30 January 2004. If you want to make sure to remember something, sleep on it. Sleep research confirms this adage, and indeed, its chemical underpinnings may have surprising implications for Alzheimer’s disease treatment. Neurons communicate with one another to solidify newly acquired information into memories, and while acetylcholine (ACh) clearly is a crucial neurotransmitter in this process, the optimal timing and level of its activity have yet to be fully explored. In this week’s early online PNAS, Steffen Gais and Jan Born of the University of Lubeck, Germany, report that memory consolidation during deep slow-wave sleep (SWS) works best if cholinergic activity is at a minimum. At first blush, this may seem paradoxical, given that Alzheimer’s disease is marked by memory problems and a progressive cholinergic deficit.
During long-term memory consolidation, newly acquired memories stored in the hippocampus become reactivated and transmitted to neocortical networks. This dialogue requires that the inhibition of excitatory feedback synapses along the pathway be lifted, and a silencing of cholinergic activity is thought to facilitate this. Therefore, according to this model, high levels of ACh during SWS will thwart consolidation. In the present study, 29 healthy male volunteers learned a word-pair list (a declarative, hippocampus-dependent task) and a mirror tracing task, which is non-declarative and hippocampus-independent. After training, some men slept for three hours, during which they received the cholinesterase inhibitor physostigmine. Meanwhile, one control group remained awake on the same physostigmine infusion, and a second received a placebo after learning.
Following physostigmine administration, the researchers tested the subjects’ recall. They found that physostigmine diminished the consolidating effect of sleep on declarative memory, but not on non-declarative memory retention, compared to placebo. By contrast, the rise in ACh due to physostigmine administration did not impair memory retrieval in the wake group. In fact, these men appeared to do slightly better than placebo-treated ones in both the declarative and non-declarative memory performance tests.
Overall cholinergic neurotransmission is known to dwindle in Alzheimer’s disease (AD), and cholinesterase inhibitors are commonly prescribed to patients (see Live Discussion). In light of their findings, the authors suggest that administration of these drugs before sleep be reevaluated.—Erene Mina.
Erene Mina is a graduate student at the University of California, Irvine.
Gais S, Born J. Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proc Natl Acad Sci U S A. 2004 Feb 6 [Epub ahead of print] Abstract
Q&A with Steffen Gais and Jan Born. Questions by Erene Mina.
Q: What exactly are the implications of your work for the use of the three cholinesterase inhibitor drugs donepezil, rivastigmine, and galantamine? Does the pharmacokinetics of these drugs allow for dosing them such that brain levels are low at night?
A: Our work has been done in healthy subjects and should not be used as a basis for treatment recommendations. However, our results suggest that daytime administration could be more effective than nighttime administration. The available drugs have different half-lives. Especially, those drugs usually given multiple times a day have pharmacokinetics which would allow this kind of administration.
Q: This is one small study; what other research is needed before physicians should reconsider the drug regimen they prescribe?
A: Acetylcholinesterase inhibitor administration in the morning should be compared to conventional treatment in a larger sample of AD patients. Especially, long-term memory (retention over more than 24 hours) should be tested.
Q: These drugs have been tested in thousands of patients; have you looked at the trial data to see if you can find indications of a memory deficit as predicted by your work?
A: Sleep-associated long-term memory formation has not been tested in AD. Generally, this aspect of memory formation has been totally ignored in patients with memory deficits.
Q: Could it be that the overall cognitive improvement observed in patients on these drugs masks a selective, sleep-related memory deficit?
A: Yes. According to known data, these drugs improve acquisition of new memories. Long-term consolidation of these memories, however, suffers from the high levels of ACh during sleep.
Q: Many AD patients have disturbed sleep cycles; they get up at night to "go to work," for example. Does this tie in with your findings?
A: It is known that high levels of ACh can interfere with sleep. Discontinuing treatment before sleep could improve sleep also in AD patients (as well as confusion during intermittent awakenings). However, this needs to be tested.
Q: Why did you decide to choose men only for your study?
A: Women are harder (and more expensive) to test in pharmacological trials (exclusion of pregnancy, intake of oral contraceptives, control of menstrual cycle, etc).
Q: How did the drowsiness, fatigue, motivation, and sleep quality of the subjects affect the results?
A: All these factors were controlled for and excluded as possible confounds.
Q: What did the subjects in the wake group do while the sleep group slept? Did this affect their performance?
A: The main comparison was between placebo and physostigmine. Because the subjects were doing the same things during placebo and physostigmine conditions (watching movies in the wake group), the conclusion regarding the effect of physostigmine does not depend on waking activity. In addition, other studies could show that staying awake for a short time (three hours) does not impair memory performance.
Q: Is there a "window of opportunity" for consolidation to occur? I mean, if you took the subjects off physostigmine and repeated the experiment, do you think you would see a difference (i.e., recovery)?
A: This may be the case. We believe that the process of sleep-related consolidation is strongest in the night after learning, but may continue, perhaps to a lesser degree, on subsequent nights. This is, in fact, the issue of a current study.
Q: Do your results merely suggest that cholinesterase inhibitors be administered when patients are awake? Or are they generally just not as useful as we think?
A: They are useful. Optimal levels of ACh are necessary for the acquisition of new memories. However, strengthening [consolidation] of newly learned memories seems to benefit from low levels of ACh during sleep. From these results, it might be beneficial to take the medication in the morning and not before sleep.