CHOLINERGIC REGULATION OF ENTORHINAL NETWORK FUNCTION

这项研究结合了建模和生理学，以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，高水平的乙酰胆碱可能会设置适当的动态持续活动的内嗅皮层，这可能会允许缓冲的新的输入模式在短时间内延迟匹配到样本任务，并可能提高形成的记忆痕迹在海马体中，而低水平的乙酰胆碱可能会设置适当的动态巩固额外的记忆痕迹。 研究将集中在两个假设：假设1。较高的乙酰胆碱水平增强内嗅皮层对新活动模式的缓冲，从而增强记忆编码。 这一假设的测试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。 然后将这些模拟结合在内嗅皮层的网络模拟中，集中于体外和体内网络活动的复制。 生理学工作将使用药理学阻断来测试切片制备中的网络动力学机制。 此外，实验将测试胆碱能受体阻滞剂对内嗅皮层神经元反应的影响，包括大鼠在执行延迟非匹配样本任务期间的持续延迟活动和匹配增强。假设二。内嗅皮层和海马体中的低乙酰胆碱水平允许形成额外的记忆痕迹的强反馈。 这一假设的检验将包括分析内嗅皮层V层尖波和涟漪活动的启动和传播的内嗅皮层网络动力学，以及海马CA 3区和内嗅皮层兴奋性反馈连接的胆碱能调制研究。乙酰胆碱水平在清醒和睡眠的不同阶段会发生巨大变化。 阻断乙酰胆碱受体会导致健忘症和幻觉。 这种调节的障碍可能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REM睡眠障碍，以及发育障碍如Landau-Kleffner综合征中的慢波睡眠障碍。 了解参与这些过程的乙酰胆碱的细胞效应可以在治疗疾病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.