼动睡眠障碍以及朗道-克莱夫纳综合征等发育障碍中的慢波睡眠障碍。 了解乙酰胆碱参与这些过程的细胞效应可以允许在疾病治疗中针对特定受体效应。