Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation

Abstract

The neurotransmitter acetylcholine is considered essential for proper functioning of the hippocampus-dependent declarative memory system, and it represents a major neuropharmacological target for the treatment of memory deficits, such as those in Alzheimer's disease. During slow-wave sleep (SWS), however, declarative memory consolidation is particularly strong, while acetylcholine levels in the hippocampus drop to a minimum. Observations in rats led to the hypothesis that the low cholinergic tone during SWS is necessary for the replay of new memories in the hippocampus and their long-term storage in neocortical networks. However, this low tone should not affect nondeclarative memory systems. In this study, increasing central nervous cholinergic activation during SWS-rich sleep by posttrial infusion of 0.75 mg of the cholinesterase inhibitor physostigmine completely blocked SWS-related consolidation of declarative memories for word pairs in human subjects. The treatment did not interfere with consolidation of a nondeclarative mirror tracing task. Also, physostigmine did not alter memory consolidation during waking, when the endogenous central nervous cholinergic tone is maximal. These findings are in line with predictions that a low cholinergic tone during SWS is essential for declarative memory consolidation.

Fig. 1.

Memory performance after physostigmine and placebo were administered during sleep and wake periods. Memory is indicated by the difference in performance between learning and recall sessions (physostigmine, filled bars; placebo, open bars). (A and B) As expected from previous studies, placebo-treated subjects retained significantly more words under the sleep than the wake condition (P < 0.001). Physostigmine completely eliminated the consolidating effect of sleep on hippocampus-dependent declarative memory (P < 0.001), whereas it had no effect during wakefulness (P > 0.40). (C and D) Hippocampus-independent memory for mirror tracing performance showed no detrimental effect of physostigmine during either sleep or wakefulness (P > 0.40).

Fig. 2.

Correlation between the change in SWS and word recall after physostigmine as compared with placebo administration in the entire subject sample (n = 18). Although most subjects experienced a reduction in SWS, this reduction was not correlated with impaired recall performance. This finding shows that the effect of physostigmine on SWS is independent of its effect on memory performance.