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.
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