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1.  Transcriptome profiling of sleeping, waking, and sleep deprived adult heterozygous Aldh1L1 – eGFP-L10a mice 
Genomics data  2015;6:114-117.
Transcriptomic studies revealed that hundreds of mRNAs show differential expression in the brains of sleeping relative to awake rats, mice, flies, and sparrows. Although these results have offered clues regarding the molecular consequences of sleep and sleep loss, their functional significance thus far has been limited. This is probably because the previous studies pooled transcripts from all brain cells, including neurons and glia. In Bellesi et al. 2015 [1], we used the translating ribosome affinity purification technology (TRAP) and microarray analysis to obtain a genome-wide mRNA profiling of astrocytes as a function of sleep and wake. We used bacterial artificial chromosome (BAC) transgenic mice expressing eGFP tagged ribosomal protein L10a under the promoter of the Aldh1L1 gene, a highly expressed astrocytic gene. Using this approach, we could extract only the astrocytic mRNAs, and only those already committed to be translated into proteins (L10a is part of the translational machinery). Here, we report a detailed description of the protocol used in the study [1]. Array data have been submitted to NCBI GEO under accession number (GSE69079).
doi:10.1016/j.gdata.2015.08.031
PMCID: PMC4580259  PMID: 26413480
2.  Contribution of sleep to the repair of neuronal DNA double-strand breaks: evidence from flies and mice 
Scientific Reports  2016;6:36804.
Exploration of a novel environment leads to neuronal DNA double-strand breaks (DSBs). These DSBs are generated by type 2 topoisomerase to relieve topological constrains that limit transcription of plasticity-related immediate early genes. If not promptly repaired, however, DSBs may lead to cell death. Since the induction of plasticity-related genes is higher in wake than in sleep, we asked whether it is specifically wake associated with synaptic plasticity that leads to DSBs, and whether sleep provides any selective advantage over wake in their repair. In flies and mice, we find that enriched wake, more than simply time spent awake, induces DSBs, and their repair in mice is delayed or prevented by subsequent wake. In both species the repair of irradiation-induced neuronal DSBs is also quicker during sleep, and mouse genes mediating the response to DNA damage are upregulated in sleep. Thus, sleep facilitates the repair of neuronal DSBs.
doi:10.1038/srep36804
PMCID: PMC5103291  PMID: 27830758
3.  Effects of Chronic Sleep Restriction during Early Adolescence on the Adult Pattern of Connectivity of Mouse Secondary Motor Cortex123 
eNeuro  2016;3(2):ENEURO.0053-16.2016.
Abstract
Cortical circuits mature in stages, from early synaptogenesis and synaptic pruning to late synaptic refinement, resulting in the adult anatomical connection matrix. Because the mature matrix is largely fixed, genetic or environmental factors interfering with its establishment can have irreversible effects. Sleep disruption is rarely considered among those factors, and previous studies have focused on very young animals and the acute effects of sleep deprivation on neuronal morphology and cortical plasticity. Adolescence is a sensitive time for brain remodeling, yet whether chronic sleep restriction (CSR) during adolescence has long-term effects on brain connectivity remains unclear. We used viral-mediated axonal labeling and serial two-photon tomography to measure brain-wide projections from secondary motor cortex (MOs), a high-order area with diffuse projections. For each MOs target, we calculated the projection fraction, a combined measure of passing fibers and axonal terminals normalized for the size of each target. We found no homogeneous differences in MOs projection fraction between mice subjected to 5 days of CSR during early adolescence (P25–P30, ≥50% decrease in daily sleep, n=14) and siblings that slept undisturbed (n=14). Machine learning algorithms, however, classified animals at significantly above chance levels, indicating that differences between the two groups exist, but are subtle and heterogeneous. Thus, sleep disruption in early adolescence may affect adult brain connectivity. However, because our method relies on a global measure of projection density and was not previously used to measure connectivity changes due to behavioral manipulations, definitive conclusions on the long-term structural effects of early CSR require additional experiments.
doi:10.1523/ENEURO.0053-16.2016
PMCID: PMC4913218  PMID: 27351022
adolescence; sensitive period; secondary motor cortex; sleep loss
4.  Cortical development, EEG rhythms, and the sleep/wake cycle 
Biological psychiatry  2014;77(12):1071-1078.
During adulthood electroencephalographic (EEG) recordings are used to distinguish wake, non rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. However, the close association between behavioral states and EEG rhythms is reached only late during development, after birth in humans and by the end of the second postnatal week in rats and mice. This critical time is also when cortical activity switches from a discontinuous to a continuous pattern, and we will review the major cellular and network changes that can account for this transition. After this close link is established, new evidence suggests that the slow waves of NREM sleep may function as markers to track cortical development. Before the EEG can be used to identify behavioral states, however, two distinct sleep phases – quiet sleep and active sleep – are identified based on behavioral criteria and muscle activity. During this early phase of development cortical activity is far from being disorganized, despite the presence of long periods of neuronal silence and the poor modulation by behavioral states. Specific EEG patterns such as spindle bursts and gamma oscillations have been identified very early on, and are believed to play a significant role in the refinement of brain circuits. Since most early EEG patterns do not map to a specific behavioral state, their contribution to the presumptive role of sleep in brain maturation remains to be established, and should be a major focus for future research.
doi:10.1016/j.biopsych.2014.12.017
PMCID: PMC4444390  PMID: 25680672
active sleep; REM sleep; quiet sleep; NREM sleep; gamma activity; spindle bursts; theta activity
5.  Single neuron activity and eye movements during human REM sleep and awake vision 
Nature communications  2015;6:7884.
Are rapid eye movements (REMs) in sleep associated with visual-like activity, as during wakefulness? Here we examine single-unit activities (n=2057) and intracranial EEG across the human medial temporal lobe (MTL) and neocortex during sleep, wakefulness, and during visual stimulation with fixation. During sleep and wakefulness, REM onsets are associated with distinct intracranial potentials, reminiscent of ponto-geniculate-occipital waves. Individual neurons, especially in the MTL, exhibit reduced firing rates prior to REMs as well as transient increases in firing rate immediately after, similar to activity patterns observed upon image presentation during fixation without eye movements. Moreover, the selectivity of individual units is correlated with their response latency, such that units activated after a small number of images or REMs exhibit delayed increases in firing rates. Finally, the phase of theta oscillations is similarly reset following REMs in sleep and wakefulness, and upon controlled visual stimulation. Our results suggest that REMs during sleep rearrange discrete epochs of visual-like processing as during wakefulness.
doi:10.1038/ncomms8884
PMCID: PMC4866865  PMID: 26262924
Human; single-unit; eye movements; saccades; REM sleep; wakefulness; vision; medial temporal lobe
6.  Auditory Responses and Stimulus-Specific Adaptation in Rat Auditory Cortex are Preserved Across NREM and REM Sleep 
Cerebral Cortex (New York, NY)  2013;25(5):1362-1378.
Sleep entails a disconnection from the external environment. By and large, sensory stimuli do not trigger behavioral responses and are not consciously perceived as they usually are in wakefulness. Traditionally, sleep disconnection was ascribed to a thalamic “gate,” which would prevent signal propagation along ascending sensory pathways to primary cortical areas. Here, we compared single-unit and LFP responses in core auditory cortex as freely moving rats spontaneously switched between wakefulness and sleep states. Despite robust differences in baseline neuronal activity, both the selectivity and the magnitude of auditory-evoked responses were comparable across wakefulness, Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (pairwise differences <8% between states). The processing of deviant tones was also compared in sleep and wakefulness using an oddball paradigm. Robust stimulus-specific adaptation (SSA) was observed following the onset of repetitive tones, and the strength of SSA effects (13–20%) was comparable across vigilance states. Thus, responses in core auditory cortex are preserved across sleep states, suggesting that evoked activity in primary sensory cortices is driven by external physical stimuli with little modulation by vigilance state. We suggest that sensory disconnection during sleep occurs at a stage later than primary sensory areas.
doi:10.1093/cercor/bht328
PMCID: PMC4415088  PMID: 24323498
auditory cortex; NREM sleep; oddball; rat; REM sleep; single unit
7.  Disrupted Sleep: From Molecules to Cognition 
The Journal of Neuroscience  2015;35(41):13889-13895.
Although the functions of sleep remain to be fully elucidated, it is clear that there are far-reaching effects of its disruption, whether by curtailment for a single night, by a few hours each night over a long period, or by disruption in sleep continuity. Epidemiological and experimental studies of these different forms of sleep disruption show deranged physiology from subcellular levels to complex affective behavior. In keeping with the multifaceted influence of sleep on health and well-being, we illustrate how the duration of sleep, its timing, and continuity can affect cellular ultrastructure, gene expression, metabolic and hormone regulation, mood, and vigilance. Recent brain imaging studies provide some clues on mechanisms underlying the most common cause of disrupted sleep (insomnia). These insights should ultimately result in adequate interventions to prevent and treat sleep disruption because of their high relevance to our most prevalent health problems.
SIGNIFICANCE STATEMENT Disruption of the duration, timing, and continuity of sleep affects cellular ultrastructure, gene expression, appetite regulation, hormone production, vigilance, and reward functions.
doi:10.1523/JNEUROSCI.2592-15.2015
PMCID: PMC4604227  PMID: 26468189
sleep disruption; cellular ultrastructure; gene expression; metabolism; mood; insomnia
8.  Practice changes beta power at rest and its modulation during movement in healthy subjects but not in patients with Parkinson's disease 
Brain and Behavior  2015;5(10):e00374.
Abstract
Background
PD (Parkinson's disease) is characterized by impairments in cortical plasticity, in beta frequency at rest and in beta power modulation during movement (i.e., event‐related ERS [synchronization] and ERD [desynchronization]). Recent results with experimental protocols inducing long‐term potentiation in healthy subjects suggest that cortical plasticity phenomena might be reflected by changes of beta power recorded with EEG during rest. Here, we determined whether motor practice produces changes in beta power at rest and during movements in both healthy subjects and patients with PD. We hypothesized that such changes would be reduced in PD.
Methods
We thus recorded EEG in patients with PD and age‐matched controls before, during and after a 40‐minute reaching task. We determined posttask changes of beta power at rest and assessed the progressive changes of beta ERD and ERS during the task over frontal and sensorimotor regions.
Results
We found that beta ERS and ERD changed significantly with practice in controls but not in PD. In PD compared to controls, beta power at rest was greater over frontal sensors but posttask changes, like those during movements, were far less evident. In both groups, kinematic characteristics improved with practice; however, there was no correlation between such improvements and the changes in beta power.
Conclusions
We conclude that prolonged practice in a motor task produces use‐dependent modifications that are reflected in changes of beta power at rest and during movement. In PD, such changes are significantly reduced; such a reduction might represent, at least partially, impairment of cortical plasticity.
doi:10.1002/brb3.374
PMCID: PMC4614055  PMID: 26516609
Event‐related desynchronization; event‐related synchronization; kinematics; motor task; plasticity; RRID:nif‐0000‐00076; RRID:nlx_143928; RRID:nlx_155825; RRID:rid_000042
9.  Neural and Behavioral Correlates of Extended Training during Sleep Deprivation in Humans: Evidence for Local, Task-Specific Effects 
The Journal of Neuroscience  2015;35(11):4487-4500.
Recent work has demonstrated that behavioral manipulations targeting specific cortical areas during prolonged wakefulness lead to a region-specific homeostatic increase in theta activity (5–9 Hz), suggesting that theta waves could represent transient neuronal OFF periods (local sleep). In awake rats, the occurrence of an OFF period in a brain area relevant for behavior results in performance errors. Here we investigated the potential relationship between local sleep events and negative behavioral outcomes in humans.
Volunteers participated in two prolonged wakefulness experiments (24 h), each including 12 h of practice with either a driving simulation (DS) game or a battery of tasks based on executive functions (EFs). Multiple high-density EEG recordings were obtained during each experiment, both in quiet rest conditions and during execution of two behavioral tests, a response inhibition test and a motor test, aimed at assessing changes in impulse control and visuomotor performance, respectively. In addition, fMRI examinations obtained at 12 h intervals were used to investigate changes in inter-regional connectivity.
The EF experiment was associated with a reduced efficiency in impulse control, whereas DS led to a relative impairment in visuomotor control. A specific spatial and temporal correlation was observed between EEG theta waves occurring in task-related areas and deterioration of behavioral performance. The fMRI connectivity analysis indicated that performance impairment might partially depend on a breakdown in connectivity determined by a “network overload.”
Present results demonstrate the existence of an association between theta waves during wakefulness and performance errors and may contribute explaining behavioral impairments under conditions of sleep deprivation/restriction.
doi:10.1523/JNEUROSCI.4567-14.2015
PMCID: PMC4363380  PMID: 25788668
fMRI; hd-EEG; impulse control; local sleep; performance; theta waves
10.  Transcriptome profiling of sleeping, waking, and sleep deprived adult heterozygous Aldh1L1–eGFP-L10a mice 
Genomics Data  2015;6:114-117.
Transcriptomic studies revealed that hundreds of mRNAs show differential expression in the brains of sleeping relative to awake rats, mice, flies, and sparrows. Although these results have offered clues regarding the molecular consequences of sleep and sleep loss, their functional significance thus far has been limited. This is probably because the previous studies pooled transcripts from all brain cells, including neurons and glia. In Bellesi et al. (2015) [1], we used the translating ribosome affinity purification technology (TRAP) and microarray analysis to obtain a genome-wide mRNA profiling of astrocytes as a function of sleep and wake. We used bacterial artificial chromosome (BAC) transgenic mice expressing eGFP tagged ribosomal protein L10a under the promoter of the Aldh1L1 gene, a highly expressed astrocytic gene. Using this approach, we could extract only the astrocytic mRNAs, and only those already committed to be translated into proteins (L10a is part of the translational machinery).
Here, we report a detailed description of the protocol used in the study (Bellesi et al., 2015 [1]). Array data have been submitted to NCBI GEO under accession number (GSE69079).
doi:10.1016/j.gdata.2015.08.031
PMCID: PMC4580259  PMID: 26413480
Sleep; Wake; Sleep deprivation; BacTRAP; Microarray
11.  Sleep and synaptic changes 
Current opinion in neurobiology  2013;23(5):841-846.
Several recent studies, using molecular, electrophysiological, or structural approaches, have investigated how synapses are affected by sleep, spontaneous wake, chronic sleep restriction, and acute sleep deprivation. Overall, the results have found that even a few hours of sleep or wake can modify the molecular composition of excitatory synapses, change their efficacy, and make synapses grow or shrink. Moreover, partial and total loss of sleep affect the ability of synapses to undergo long-term potentiation, an effect that may underlie some of the negative consequences of sleep deprivation on memory and other cognitive functions.
doi:10.1016/j.conb.2013.04.001
PMCID: PMC4552336  PMID: 23623392
12.  Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies 
BMC Biology  2015;13:66.
Background
Astrocytes can mediate neurovascular coupling, modulate neuronal excitability, and promote synaptic maturation and remodeling. All these functions are likely to be modulated by the sleep/wake cycle, because brain metabolism, neuronal activity and synaptic turnover change as a function of behavioral state. Yet, little is known about the effects of sleep and wake on astrocytes.
Results
Here we show that sleep and wake strongly affect both astrocytic gene expression and ultrastructure in the mouse brain. Using translating ribosome affinity purification technology and microarrays, we find that 1.4 % of all astrocytic transcripts in the forebrain are dependent on state (three groups, sleep, wake, short sleep deprivation; six mice per group). Sleep upregulates a few select genes, like Cirp and Uba1, whereas wake upregulates many genes related to metabolism, the extracellular matrix and cytoskeleton, including Trio, Synj2 and Gem, which are involved in the elongation of peripheral astrocytic processes. Using serial block face scanning electron microscopy (three groups, sleep, short sleep deprivation, chronic sleep restriction; three mice per group, >100 spines per mouse, 3D), we find that a few hours of wake are sufficient to bring astrocytic processes closer to the synaptic cleft, while chronic sleep restriction also extends the overall astrocytic coverage of the synapse, including at the axon–spine interface, and increases the available astrocytic surface in the neuropil.
Conclusions
Wake-related changes likely reflect an increased need for glutamate clearance, and are consistent with an overall increase in synaptic strength when sleep is prevented. The reduced astrocytic coverage during sleep, instead, may favor glutamate spillover, thus promoting neuronal synchronization during non-rapid eye movement sleep.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0176-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-015-0176-7
PMCID: PMC4548305  PMID: 26303010
Mouse; Forebrain; Sleep; Wake; Sleep deprivation; bacTRAP
13.  Single-neuron activity and eye movements during human REM sleep and awake vision 
Nature Communications  2015;6:7884.
Are rapid eye movements (REMs) in sleep associated with visual-like activity, as during wakefulness? Here we examine single-unit activities (n=2,057) and intracranial electroencephalography across the human medial temporal lobe (MTL) and neocortex during sleep and wakefulness, and during visual stimulation with fixation. During sleep and wakefulness, REM onsets are associated with distinct intracranial potentials, reminiscent of ponto-geniculate-occipital waves. Individual neurons, especially in the MTL, exhibit reduced firing rates before REMs as well as transient increases in firing rate immediately after, similar to activity patterns observed upon image presentation during fixation without eye movements. Moreover, the selectivity of individual units is correlated with their response latency, such that units activated after a small number of images or REMs exhibit delayed increases in firing rates. Finally, the phase of theta oscillations is similarly reset following REMs in sleep and wakefulness, and after controlled visual stimulation. Our results suggest that REMs during sleep rearrange discrete epochs of visual-like processing as during wakefulness.
Since the discovery of rapid eye movements (REMs), a critical question endures as to whether they represent time points at which visual-like processing is updated. Here the authors demonstrate that cortical activity during sleep REMs shares many properties with that observed during saccades and vision.
doi:10.1038/ncomms8884
PMCID: PMC4866865  PMID: 26262924
14.  Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration 
Neuron  2014;81(1):12-34.
Summary
Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain. This increases cellular needs for energy and supplies, decreases signal-to-noise ratios, and saturates learning. During sleep, spontaneous activity renormalizes net synaptic strength and restores cellular homeostasis. Activity-dependent down-selection of synapses can also explain the benefits of sleep on memory acquisition, consolidation, and integration. This happens through the off-line, comprehensive sampling of statistical regularities incorporated in neuronal circuits over a lifetime. This review considers the rationale and evidence for SHY and points to open issues related to sleep and plasticity.
doi:10.1016/j.neuron.2013.12.025
PMCID: PMC3921176  PMID: 24411729
15.  Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats 
Journal of sleep research  2013;22(3):264-271.
Summary
Prolonged wakefulness or a lack of sleep lead to cognitive deficits, but little is known about the underlying cellular mechanisms. We recently found that sleep deprivation affects spontaneous neuronal activity in the neocortex of sleeping and awake rats. While it is well known that synaptic responses are modulated by ongoing cortical activity, it remains unclear whether prolonged waking affects responsiveness of cortical neurons to incoming stimuli. By applying local electrical microstimulation to the frontal area of the neocortex, we found that after a 4-hour period of waking the initial neuronal response in the contralateral frontal cortex was stronger and more synchronous, and was followed by a more profound inhibition of neuronal spiking as compared to the control condition. These changes in evoked activity suggest increased neuronal excitability and indicate that after staying awake cortical neurons become transiently bistable. We propose that some of the detrimental effects of sleep deprivation may be a result of altered neuronal responsiveness to incoming intrinsic and extrinsic inputs.
doi:10.1111/jsr.12009
PMCID: PMC3723708  PMID: 23607417
sleep; LFP; evoked responses; cerebral cortex; multi-unit recording; prolonged wakefulness
16.  Effects of Sleep and Wake on Oligodendrocytes and Their Precursors 
The Journal of Neuroscience  2013;33(36):14288-14300.
Previous studies of differential gene expression in sleep and wake pooled transcripts from all brain cells and showed that several genes expressed at higher levels during sleep are involved in the synthesis/maintenance of membranes in general and of myelin in particular, a surprising finding given the reported slow turnover of many myelin components. Other studies showed that oligodendrocyte precursor cells (OPCs) are responsible for the formation of new myelin in both the injured and the normal adult brain, and that glutamate released from neurons, via neuron–OPC synapses, can inhibit OPC proliferation and affect their differentiation into myelin-forming oligodendrocytes. Because glutamatergic transmission is higher in wake than in sleep, we asked whether sleep and wake can affect oligodendrocytes and OPCs. Using the translating ribosome affinity purification technology combined with microarray analysis in mice, we obtained a genome-wide profiling of oligodendrocytes after sleep, spontaneous wake, and forced wake (acute sleep deprivation). We found that hundreds of transcripts being translated in oligodendrocytes are differentially expressed in sleep and wake: genes involved in phospholipid synthesis and myelination or promoting OPC proliferation are transcribed preferentially during sleep, while genes implicated in apoptosis, cellular stress response, and OPC differentiation are enriched in wake. We then confirmed through BrdU and other experiments that OPC proliferation doubles during sleep and positively correlates with time spent in REM sleep, whereas OPC differentiation is higher during wake. Thus, OPC proliferation and differentiation are not perfectly matched at any given circadian time but preferentially occur during sleep and wake, respectively.
doi:10.1523/JNEUROSCI.5102-12.2013
PMCID: PMC3874087  PMID: 24005282
17.  Enhancement of sleep slow waves: underlying mechanisms and practical consequences 
Even modest sleep restriction, especially the loss of sleep slow wave activity (SWA), is invariably associated with slower electroencephalogram (EEG) activity during wake, the occurrence of local sleep in an otherwise awake brain, and impaired performance due to cognitive and memory deficits. Recent studies not only confirm the beneficial role of sleep in memory consolidation, but also point to a specific role for sleep slow waves. Thus, the implementation of methods to enhance sleep slow waves without unwanted arousals or lightening of sleep could have significant practical implications. Here we first review the evidence that it is possible to enhance sleep slow waves in humans using transcranial direct-current stimulation (tDCS) and transcranial magnetic stimulation. Since these methods are currently impractical and their safety is questionable, especially for chronic long-term exposure, we then discuss novel data suggesting that it is possible to enhance slow waves using sensory stimuli. We consider the physiology of the K-complex (KC), a peripheral evoked slow wave, and show that, among different sensory modalities, acoustic stimulation is the most effective in increasing the magnitude of slow waves, likely through the activation of non-lemniscal ascending pathways to the thalamo-cortical system. In addition, we discuss how intensity and frequency of the acoustic stimuli, as well as exact timing and pattern of stimulation, affect sleep enhancement. Finally, we discuss automated algorithms that read the EEG and, in real-time, adjust the stimulation parameters in a closed-loop manner to obtain an increase in sleep slow waves and avoid undesirable arousals. In conclusion, while discussing the mechanisms that underlie the generation of sleep slow waves, we review the converging evidence showing that acoustic stimulation is safe and represents an ideal tool for slow wave sleep (SWS) enhancement.
doi:10.3389/fnsys.2014.00208
PMCID: PMC4211398  PMID: 25389394
EEG; acoustic stimulation; arousal systems; closed-loop; NREM sleep
18.  SLEEP/WAKE DEPENDENT CHANGES IN CORTICAL GLUCOSE CONCENTRATIONS 
Journal of neurochemistry  2012;124(1):79-89.
Most of the energy in the brain comes from glucose and supports glutamatergic activity. The firing rate of cortical glutamatergic neurons, as well as cortical extracellular glutamate levels, increase with time spent awake and decline throughout non rapid eye movement (NREM) sleep, raising the question whether glucose levels reflect behavioral state and sleep/wake history. Here chronic (2–3 days) electroencephalographic (EEG) recordings in the rat cerebral cortex were coupled with fixed-potential amperometry to monitor the extracellular concentration of glucose ([gluc]) on a second-by-second basis across the spontaneous sleep-wake cycle and in response to 3 hours of sleep deprivation. [Gluc] progressively increased during NREM sleep and declined during REM sleep, while during wake an early decline in [gluc] was followed by an increase 8–15 minutes after awakening. There was a significant time of day effect during the dark phase, when rats are mostly awake, with [gluc] being significantly lower during the last 3–4 hours of the night relative to the first 3–4 hours. Moreover, the duration of the early phase of [gluc] decline during wake was longer after prolonged wake than after consolidated sleep. Thus, the sleep/wake history may affect the levels of glucose available to the brain upon awakening.
doi:10.1111/jnc.12063
PMCID: PMC3518620  PMID: 23106535
glucose; in vivo amperometry; sleep; rat; cerebral cortex; EEG; slow wave activity
19.  Sleep-Dependent Synaptic Down-Selection (I): Modeling the Benefits of Sleep on Memory Consolidation and Integration 
Sleep can favor the consolidation of both procedural and declarative memories, promote gist extraction, help the integration of new with old memories, and desaturate the ability to learn. It is often assumed that such beneficial effects are due to the reactivation of neural circuits in sleep to further strengthen the synapses modified during wake or transfer memories to different parts of the brain. A different possibility is that sleep may benefit memory not by further strengthening synapses, but rather by renormalizing synaptic strength to restore cellular homeostasis after net synaptic potentiation in wake. In this way, the sleep-dependent reactivation of neural circuits could result in the competitive down-selection of synapses that are activated infrequently and fit less well with the overall organization of memories. By using computer simulations, we show here that synaptic down-selection is in principle sufficient to explain the beneficial effects of sleep on the consolidation of procedural and declarative memories, on gist extraction, and on the integration of new with old memories, thereby addressing the plasticity-stability dilemma.
doi:10.3389/fneur.2013.00143
PMCID: PMC3786405  PMID: 24137153
neurons; plasticity and learning; sleep; homeostatic regulation; declarative memory; procedural memory
20.  Sleep Patterns and Homeostatic Mechanisms in Adolescent Mice 
Brain sciences  2013;3(1):318-343.
Sleep changes were studied in mice (n = 59) from early adolescence to adulthood (postnatal days P19–111). REM sleep declined steeply in early adolescence, while total sleep remained constant and NREM sleep increased slightly. Four hours of sleep deprivation starting at light onset were performed from ages P26 through adulthood (>P60). Following this acute sleep deprivation all mice slept longer and with more consolidated sleep bouts, while NREM slow wave activity (SWA) showed high interindividual variability in the younger groups, and increased consistently only after P42. Three parameters together explained up to 67% of the variance in SWA rebound in frontal cortex, including weight-adjusted age and increase in alpha power during sleep deprivation, both of which positively correlated with the SWA response. The third, and strongest predictor was the SWA decline during the light phase in baseline: mice with high peak SWA at light onset, resulting in a large SWA decline, were more likely to show no SWA rebound after sleep deprivation, a result that was also confirmed in parietal cortex. During baseline, however, SWA showed the same homeostatic changes in adolescents and adults, declining in the course of sleep and increasing across periods of spontaneous wake. Thus, we hypothesize that, in young adolescent mice, a ceiling effect and not the immaturity of the cellular mechanisms underlying sleep homeostasis may prevent the SWA rebound when wake is extended beyond its physiological duration.
doi:10.3390/brainsci3010318
PMCID: PMC3682503  PMID: 23772316
adolescence; cerebral cortex; sleep deprivation; slow wave activity
21.  Sleep Patterns and Homeostatic Mechanisms in Adolescent Mice 
Brain Sciences  2013;3(1):318-343.
Sleep changes were studied in mice (n = 59) from early adolescence to adulthood (postnatal days P19–111). REM sleep declined steeply in early adolescence, while total sleep remained constant and NREM sleep increased slightly. Four hours of sleep deprivation starting at light onset were performed from ages P26 through adulthood (>P60). Following this acute sleep deprivation all mice slept longer and with more consolidated sleep bouts, while NREM slow wave activity (SWA) showed high interindividual variability in the younger groups, and increased consistently only after P42. Three parameters together explained up to 67% of the variance in SWA rebound in frontal cortex, including weight-adjusted age and increase in alpha power during sleep deprivation, both of which positively correlated with the SWA response. The third, and strongest predictor was the SWA decline during the light phase in baseline: mice with high peak SWA at light onset, resulting in a large SWA decline, were more likely to show no SWA rebound after sleep deprivation, a result that was also confirmed in parietal cortex. During baseline, however, SWA showed the same homeostatic changes in adolescents and adults, declining in the course of sleep and increasing across periods of spontaneous wake. Thus, we hypothesize that, in young adolescent mice, a ceiling effect and not the immaturity of the cellular mechanisms underlying sleep homeostasis may prevent the SWA rebound when wake is extended beyond its physiological duration.
doi:10.3390/brainsci3010318
PMCID: PMC3682503  PMID: 23772316
adolescence; cerebral cortex; sleep deprivation; slow wave activity
22.  Sleep spindles in humans: insights from intracranial EEG and unit recordings 
The Journal of Neuroscience  2011;31(49):17821-17834.
Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we utilized a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13-15Hz) centroparietal spindles often occurring with slow wave up-states, and slow (9-12Hz) frontal spindles occurring 200ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency.
doi:10.1523/JNEUROSCI.2604-11.2011
PMCID: PMC3270580  PMID: 22159098
23.  Sleep and wake modulate spine turnover in the adolescent mouse cortex 
Nature neuroscience  2011;14(11):1418-1420.
Cortical development involves synaptic formation and elimination. While synaptogenesis predominates earlier and pruning later, the two processes are thought to happen concurrently. Since in adults synaptic strength is modulated by behavioral state, we asked if synaptic remodeling may be affected by sleep and wake. Using two-photon microscopy in adolescent mice, we found that wake results in a net increase in cortical spines, whereas sleep is associated with net spine loss.
doi:10.1038/nn.2934
PMCID: PMC3203346  PMID: 21983682
sleep; cortex; synapse; adolescence; pruning
24.  Time to Be SHY? Some Comments on Sleep and Synaptic Homeostasis 
Neural Plasticity  2012;2012:415250.
Sleep must serve an essential, universal function, one that offsets the risk of being disconnected from the environment. The synaptic homeostasis hypothesis (SHY) is an attempt to identify this essential function. Its core claim is that sleep is needed to reestablish synaptic homeostasis, which is challenged by the remarkable plasticity of the brain. In other words, sleep is “the price we pay for plasticity.” In this issue, M. G. Frank reviewed several aspects of the hypothesis and raised several issues. The comments below provide a brief summary of the motivations underlying SHY and clarify that SHY is a hypothesis not about specific mechanisms, but about a universal, essential function of sleep. This function is the preservation of synaptic homeostasis in the face of a systematic bias toward a net increase in synaptic strength—a challenge that is posed by learning during adult wake, and by massive synaptogenesis during development.
doi:10.1155/2012/415250
PMCID: PMC3350977  PMID: 22619736
25.  Regional Slow Waves and Spindles in Human Sleep 
Neuron  2011;70(1):153-169.
SUMMARY
The most prominent EEG events in sleep are slow waves, reflecting a slow (<1 Hz) oscillation between up and down states in cortical neurons. It is unknown whether slow oscillations are synchronous across the majority or the minority of brain regions—are they a global or local phenomenon? To examine this, we recorded simultaneously scalp EEG, intracerebral EEG, and unit firing in multiple brain regions of neurosurgical patients. We find that most sleep slow waves and the underlying active and inactive neuronal states occur locally. Thus, especially in late sleep, some regions can be active while others are silent. We also find that slow waves can propagate, usually from medial prefrontal cortex to the medial temporal lobe and hippocampus. Sleep spindles, the other hallmark of NREM sleep EEG, are likewise predominantly local. Thus, intracerebral communication during sleep is constrained because slow and spindle oscillations often occur out-of-phase in different brain regions.
doi:10.1016/j.neuron.2011.02.043
PMCID: PMC3108825  PMID: 21482364

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