Animal Models of Sleep Deprivation
ReviewSleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function
Introduction
Sleep is a condition of partial unconsciousness, characterized by reduced motor activity and responsiveness, from which an individual can be aroused by stimulation (Siegel, 2009). Birds and mammals display two distinct types of sleep, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, which are most easily distinguished on the basis of their patterns of brain activity (electroencephalogram, EEG) and muscle activity (electromyogram, EMG). The two types of sleep alternate with a cycle that varies in length between species, but correlate with body or brain size (Siegel, 2005, Lesku et al., 2006, Lesku et al., 2008). The NREM–REM sleep cycle is repeated throughout the sleep phase, with most species displaying an overall NREM to REM sleep ratio of about 4 to 1 (Tobler and Jaggi, 1987, Hsieh et al., 2008). Since sleep causes a reduction in responsiveness to environmental stimuli and, therefore, exposes the organism to potential danger, it has to serve certain vital functions. Currently there is no consensus about the precise purpose of sleep, however, multiple theories advocate its involvement in neuronal recovery and plasticity, both processes which are crucial for proper brain functioning and, ultimately, for cognition and emotion (Stickgold, 1998, Krueger et al., 1999, Benington and Frank, 2003, Tononi and Cirelli, 2006). Despite the ongoing fundamental controversy, substantial evidence deriving from animal and human studies clearly indicates that sleep benefits proper cognitive functioning, whereas sleep loss or sleep disturbance have opposing effects, resulting in cognitive deficits, such as impaired attention, decision making, learning and various types of memory (for reviews, see Walker and Stickgold, 2004, Walker, 2008, Diekelmann and Born, 2010, Havekes et al., 2012, Abel et al., 2013).
One of the brain regions that is crucially involved in many cognitive functions is the hippocampus, a neural structure in the medial temporal lobe and part of a functional system entitled the hippocampal formation, which comprises the hippocampus, including the dentate gyrus (DG) and the subiculum, the presubiculum and the entorhinal cortex (Lavenex et al., 2007). The hippocampal formation receives sensory information from various cortical sources and its functions include learning and memory processes, spatial coding, as well as the regulation of emotional behaviors and anxiety via the formation of episodic representations of emotional significance (Bannerman et al., 2004, Phelps, 2004, Bieri et al., 2014). In this paper we will review the literature suggesting that the hippocampus is a brain region particularly sensitive to sleep loss, and that altered hippocampal plasticity is one of the main mechanisms underlying sleep deprivation (SD)-induced learning and memory deficits. Since restricted or disrupted sleep is highly prevalent in our modern society, understanding its effects on brain function and cognition is of great importance.
Section snippets
SD prior to learning impairs the formation of new hippocampus-dependent memories
SD may have an effect on different phases of memory formation. Whereas sleep disruption prior to learning may particularly affect the memory encoding phase, post-learning SD seems to influence memory consolidation (Abel et al., 2013). In this first section we will discuss how SD prior to learning may affect the capacity of the brain to process new information and the ability to encode new memories. Several human and animal studies have shown that pre-training SD impairs acquisition and memory
SD after learning impairs the consolidation of hippocampus-dependent memories
Early studies investigating the consequences of brief SD immediately following learning showed impaired memory formation later on and, hence, provided preliminary evidence that SD is corruptive for memory consolidation (Fishbein, 1971, Fishbein and Gutwein, 1977). Later research aimed at identifying brain regions accountable for the cognitive deficits and revealed the hippocampus as a vulnerable target region for SD. A commonly used animal model for studies on memory formation is the
SD impairs long-term potentiation (LTP)
As outlined above, sleep is a decisive aspect of memory formation and its loss can have detrimental effects on its consolidation, particularly at the level of hippocampus-dependent memory. Although the molecular mechanisms underlying sleep and memory formation remain to be investigated, emerging evidence suggests that sleep facilitates neuronal plasticity, whereas SD is associated with deleterious effects on hippocampal synaptic plasticity. Indeed, activity-dependent synaptic plasticity has
Stress hormones are not responsible for SD-induced memory deficits
One commonly proposed mechanism of SD-induced memory impairments is stress and stress hormones. Shortage or disruption of sleep may be stressful in itself, but in some experiments stress may partly be a side effect of the method used to keep subjects awake (Meerlo et al., 2008). This might be particularly relevant in animals that are sleep deprived by various methods of stimulation, forced activity, or confinement on a platform over water (see Box 1).
Adenosine impairs hippocampal plasticity
One of the neuromodulators in the brain that might be involved in the SD-induced learning and memory deficits is adenosine, which is considered to be an important sleep regulatory substance (Basheer et al., 2004, Bjorness and Greene, 2009). Adenosine is a degradation product of ATP and cyclic adenosine monophosphate (cAMP). When neuronal activity is high, ATP is co-released with other signaling molecules and dephosphorylated into adenosine diphosphate, adenosine monophosphate, and finally,
SD impairs hippocampal cAMP signaling
One of the key elements underlying cognitive impairments following SD seems to be an attenuation of cAMP signaling. Under normal conditions, learning generates a rise of calcium (Ca2+) in the hippocampus, leading to increased activity of Ca2+-dependent adenylyl cyclase. Activation of this enzyme induces the production of cAMP, a second messenger that is in charge of the nuclear translocation and activation of protein kinase A (PKA), which, in turn, promotes the phosphorylation of transcription
SD alters glutamate receptor expression and function
An important component of the mechanism underlying cognitive impairments following SD may be the reduced expression and functionality of glutamate receptors in the hippocampus (Ravassard et al., 2009, Hagewoud et al., 2010a). One of the glutamate receptor families involved in LTP and LTD is the ionotropic receptor family which includes N-methyl-d-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Watkins and Jane, 2006). The NMDA receptor is a
SD alters gene expression and translational processes
Given the attenuation of cAMP signaling after SD discussed in earlier sections, one might expect a decreased activity of transcription factors, such as CREB, which are normally activated by cAMP-PKA signaling. Indeed, studies in laboratory rodents have shown that brief SD for only five to six hours can attenuate basal CREB phosphorylation in the hippocampus (Vecsey et al., 2009) and may also attenuate the increase in CREB phosphorylation normally associated with learning and memory processes (
Chronic SD impairs hippocampal neurogenesis
One important aspect of hippocampal plasticity that might make it sensitive to SD, and also differentiates it from most other brain regions, is the fact that the hippocampus still contains stem cells that give rise to new neurons even in adulthood. Neurogenesis comprises cell proliferation, differentiation, maturation, migration, survival, as well as the functional integration of new cells into the existing hippocampal network (Abrous et al., 2005, Ming and Song, 2011). The newly generated
Chronic sleep disturbance reduces hippocampal volume
While acute SD may alter hippocampal plasticity processes in different and subtle ways, chronic sleep restriction reduces neurogenesis and may ultimately lead to morphological changes. Indeed, recent studies suggest that chronically restricted or disrupted sleep is associated with shrinkage of the hippocampus. Whereas short durations of SD do not appear to affect hippocampus size in laboratory rodents (Guzmán-Marín et al., 2003, Tung et al., 2005, Mueller et al., 2008), restricting sleep to
Concluding remarks
While the precise purpose of sleep remains largely unknown, emerging evidence suggests that sleep plays a decisive role in brain plasticity and memory formation. By applying brief and prolonged periods of SD, a large body of work has provided insights into the molecular mechanisms underlying learning and memory deficits, and identified a variety of interacting genes and signaling pathways responsible for associated changes in hippocampal neuroplasticity. While acute SD may alter hippocampal
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