PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (35)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
1.  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
2.  Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats 
Journal of sleep research  2012;10.1111/jsr.12009.
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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Reduction of EEG Theta Power and Changes in Motor Activity in Rats Treated with Ceftriaxone 
PLoS ONE  2012;7(3):e34139.
The glutamate transporter GLT-1 is responsible for the largest proportion of total glutamate transport. Recently, it has been demonstrated that ceftriaxone (CEF) robustly increases GLT-1 expression. In addition, physiological studies have shown that GLT-1 up-regulation strongly affects synaptic plasticity, and leads to an impairment of the prepulse inhibition, a simple form of information processing, thus suggesting that GLT-1 over-expression may lead to dysfunctions of large populations of neurons. To test this possibility, we assessed whether CEF affects cortical electrical activity by using chronic electroencephalographic (EEG) recordings in male WKY rats. Spectral analysis showed that 8 days of CEF treatment resulted in a delayed reduction in EEG theta power (7–9 Hz) in both frontal and parietal derivations. This decrease peaked at day 10, i.e., 2 days after the end of treatment, and disappeared by day 16. In addition, we found that the same CEF treatment increased motor activity, especially when EEG changes are more prominent. Taken together, these data indicate that GLT-1 up-regulation, by modulating glutamatergic transmission, impairs the activity of widespread neural circuits. In addition, the increased motor activity and prepulse inhibition alterations previously described suggest that neural circuits involved in sensorimotor control are particularly sensitive to GLT-1 up-regulation.
doi:10.1371/journal.pone.0034139
PMCID: PMC3316604  PMID: 22479544
14.  Electrophysiological correlates of sleep homeostasis in freely behaving rats 
Progress in brain research  2011;193:17-38.
The electrical activity of the brain does not only reflect the current level of arousal, ongoing behavior or involvement in a specific task, but is also influenced by what kind of activity, and how much sleep and waking occurred before. The best marker of sleep-wake history is the electroencephalogram (EEG) spectral power in slow frequencies (slow-wave activity, 0.5–4 Hz, SWA) during sleep, which is high after extended wakefulness and low after consolidated sleep. While sleep homeostasis has been well characterized in various species and experimental paradigms, the specific mechanisms underlying homeostatic changes in brain activity or their functional significance remain poorly understood. However, several recent studies in humans, rats and computer simulations shed light on the cortical mechanisms underlying sleep regulation. First, it was found that the homeostatic changes in SWA can be fully accounted for by the variations in amplitude and slope of EEG slow waves, which are in turn determined by the efficacy of cortico-cortical connectivity. Specifically, the slopes of sleep slow waves were steeper in early sleep compared to late sleep. Second, the slope of cortical evoked potentials, which is an established marker of synaptic strength, was steeper after waking and decreased after sleep. Furthermore, cortical long-term potentiation (LTP) was partially occluded if it was induced after a period of waking, but it could again be fully expressed after sleep. Finally, multiunit activity recordings during sleep revealed that cortical neurons fired more synchronously after waking, and less so after a period of consolidated sleep. The decline of all these electrophysiological measures - the slopes of slow waves and evoked potentials and neuronal synchrony – during sleep correlated with the decline of the traditional marker of sleep homeostasis, EEG SWA. Taken together, these data suggest that homeostatic changes in sleep EEG are the result of altered neuronal firing and synchrony, which in turn arise from changes in functional neuronal connectivity.
doi:10.1016/B978-0-444-53839-0.00002-8
PMCID: PMC3160719  PMID: 21854953
sleep homeostasis; synaptic homeostasis; multiunit activity; neurons; cortex
15.  From genetics to structure to function: Exploring sleep in Drosophila 
Outline
Sleep consists of quiescent periods with reduced responsiveness to external stimuli. Despite being maladaptive in that when asleep, animals are less able to respond to dangerous stimuli, sleep behavior is conserved in all animal species studied to date. Thus, sleep must be performing at least one fundamental, conserved function that is necessary, and/ or whose benefits outweigh its maladaptive consequences. Currently, there is no consensus on what that function might be. Over the last 10 years, multiple groups have started to characterize the molecular mechanisms and brain structures necessary for normal sleep in Drosophila melanogaster. These researchers are exploiting genetic tools developed in Drosophila over the past century to identify and manipulate gene expression. Forward genetic screens can identify molecular components in complex biological systems and once identified, these genes can be manipulated within specific brain areas to determine which neuronal groups are important to initiate and maintain sleep. Screening for mutations and brain regions necessary for normal sleep has revealed that several genes that affect sleep are involved in synaptic plasticity and have preferential expression in the mushroom bodies (MB). Moreover, altering MB neuronal activity alters sleep. Previous genetic screens found that the same genes enriched in MB are necessary for learning and memory. Increasing evidence in mammals, including humans, points to a beneficial role for sleep in synaptic plasticity, learning and memory. Thus, results from both flies and mammals suggest a strong link between sleep need and wake plasticity.
doi:10.1016/B978-0-12-387003-2.00009-4
PMCID: PMC3172676  PMID: 21906542
16.  Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila 
Science (New York, N.Y.)  2011;332(6037):1576-1581.
The functions of sleep remain elusive, but a strong link exists between sleep need and neuronal plasticity. We tested the hypothesis that plastic processes during wake lead to a net increase in synaptic strength, and sleep is necessary for synaptic renormalization. We found that, in 3 Drosophila neuronal circuits, synapse size or number increases after a few hours of wake and decreases only if flies are allowed to sleep. A richer wake experience resulted in both larger synaptic growth and greater sleep need. Finally, we demonstrate that the gene Fmr1 (fragile X mental retardation 1) plays an important role in sleep-dependent synaptic renormalization.
doi:10.1126/science.1202839
PMCID: PMC3128387  PMID: 21700878
17.  Unilateral Cortical Spreading Depression Affects Sleep Need and Induces Molecular and Electrophysiological Signs of Synaptic Potentiation In Vivo 
Cerebral Cortex (New York, NY)  2010;20(12):2939-2947.
Cortical spreading depression (CSD) is an electrophysiological phenomenon first described by Leao in 1944 as a suppression of spontaneous electroencephalographic activity, traveling across the cerebral cortex. In vitro studies suggest that CSD may induce synaptic potentiation. One recent study also found that CSD is followed by a non-rapid eye movement (NREM) sleep duration increase, suggesting an increased need for sleep. Recent experiments in animals and humans show that the occurrence of synaptic potentiation increases subsequent sleep need as measured by larger slow wave activity (SWA) during NREM sleep, prompting the question whether CSD can affect NREM SWA. Here, we find that, in freely moving rats, local CSD induction increases corticocortical evoked responses and strongly induces brain derived neurotrophic factor (BDNF) in the affected cortical hemisphere but not in the contralateral one, consistent with synaptic potentiation in vivo. Moreover, for several hours after CSD, large slow waves occur in the affected hemisphere during rapid eye movement sleep and quiet waking but disappear during active exploration. Finally, we find that CSD increases NREM sleep duration and SWA, the latter specifically in the affected hemisphere. These effects are consistent with an increase in synaptic strength triggered by CSD, although nonphysiological phenomena associated with CSD may also play a role.
doi:10.1093/cercor/bhq041
PMCID: PMC2978242  PMID: 20348156
cerebral cortex; EEG; rat; slow wave activity
18.  Local sleep in awake rats 
Nature  2011;472(7344):443-447.
When the brain is awake, neurons in the cerebral cortex fire irregularly and the electroencephalogram (EEG) displays low amplitude, high frequency fluctuations. After falling asleep, neurons start oscillating between ON periods, when they fire as during wake, and OFF periods, when they stop firing altogether, and the EEG displays high amplitude slow waves. But what happens to neuronal firing after a long period of wake? We show here in freely behaving rats that, after prolonged wake, cortical neurons can go briefly “OFF line” as they do in sleep, accompanied by slower waves in the local EEG. Strikingly, neurons often go OFF line in one cortical area and not in another. During these periods of “local sleep”, whose incidence increases with wake duration, rats appear awake, active, and display a wake EEG. However, they are progressively impaired in a sugar pellet reaching task. Thus, though both the EEG and behavior indicate wakefulness, local populations of neurons in the cortex may be falling asleep, with negative consequences on performance.
doi:10.1038/nature10009
PMCID: PMC3085007  PMID: 21525926
slow wave sleep; slow oscillations; EEG; cerebral cortex; multi-unit recording; reaching task; sleep deprivation
19.  Direct evidence for wake-related increases and sleep-related decreases in synaptic strength in rodent cortex 
Despite evidence that waking is associated with net synaptic potentiation and sleep with depression, direct proof for changes in synaptic currents is lacking in large brain areas such as the cerebral cortex. By recording miniature excitatory postsynaptic currents (mEPSCs) from frontal cortex slices of mice and rats that had been awake or asleep, we found that the frequency and amplitude of mEPSCs increased after wake and decreased after sleep. Recovery sleep after sleep deprivation also decreased mEPSCs, suggesting that sleep favors synaptic homeostasis. Since stronger synapses require more energy, space, and supplies, a generalized downscaling of synapses may be an important function of sleep.
doi:10.1523/JNEUROSCI.1409-10.2010
PMCID: PMC2903226  PMID: 20573912
synaptic plasticity; glutamatergic transmission; sleep/wake cycle; frontal cortex; pyramidal neuron; behavioral state
20.  Cortical firing and sleep homeostasis 
Neuron  2009;63(6):865-878.
SUMMARY
The need to sleep grows with the duration of wakefulness and dissipates with time spent asleep, a process called sleep homeostasis. What are the consequences of staying awake on brain cells, and why is sleep needed? Surprisingly, we do not know whether the firing of cortical neurons is affected by how long an animal has been awake or asleep. Here we found that after sustained wakefulness cortical neurons fire at higher frequencies in all behavioral states. During early NREM sleep after sustained wakefulness, periods of population activity (ON) are short, frequent, and associated with synchronous firing, while periods of neuronal silence are long and frequent. After sustained sleep, firing rates and synchrony decrease, while the duration of ON periods increases. Changes in firing patterns in NREM sleep correlate with changes in slow-wave-activity, a marker of sleep homeostasis. Thus, the systematic increase of firing during wakefulness is counterbalanced by staying asleep.
doi:10.1016/j.neuron.2009.08.024
PMCID: PMC2819325  PMID: 19778514
slow wave sleep; slow oscillations; EEG; rat; cerebral cortex; multi-unit recording
21.  Proteomic profiling of the rat cerebral cortex in sleep and waking 
Archives italiennes de biologie  2009;147(3):59-68.
Transcriptomic studies have shown that hundreds of genes change their expression levels across the sleep/waking cycle, and found that waking-related and sleep-related mRNAs belong to different functional categories. Proteins, however, rather than DNA or RNA, carry out most of the cellular functions, and direct measurements of protein levels and activity are required to assess the effects of behavioral states on the overall functional state of the cell. Here we used surface-enhanced laser desorption-ionization (SELDI), followed by time-of-flight mass spectrometry, to obtain a large-scale profiling of the proteins in the rat cerebral cortex whose expression is affected by sleep, spontaneous waking, short (6 hours) and long (7 days) sleep deprivation. Each of the 94 cortical samples was profiled in duplicate on 4 different ProteinChip Array surfaces using 2 different matrix molecules. Overall, 1055 protein peaks were consistently detected in cortical samples and 15 candidate biomarkers were selected for identification based on significant changes in multiple conditions (conjunction analysis): 8 “sleep” peaks, 4 “waking” peaks, and 4 “long sleep deprivation” peaks. Four candidate biomarkers were purified and positively identified. The 3353 Da candidate sleep marker was identified as the 30 amino acid C-terminal fragment of rat histone H4. This regions encompasses the osteogenic growth peptide, but a possible link between sleep and this peptide remains highly speculative. Two peaks associated with short and long sleep deprivation were identified as hemoglobin alpha1/2 and beta, respectively, while another peak associated with long sleep deprivation was identified as cytochrome C. The upregulation of hemoglobins and cytochrome C may be part of a cellular stress response triggered by even short periods of sleep loss.
PMCID: PMC2796588  PMID: 20014652
rat; sleep; proteomics
22.  The genetic and molecular regulation of sleep: from fruit flies to humans 
Nature reviews. Neuroscience  2009;10(8):549-560.
It has been known for a long time that genetic factors affect sleep quantity and quality. Genetic screens identified several mutations that affect sleep across species, pointing to an evolutionary conserved regulation of sleep. Moreover, it has also been recognized that sleep affects the expression of genes. These findings have given valuable clues about the molecular underpinnings of sleep regulation and function that might lead the way to more efficient treatments for sleep disorders.
doi:10.1038/nrn2683
PMCID: PMC2767184  PMID: 19617891
23.  pySolo: a complete suite for sleep analysis in Drosophila 
Bioinformatics  2009;25(11):1466-1467.
Summary: pySolo is a multiplatform software for analysis of sleep and locomotor activity in Drosophila melanogaster. pySolo provides a user-friendly graphic interface and it has been developed with the specific aim of being accessible, portable, fast and easily expandable through an intuitive plug-in structure. Support for development of additional plug-ins is provided through a community website.
Availability: Software and documentation are located at http://www.pysolo.net. pySolo is a free software released under the GNU General Public License.
Contact: gilestro@wisc.edu
doi:10.1093/bioinformatics/btp237
PMCID: PMC2732309  PMID: 19369499
24.  Sleep, aging, and lifespan in Drosophila 
BMC Neuroscience  2010;11:56.
Background
Epidemiological studies in humans suggest that a decrease in daily sleep duration is associated with reduced lifespan, but this issue remains controversial. Other studies in humans also show that both sleep quantity and sleep quality decrease with age. Drosophila melanogaster is a useful model to study aging and sleep, and inheriting mutations affecting the potassium current Shaker results in flies that sleep less and have a shorter lifespan. However, whether the link between short sleep and reduced longevity exists also in wild-type flies is unknown. Similarly, it is unknown whether such a link depends on sleep amount per se, rather than on other factors such as waking activity. Also, sleep quality has been shown to decrease in old flies, but it remains unclear whether aging-related sleep fragmentation is a generalized phenomenon.
Results
We compared 3 short sleeping mutant lines (Hk1, HkY and Hk2) carrying a mutation in Hyperkinetic, which codes for the beta subunit of the Shaker channel, to wild-type siblings throughout their entire lifespan (all flies kept at 20°C). Hk1 and HkY mutants were short sleeping relative to wild-type controls from day 3 after eclosure, and Hk2 flies became short sleepers about two weeks later. All 3 Hk mutant lines had reduced lifespan relative to wild-type flies. Total sleep time showed a trend to increase in all lines with age, but the effect was most pronounced in Hk1 and HkY flies. In both mutant and wild-type lines sleep quality did not decay with age, but the strong preference for sleep at night declined starting in "middle age". Using Cox regression analysis we found that in Hk1 and HkY mutants and their control lines there was a negative relationship between total sleep amount during the first 2 and 4 weeks of age and hazard (individual risk of death), while no association was found in Hk2 flies and their wild-type controls. Hk1 and HkY mutants and their control lines also showed an association between total daily wake activity over the first 2 and 4 weeks of age and hazard. However, when both sleep duration and wake activity were used in the same regression, the effects of activity were much reduced, while most of the sleep effects remained significant. Finally, Hk1 flies and wild-type siblings were also tested at 25°C, and results were similar to those at 20°C. Namely, Hk1 mutants were short sleeping, hyperactive, and short lived relative to controls, and sleep quality in both groups did not decrease with age.
Conclusions
Different Hk mutations affect the sleep phenotype, and do so in an age-dependent manner. In 4 of the 6 lines tested sleep associates significantly with lifespan variation even after any effect of activity is removed, but activity does not associate significantly with lifespan after the effects of sleep are removed. Thus, in addition to environmental factors and genetic background, sleep may also affect longevity. Sleep quality does not necessarily decay as flies age, suggesting that aging-related sleep fragmentation may also depend on many factors, including genetic background and rearing conditions.
doi:10.1186/1471-2202-11-56
PMCID: PMC2871268  PMID: 20429945
25.  Widespread Changes in Synaptic Markers as a Function of Sleep and Wakefulness in Drosophila 
Science (New York, N.Y.)  2009;324(5923):109-112.
Sleep is universal, strictly regulated, and necessary for cognition. Why this is so remains a mystery, though recent work suggests a link between sleep, memory, and plasticity. However, little is known about how wakefulness and sleep affect synapses. Using Western blots and confocal microscopy in Drosophila, we found that protein levels of key components of central synapses were high after waking and low after sleep. These changes were related to behavioral state rather than time of day and occurred in all major areas of the Drosophila brain. The decrease of synaptic markers during sleep was progressive and sleep was necessary for their decline. Thus, sleep may be involved in maintaining synaptic homeostasis altered by waking activities.
doi:10.1126/science.1166673
PMCID: PMC2715914  PMID: 19342593

Results 1-25 (35)