CHOLINERGIC REGULATION OF ENTORHINAL NETWORK FUNCTION

内嗅网络功能的胆碱能调节

• 批准号: 6091433
• 负责人: Michael E Hasselmo
• 金额: $ 36.69万
• 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/6091433
• 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.

拟议的研究结合了建模和生理学，以探讨乙酰胆碱如何改变内嗅皮层中的细胞和网络动态，以在内存功能的不同方面改变。生理数据表明，较高的乙酰胆碱水平可能会为内河皮层中的持续活动设定适当的动态，这可能允许在延迟匹配到样本任务的短时间间隔内对新的输入模式进行缓冲，并且可能会增强海马中的记忆痕迹的形成，而乙酰胆碱水平较低，可以使乙酰胆碱水平较低，以使适当的动力学进行适当的多余的记忆累积累积累积累积。 研究将侧重于两个假设：假设1。较高的乙酰胆碱水平增强了内嗅皮层中新型活性模式的缓冲，从而增强了记忆编码。 该假设的测试包括对胆碱能对内嗅非固定物和星状神经元的影响进行建模，以确定持续活性和网络振荡的细胞机制。 然后，将将这些模拟组合在集中在体外和体内复制网络活动的内嗅皮层的网络模拟中。 生理工作将使用药理学阻滞来测试切片制剂中网络动力学的机制。 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，包括持续的延迟活性和在延迟不匹配对大鼠样本任务的性能过程中的匹配增强。假设2。内嗅皮层和海马中的低乙酰胆碱水平可提供适合形成其他记忆痕迹的强烈反馈。 该假设的测试将包括分析内嗅皮层的网络皮层中网络动力学的分析，以及内hinal骨皮层V层中尖锐波和涟漪活性的传播，以及对海马区域CA3和Intorhinal Cortex中兴奋反馈连接的胆碱能调节的研究。在醒来和睡眠的不同阶段，乙酰胆碱水平发生了巨大变化。 乙酰胆碱受体的封锁会引起健忘症和幻觉。 这种调节的疾病可能导致阿尔茨海默氏病的记忆缺陷和刘易体内痴呆症，抑郁症中的REM睡眠障碍以及发育障碍中慢波睡眠的崩溃（如Landau-Kleffner综合征）。 了解参与这些过程的乙酰胆碱的细胞作用可以允许靶向特定的受体作用在疾病治疗中。