. Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2140-4. PubMed.

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  1. Comment by Alireza Atri, Chantal Stern, and Michael Hasselmo

    There is an exciting link between the important recent article by Gais and Born on cholinergic mechanisms in memory and our own article in the current issue of Behavioral Neuroscience. In their study, Born and Gais showed that augmentation of cholinergic function during slow-wave sleep (SWS) by injection of physostigmine impaired the memory consolidation effect of SWS on learning of word-pairs in 29 young healthy male volunteers. This result is complementary to the findings of our recently published study (Atri et al., 2004).

    The major finding in our own study was that lowering cholinergic function in waking increases proactive interference—the interference of older memories with the learning and remembrance of new ones. Proactive interference influences common tasks such as remembering where we parked the car or where we left the keys. If one parks in the same lot every day, the memory of previous parking locations interferes when we try to encode and retrieve a new but similar parking place (this is called proactive interference).

    In our study, we transiently lowered cholinergic function in awake young healthy volunteers by injecting them with scopolamine. Scopolamine is a drug that transiently blocks acetylcholine (ACh) receptors and which has been commonly used for decades for a variety of purposes, including as a treatment for motion sickness. Using a word paired-associate memory paradigm, our results supported the a priori hypotheses that lowering cholinergic function, by scopolamine, should impair new learning of novel word pairs and increase proactive interference, but not impair memory for previously learned novel word pairs. The study involved 28 young healthy participants who were divided into three groups and either received scopolamine, glycopyrrolate (a more peripherally acting anticholinergic medication that has fewer effects in the brain) or no drug.

    The findings of Gais and Born are complementary with ours in that they both support predictions from theoretical models (Hasselmo, 1999). These models suggest that acetylcholine (ACh) is important to prevent proactive interference in the hippocampus during initial learning by suppressing retrieval of previously stored memories, to prevent them from interfering with new encoding, but that the release of this suppression is necessary to allow consolidation of new memories. Our study supports the idea that high brain ACh levels during wakefulness are important to acquire new memories and to reduce proactive interference, and that blocking the effects of ACh with scopolamine enhances proactive interference.

    The other side of this hypothesis is supported by the findings of Born and Gais: that during SWS, lower ACh levels are required for proper consolidation of newly acquired memories by allowing stronger excitatory feedback transmission to reactivate memories for consolidation within neocortical brain areas.

    It is interesting to speculate that these findings and model of cholinergic function may offer partial explanations for some of the memory and psychiatric symptoms (including delusions and hallucinations) that are found in many of the conditions known to be associated with lowered levels of ACh in the brain (such as Alzheimer's disease, Lewy body dementia, Parkinson's disease, and schizophrenia), and also for the partial improvement of these symptoms by the use of medications (acetylcholinesterase inhibitors) that increase brain ACh levels.

    Obviously, from the isolated standpoint of cognitive health, the chronic use of medications with anticholinergic effects by elderly individuals, especially those who are cognitively impaired, would be highly discouraged unless they are truly necessary. Use of anticholinergic medications, even in young healthy individuals, and particularly during waking hours, would be expected to interfere with acquisition and future recall of new and especially related memories. Until specific studies address these issues, these two studies may infer that a good strategy, at least in young healthy individuals, would be to take anticholinergic medications at bedtime, and procholinergic medications during the day. In the absence of additional data, to further stretch this inference to the timing of administration of medications for patients with Alzheimer's disease may well be a worthwhile strategy to consider in the interim.

    References:

    . Neuromodulation: acetylcholine and memory consolidation. Trends Cogn Sci. 1999 Sep;3(9):351-359. PubMed.

    View all comments by Michael Hasselmo
  2. I found your article interesting. I am not a reseacher, but my father has AD, and he tells me that Aricept makes him dream vividly throughout the night. I also worked in a sleep clinic for a number of years, and we were told by our supervisors that it was believed that REM sleep had something to do with memory consolidation. Therefore, I assumed that the increased REM activity Dad experiences had something to do with why drugs in the Aricept family slow memory loss. However, what you are describing is interesting as it is different from what I thought about sleep and memory. Anyway, I found some references that might be of interest to you.

    References:

    . Is Alzheimer's disease related to a deficit or malfunction of rapid eye movement (REM) sleep?. Med Hypotheses. 1993 Nov;41(5):435-9. PubMed.

    . Sleep and brain lesions: a critical review of the literature and additional new cases. Neurophysiol Clin. 2001 Dec;31(6):356-75. PubMed.

    . Dementia--the failure of hippocampal plasticity and dreams. Is there a preventative role for melatonin?. Med Hypotheses. 1987 Sep;24(1):59-68. PubMed.

    View all comments by Tori Watson

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