ReviewThe impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity
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.).
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These authors contributed equally to this work.