CHOLINERGIC REGULATION OF ENTORHINAL NETWORK FUNCTION

这项拟议的研究将建模和生理学相结合，以探索乙酰胆碱如何改变内嗅皮层中记忆功能的不同方面的细胞和网络动力学。生理数据表明，高水平的乙酰胆碱可以为内嗅皮层的持续活动设置适当的动力学，这可能允许在与样本任务延迟匹配的短时间间隔内缓冲新的输入模式，并可能促进海马区记忆痕迹的形成，而低水平的乙酰胆碱可能为巩固额外的记忆痕迹设置适当的动力学。研究将集中在两个假设上：假设1。更高的乙酰胆碱水平增强了内嗅皮层新活动模式的缓冲，从而增强了记忆编码。对这一假说的检验包括模拟胆碱能对内嗅神经元、非星状神经元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，这些模拟将被结合到内嗅皮层的网络模拟中，重点是在体外和体内复制网络活动。生理学工作将使用药物阻断来测试片剂中网络动力学的机制。此外，实验还将测试胆碱能受体阻断对大鼠内嗅皮层神经元反应的影响，包括在延迟不匹配到样本任务时的持续延迟活动和匹配增强。假设2：内嗅皮层和海马区的乙酰胆碱水平较低，可提供形成额外记忆痕迹所需的强反馈。对这一假说的验证将包括分析内嗅皮层第V层尖锐波和波纹活动的起始和传播的网络动力学，以及研究海马区CA3区和内嗅皮层兴奋性反馈联系的胆碱能调制。乙酰胆碱水平在清醒和睡眠的不同阶段变化很大。阻断乙酰胆碱受体会导致健忘和幻觉。这种调节机制的紊乱可能导致阿尔茨海默病和路易体痴呆的记忆缺陷，抑郁症的REM睡眠障碍，以及Landau-Kleffner综合征等发育障碍的慢波睡眠崩溃。了解参与这些过程的乙酰胆碱的细胞效应，可以在疾病的治疗中靶向特定的受体效应。

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.