Elsevier

Cellular Signalling

Volume 24, Issue 6, June 2012, Pages 1251-1260
Cellular Signalling

Review
The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity

https://doi.org/10.1016/j.cellsig.2012.02.010Get rights and content

Abstract

Sleep deprivation is a common feature in modern society, and one of the consequences of sleep loss is the impairment of cognitive function. Although it has been widely accepted that sleep deprivation affects learning and memory, only recently has research begun to address which molecular signaling pathways are altered by sleep loss and, more importantly, which pathways can be targeted to reverse the memory impairments resulting from sleep deprivation. In this review, we discuss the different methods used to sleep deprive animals and the effects of different durations of sleep deprivation on learning and memory with an emphasis on hippocampus-dependent memory. We then review the molecular signaling pathways that are sensitive to sleep loss, with a focus on those thought to play a critical role in the memory and synaptic plasticity deficits observed after sleep deprivation. Finally, we highlight several recent attempts to reverse the effects of sleep deprivation on memory and synaptic plasticity. Future research building on these studies promises to contribute to the development of novel strategies to ameliorate the effects of sleep loss on cognition.

Highlights

► Hippocampal function is particularly sensitive to sleep loss. ► Sleep deprivation alters hippocampal glutamate, acetylcholine, and GABA systems. ► Sleep deprivation attenuates hippocampal cAMP signaling. ► Rescuing cAMP signaling prevents effects of sleep deprivation on the hippocampus. ► Astrocytes contribute to the effects of sleep deprivation on memory and plasticity.

Introduction

Millions of people worldwide experience sleep deprivation on a daily basis [1]. The pressure to stay up longer in our modern 24/7 society impacts a growing percentage of the population [2], [3]. A population-based study indicated that, over the past 50 years, sleep duration in adult and adolescent Americans has decreased by 1.5–2 h per night in adults and adolescents, with 30% reporting sleep of 6 h per night or less [4].

One of the first indications that sleep might be beneficial for the formation of memories came from a study by Jenkins and Dallenbach [5] that showed that sleep attenuated the rate of forgetting. In the 1960s, Morris and colleagues found that sleep deprivation impaired memory processing [6]. In the decades thereafter, it became apparent in both humans and animal models that specific forms of memory are affected by sleep deprivation [7], [8], [9], [10]. To combat the effects of sleep deprivation, it is critical to understand the molecular and cellular mechanisms by which sleep deprivation leads to cognitive deficits. Here, we review current knowledge of the intracellular signaling pathways that are affected by sleep deprivation, with an emphasis on the impact of sleep deprivation on hippocampal function (see Fig. 1 for a schematic summary). In addition, we discuss the different approaches that have been developed to reverse memory and plasticity deficits induced by sleep deprivation.

Section snippets

Methods for sleep deprivation in rodents: advantages and drawbacks

To elucidate which cellular and molecular effects of sleep deprivation lead to memory impairments, many research laboratories have utilized rodents as study objects. Three primary techniques have been used to deprive laboratory rodents of sleep. Each of these methods has particular advantages and drawbacks, as discussed below.

The first is the platform-over-water, pedestal, or “flower pot” method, which is the best method to selectively deprive animals of rapid eye movement (REM) sleep for one

Sleep deprivation and memory

Using the platform-over-water method, Fishbein and colleagues [35] tested the effects of 24 h of REM sleep deprivation immediately prior to training in a classical conditioning task called inhibitory avoidance. Although 24 h of REM sleep deprivation had no effect on acquisition and short-term memory, long-term memory (tested 1–7 days after training) was significantly impaired [35], [36]. Follow-up studies applying REM sleep deprivation directly after conditioning also attenuated memory formation

Sleep deprivation and hippocampal synaptic plasticity

As described above, behavioral studies looking at the effect of sleep deprivation on memory indicated that the hippocampus is particularly vulnerable to sleep loss. Therefore, electrophysiological studies were conducted to determine the effect of sleep deprivation on various forms of hippocampal synaptic plasticity. One prominent form of hippocampal synaptic plasticity is long-term potentiation (LTP), a long-lasting change in the strength of synaptic connections that is a frequently used model

Sleep deprivation, cholinergic, and GABAergic signaling

The cholinergic system plays a critical role in memory formation (reviewed in [80], [81]) and is a major modulator of neuronal activity (reviewed in [82]). Ninety-six hours of REM sleep deprivation increases acetylcholinesterase (the enzyme that breaks down acetylcholine) in the pons, thalamus, and medulla oblongata, but not in other brain regions including the hippocampus [83]. It is important to note that the pons contains cholinergic cells involved in the generation of REM, while the

Sleep deprivation and cAMP signaling

As mentioned previously, sleep deprivation can impair the maintenance of LTP without affecting LTP induction [30], [71], [72], [79]. These observations suggest that specific intracellular signaling pathways important for the maintenance of LTP are affected by brief sleep deprivation. To determine which pathways are impacted, the Abel laboratory conducted a set of electrophysiological experiments with differing molecular requirements [30]. The authors found that 5 h of sleep deprivation impaired

Sleep deprivation, adenosine, and astrocytes

Adenosine, a degradation product of ATP whose extracellular levels increase with brain metabolism, plays a critical role in sleep regulation through the modulation of slow wave activity [116], [117], [118]. In rats, extracellular adenosine levels have been reported to be higher during the circadian active period (the dark phase) than during the resting period (the light phase) in both the hippocampus and neostriatum [119]. Adenosine levels have also been reported to decline during sleep [120].

Sleep deprivation, gene transcription, and translation

In addition to looking at specific signaling pathways to identify the mechanisms underlying the memory deficits caused by sleep loss, many laboratories have used gene expression studies to identify the molecular targets of sleep deprivation. In particular, microarray studies allowing for the simultaneous analysis of thousands of transcripts have led to the identification of many genes whose expression change after sleep deprivation (for in depth review of the gene expression studies see [132],

Conclusions and future directions

One of the hallmarks of our modern society is to work longer each day and for more days each year, usually at the expense of sleep time, which can lead to cognitive impairments. Over the last few decades, significant advances have been made in unraveling the mechanisms underlying the memory and plasticity deficits observed after both brief and longer periods of sleep deprivation. The role of specific genes and signaling pathways responsible for sleep deprivation-induced deficits have been

Acknowledgments

We thank Mathieu Wimmer, Dr. Jennifer H.K. Choi, and Dr. Sara J. Aton for input on a previous version of the manuscript and Paul Schiffmacher for help with the illustration. This research was supported by the Netherlands Organization for Scientific Research (NWO-Rubicon grant 825.07.029 to RH), NIA (5P01AG017628-09 to TA; Principal Investigator Allan Pack), NIMH (RO1 MH086415-01 to T.A.), and F32 post-doctoral NRSA, MH090711NRSA (to C.G.V.).

References (147)

  • S.M. Rajaratnam et al.

    The Lancet

    (2001)
  • R. Stickgold et al.

    Sleep Medicine

    (2007)
  • P. Whitney et al.

    Progress in Brain Research

    (2010)
  • E.Y. Kim et al.

    Neuroscience Letters

    (2005)
  • C.A. Marks et al.

    Brain Research Bulletin

    (2005)
  • L. Ledoux et al.

    Brain Research

    (1996)
  • K. van der Borght et al.

    Behavioural Brain Research

    (2006)
  • P. Meerlo et al.

    Physiology & Behavior

    (2001)
  • M. Isokawa et al.

    Physiology & Behavior

    (1983)
  • D.N. Ruskin et al.

    Life Sciences

    (2006)
  • S. Palchykova et al.

    Neurobiology of Learning and Memory

    (2006)
  • P. Meerlo et al.

    Brain Research

    (2001)
  • B. Roozendaal

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2003)
  • W. Fishbein

    Physiology & Behavior

    (1971)
  • E.R. Linden et al.

    Physiology & Behavior

    (1975)
  • W. Fishbein et al.

    Behavioral Biology

    (1977)
  • C. Smith et al.

    Physiology & Behavior

    (1996)
  • B.D. Youngblood et al.

    Physiology & Behavior

    (1997)
  • Z. Guan et al.

    Brain Research

    (2004)
  • R.H. Yang et al.

    Brain Research

    (2008)
  • M.M. Halassa et al.

    Neuron

    (2009)
  • C. Smith et al.

    Physiology & Behavior

    (1982)
  • C. Pearlman

    Physiology & Behavior

    (1973)
  • C.T. Smith et al.

    Neurobiology of Learning and Memory

    (1998)
  • L. Graves et al.

    Trends in Neurosciences

    (2001)
  • C.J. Davis et al.

    Brain Research

    (2003)
  • I.A. Alhaider et al.

    Molecular and Cellular Neurosciences

    (2011)
  • R. Tadavarty et al.

    Experimental Neurology

    (2009)
  • C. Chen et al.

    Biochemical and Biophysical Research Communications

    (2006)
  • P. Meerlo et al.

    Sleep Medicine Reviews

    (2008)
  • M.R. Bennett

    Progress in Neurobiology

    (2000)
  • R. Havekes et al.

    Behavioural Brain Research

    (2011)
  • S. Deiana et al.

    Behavioural Brain Research

    (2011)
  • A.M. Aleisa et al.

    Neuroscience Letters

    (2011)
  • M. Alkondon et al.

    European Journal of Pharmacology

    (2000)
  • A.M. Aleisa et al.

    Neurobiology of Disease

    (2006)
  • Y. Lu et al.

    Neurobiology of Learning and Memory

    (2008)
  • T. Abel et al.

    Cell

    (1997)
  • R. Havekes et al.

    Advances in Genetics

    (2009)
  • K.W. Roche et al.

    Neuron

    (1996)
  • T. Abel et al.

    Brain Research. Brain Research Reviews

    (1998)
  • C. Hublin et al.

    Sleep

    (2001)
  • M.H. Bonnet et al.

    Sleep

    (1995)
  • National Health Interview Survey

    MMWR. Morbidity and Mortality Weekly Report

    (2005)
  • J.G. Jenkins et al.

    The American Journal of Psychology

    (1924)
  • G.O. Morris et al.

    Archives of General Psychiatry

    (1960)
  • M.P. Walker

    Annals of the New York Academy of Sciences

    (2009)
  • N. Axmacher et al.

    Cellular and Molecular Life Sciences

    (2009)
  • D. Jouvet et al.

    Journal of Physiology, Paris

    (1964)
  • L. Friedman et al.

    Sleep

    (1979)
  • Cited by (150)

    • Sleep deprivation in early life: Cellular and behavioral impacts

      2024, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text