Effects of Chronic Sleep Restriction on Transcriptional Sirtuin 1 Signaling Regulation in Male Mice White Adipose Tissue.

Chronic sleep restriction (CSR) is a prevalent issue in modern society that is associated with several pathological states, ranging from neuropsychiatric to metabolic diseases. Despite its known impact on metabolism, the specific effects of CSR on the molecular mechanisms involved in maintaining metabolic homeostasis at the level of white adipose tissue (WAT) remain poorly understood. Therefore, this study aimed to investigate the influence of CSR on sirtuin 1 (SIRT1) and the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway in the WAT of young male mice. Both genes interact with specific targets involved in multiple metabolic processes, including adipocyte differentiation, browning, and lipid metabolism. The quantitative PCR (qPCR) results demonstrated a significant upregulation of SIRT-1 and some of its target genes associated with the transcriptional regulation of lipid homeostasis (i.e., PPARα, PPARγ, PGC-1α, and SREBF) and adipose tissue development (i.e., leptin, adiponectin) in CSR mice. On the contrary, DNA-binding transcription factors (i.e., CEBP-ß and C-myc), which play a pivotal function during the adipogenesis process, were found to be down-regulated. Our results also suggest that the induction of SIRT1-dependent molecular pathways prevents weight gain. Overall, these findings offer new, valuable insights into the molecular adaptations of WAT to CSR, in order to support increased energy demand due to sleep loss.

Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.

BACKGROUND: Prolonged cellular activity may overload cell function, leading to high rates of protein synthesis and accumulation of misfolded or unassembled proteins, which cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) to re-establish normal protein homeostasis. Previous molecular work has demonstrated that sleep deprivation (SD) leads to ER stress in neurons, with a number of ER-specific proteins being upregulated to maintain optimal cellular proteostasis. It is still not clear which cellular processes activated by sleep deprivation lead to ER- stress, but increased cellular metabolism, higher request for protein synthesis, and over production of oxygen radicals have been proposed as potential contributing factors. Here, we investigate the transcriptional and ultrastructural ER and mitochondrial modifications induced by sleep loss. RESULTS: We used gene expression analysis in mouse forebrains to show that SD was associated with significant transcriptional modifications of genes involved in ER stress but also in ER-mitochondria interaction, calcium homeostasis, and mitochondrial respiratory activity. Using electron microscopy, we also showed that SD was associated with a general increase in the density of ER cisternae in pyramidal neurons of the motor cortex. Moreover, ER cisternae established new contact sites with mitochondria, the so-called mitochondria associated membranes (MAMs), important hubs for molecule shuttling, such as calcium and lipids, and for the modulation of ATP production and redox state. Finally, we demonstrated that Drosophila male mutant flies (elav > linker), in which the number of MAMs had been genetically increased, showed a reduction in the amount and consolidation of sleep without alterations in the homeostatic sleep response to SD. CONCLUSIONS: We provide evidence that sleep loss induces ER stress characterized by increased crosstalk between ER and mitochondria. MAMs formation associated with SD could represent a key phenomenon for the modulation of multiple cellular processes that ensure appropriate responses to increased cell metabolism. In addition, MAMs establishment may play a role in the regulation of sleep under baseline conditions.

Integrity of Corpus Callosum Is Essential for theCross-Hemispheric Propagation of Sleep Slow Waves:A High-Density EEG Study in Split-Brain Patients.

The slow waves of non-rapid eye movement (NREM) sleep reflect experience-dependent plasticity and play a direct role in the restorative functions of sleep. Importantly, slow waves behave as traveling waves, and their propagation is assumed to occur through cortico-cortical white matter connections. In this light, the corpus callosum (CC) may represent the main responsible for cross-hemispheric slow-wave propagation. To verify this hypothesis, we performed overnight high-density (hd)-EEG recordings in five patients who underwent total callosotomy due to drug-resistant epilepsy (CPs; two females), in three noncallosotomized neurologic patients (NPs; two females), and in a sample of 24 healthy adult subjects (HSs; 13 females). In all CPs slow waves displayed a significantly reduced probability of cross-hemispheric propagation and a stronger inter-hemispheric asymmetry. In both CPs and HSs, the incidence of large slow waves within individual NREM epochs tended to differ across hemispheres, with a relative overall predominance of the right over the left hemisphere. The absolute magnitude of this asymmetry was greater in CPs relative to HSs. However, the CC resection had no significant effects on the distribution of slow-wave origin probability across hemispheres. The present results indicate that CC integrity is essential for the cross-hemispheric traveling of slow waves in human sleep, which is in line with the assumption of a direct relationship between white matter integrity and slow-wave propagation. Our findings also revealed a residual cross-hemispheric slow-wave propagation that may rely on alternative pathways, including cortico-subcortico-cortical loops. Finally, these data indicate that the lack of the CC does not lead to differences in slow-wave generation across brain hemispheres.SIGNIFICANCE STATEMENT The slow waves of NREM sleep behave as traveling waves, and their propagation has been suggested to reflect the integrity of white matter cortico-cortical connections. To directly assess this hypothesis, here we investigated the role of the corpus callosum in the cortical spreading of NREM slow waves through the study of a rare population of totally callosotomized patients. Our results demonstrate a causal role of the corpus callosum in the cross-hemispheric traveling of sleep slow waves. Additionally, we found that callosotomy does not affect the relative tendency of each hemisphere at generating slow waves. Incidentally, we also found that slow waves tend to originate more often in the right than in the left hemisphere in both callosotomized and healthy adult individuals.

Sleep Deprivation by Exposure to Novel Objects Increases Synapse Density and Axon-Spine Interface in the Hippocampal CA1 Region of Adolescent Mice.

Sleep has been hypothesized to rebalance overall synaptic strength after ongoing learning during waking leads to net synaptic potentiation. If so, because synaptic strength and size are correlated, synapses on average should be larger after wake and smaller after sleep. This prediction was recently confirmed in mouse cerebral cortex using serial block-face electron microscopy (SBEM). However, whether these findings extend to other brain regions is unknown. Moreover, sleep deprivation by gentle handling was reported to produce hippocampal spine loss, raising the question of whether synapse size and number are differentially affected by sleep and waking. Here we applied SBEM to measure axon-spine interface (ASI), the contact area between pre-synapse and post-synapse, and synapse density in CA1 stratum radiatum. Adolescent YFP-H mice were studied after 6-8 h of sleep (S = 6), spontaneous wake at night (W = 4) or wake enforced during the day by novelty exposure (EW = 4; males/females balanced). In each animal ≥425 ASIs were measured and synaptic vesicles were counted in ~100 synapses/mouse. Reconstructed dendrites included many small, nonperforated synapses and fewer large, perforated synapses. Relative to S, ASI sizes in perforated synapses shifted toward higher values after W and more so after EW. ASI sizes in nonperforated synapses grew after EW relative to S and W, and so did their density. ASI size correlated with presynaptic vesicle number but the proportion of readily available vesicles decreased after EW, suggesting presynaptic fatigue. Thus, CA1 synapses undergo changes consistent with sleep-dependent synaptic renormalization and their number increases after extended wake.SIGNIFICANCE STATEMENT Sleep benefits learning, memory consolidation, and the integration of new with old memories, but the underlying mechanisms remain highly debated. One hypothesis suggests that sleep's cognitive benefits stem from its ability to renormalize total synaptic strength, after ongoing learning during wake leads to net synaptic potentiation. Supporting evidence for this hypothesis mainly comes from the cerebral cortex, including the observation that cortical synapses are larger after wake and smaller after sleep. Using serial electron microscopy, we find here that sleep/wake synaptic changes consistent with sleep-dependent synaptic renormalization also occur in the CA1 region. Thus, the role of sleep in maintaining synaptic homeostasis may extend to the hippocampus, a key area for learning and synaptic plasticity.

The role of sleep and wakefulness in myelin plasticity.

Myelin plasticity is gaining increasing recognition as an essential partner to synaptic plasticity, which mediates experience-dependent brain structure and function. However, how neural activity induces adaptive myelination and which mechanisms are involved remain open questions. More than two decades of transcriptomic studies in rodents have revealed that hundreds of brain transcripts change their expression in relation to the sleep-wake cycle. These studies consistently report upregulation of myelin-related genes during sleep, suggesting that sleep represents a window of opportunity during which myelination occurs. In this review, we summarize recent molecular and morphological studies detailing the dependence of myelin dynamics after sleep, wake, and chronic sleep loss, a condition that can affect myelin substantially. We present novel data about the effects of sleep loss on the node of Ranvier length and provide a hypothetical mechanism through which myelin changes in response to sleep loss. Finally, we discuss the current findings in humans, which appear to confirm the important role of sleep in promoting white matter integrity.

Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves.

During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the neuronal basis of the slow wave, remains unknown. Using chemogenetic and optogenetic approaches, we provide the first evidence that links a specific class of inhibitory interneurons-somatostatin-positive cells-to the generation of slow waves during NREM sleep in freely moving mice.

Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex.

We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage.

Neural and behavioral correlates of extended training during sleep deprivation in humans: evidence for local, task-specific effects.

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.

Sleep reverts changes in human gray and white matter caused by wake-dependent training.

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites.

Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies.

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.

Effects of sleep and wake on oligodendrocytes and their precursors.

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.

Auditory stimulation during REM sleep modulates REM electrophysiology and cognitive performance.

REM sleep is critical for memory, emotion, and cognition. Manipulating brain activity during REM could improve our understanding of its function and benefits. Earlier studies have suggested that auditory stimulation in REM might modulate REM time and reduce rapid eye movement density. Building on this, we studied the cognitive effects and electroencephalographic responses related to such stimulation. We used acoustic stimulation locked to eye movements during REM and compared two overnight conditions (stimulation and no-stimulation). We evaluated the impact of this stimulation on REM sleep duration and electrophysiology, as well as two REM-sensitive memory tasks: visual discrimination and mirror tracing. Our results show that this auditory stimulation in REM decreases the rapid eye movements that characterize REM sleep and improves performance on the visual task but is detrimental to the mirror tracing task. We also observed increased beta-band activity and decreased theta-band activity following stimulation. Interestingly, these spectral changes were associated with changes in behavioural performance. These results show that acoustic stimulation can modulate REM sleep and suggest that different memory processes underpin its divergent impacts on cognitive performance.

Adolescent chronic sleep restriction promotes alcohol drinking in adulthood: evidence from epidemiological and preclinical data.

Epidemiological investigations have indicated that insufficient sleep is prevalent among adolescents, posing a globally underestimated health risk. Sleep fragmentation and sleep loss during adolescence have been linked to concurrent emotional dysregulation and an increase in impulsive, risk-taking behaviors, including a higher likelihood of substance abuse. Among the most widely used substances, alcohol stands as the primary risk factor for deaths and disability among individuals aged 15-49 worldwide. While the association between sleep loss and alcohol consumption during adolescence is well documented, the extent to which prior exposure to sleep loss in adolescence contributes to heightened alcohol use later in adulthood remains less clearly delineated. Here, we analyzed longitudinal epidemiological data spanning 9 years, from adolescence to adulthood, including 5497 participants of the Avon Longitudinal Study of Parents And Children cohort. Sleep and alcohol measures collected from interviews and questionnaires at 15 and 24 years of age were analyzed with multivariable linear regression and a cross-lagged autoregressive path model. Additionally, we employed a controlled preclinical experimental setting to investigate the causal relationship underlying the associations found in the human study and to assess comorbid behavioral alterations. Preclinical data were collected by sleep restricting Marchigian Sardinian alcohol preferring rats (msP, n=40) during adolescence and measuring voluntary alcohol drinking concurrently and in adulthood. Polysomnography was used to validate the efficacy of the sleep restriction procedure. Behavioral tests were used to assess anxiety, risky behavior, and despair. In humans, after adjusting for covariates, we found a cross-sectional association between all sleep parameters and alcohol consumption at 15 years of age but not at 24 years. Notably, alcohol consumption (Alcohol Use Disorder Identification Test for Consumption) at 24 years was predicted by insufficient sleep at 15 years whilst alcohol drinking at 15 years could not predict sleep problems at 24. In msP rats, adolescent chronic sleep restriction escalated alcohol consumption and led to increased propensity for risk-taking behavior in adolescence and adulthood. Our findings demonstrate that adolescent insufficient sleep causally contributes to higher adult alcohol consumption, potentially by promoting risky behavior.

Sleep/wake dependent changes in cortical glucose concentrations.

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 sleep, raising the question whether glucose levels reflect behavioral state and sleep/wake history. Here chronic (2-3 days) electroencephalographic 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 h of sleep deprivation. [Gluc] progressively increased during non rapid eye movement sleep and declined during rapid eye movement sleep, while during wake an early decline in [gluc] was followed by an increase 8-15 min 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 h of the night relative to the first 3-4 h. 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.

Probiotics Supplementation Attenuates Inflammation and Oxidative Stress Induced by Chronic Sleep Restriction.

Background: Insufficient sleep is a serious public health problem in modern society. It leads to increased risk of chronic diseases, and it has been frequently associated with cellular oxidative damage and widespread low-grade inflammation. Probiotics have been attracting increasing interest recently for their antioxidant and anti-inflammatory properties. Here, we tested the ability of probiotics to contrast oxidative stress and inflammation induced by sleep loss. Methods: We administered a multi-strain probiotic formulation (SLAB51) or water to normal sleeping mice and to mice exposed to 7 days of chronic sleep restriction (CSR). We quantified protein, lipid, and DNA oxidation as well as levels of gut-brain axis hormones and pro and anti-inflammatory cytokines in the brain and plasma. Furthermore, we carried out an evaluation of microglia morphology and density in the mouse cerebral cortex. Results: We found that CSR induced oxidative stress and inflammation and altered gut-brain axis hormones. SLAB51 oral administration boosted the antioxidant capacity of the brain, thus limiting the oxidative damage provoked by loss of sleep. Moreover, it positively regulated gut-brain axis hormones and reduced peripheral and brain inflammation induced by CSR. Conclusions: Probiotic supplementation can be a possible strategy to counteract oxidative stress and inflammation promoted by sleep loss.

Adolescent sleep and the foundations of prefrontal cortical development and dysfunction.

Modern life poses many threats to good-quality sleep, challenging brain health across the lifespan. Curtailed or fragmented sleep may be particularly damaging during adolescence, when sleep disruption by delayed chronotypes and societal pressures coincides with our brains preparing for adult life via intense refinement of neural connectivity. These vulnerabilities converge on the prefrontal cortex, one of the last brain regions to mature and a central hub of the limbic-cortical circuits underpinning decision-making, reward processing, social interactions and emotion. Even subtle disruption of prefrontal cortical development during adolescence may therefore have enduring impact. In this review, we integrate synaptic and circuit mechanisms, glial biology, sleep neurophysiology and epidemiology, to frame a hypothesis highlighting the implications of adolescent sleep disruption for the neural circuitry of the prefrontal cortex. Convergent evidence underscores the importance of acknowledging, quantifying and optimizing adolescent sleep's contributions to normative brain development and to lifelong mental health.

Ultrastructural effects of sleep and wake on the parallel fiber synapses of the cerebellum.

Multiple evidence in rodents shows that the strength of excitatory synapses in the cerebral cortex and hippocampus is greater after wake than after sleep. The widespread synaptic weakening afforded by sleep is believed to keep the cost of synaptic activity under control, promote memory consolidation, and prevent synaptic saturation, thus preserving the brain's ability to learn day after day. The cerebellum is highly plastic and the Purkinje cells, the sole output neurons of the cerebellar cortex, are endowed with a staggering number of excitatory parallel fiber synapses. However, whether these synapses are affected by sleep and wake is unknown. Here, we used serial block face scanning electron microscopy to obtain the full 3D reconstruction of more than 7000 spines and their parallel fiber synapses in the mouse posterior vermis. This analysis was done in mice whose cortical and hippocampal synapses were previously measured, revealing that average synaptic size was lower after sleep compared to wake with no major changes in synapse number. Here, instead, we find that while the average size of parallel fiber synapses does not change, the number of branched synapses is reduced in half after sleep compared to after wake, corresponding to ~16% of all spines after wake and ~8% after sleep. Branched synapses are harbored by two or more spines sharing the same neck and, as also shown here, are almost always contacted by different parallel fibers. These findings suggest that during wake, coincidences of firing over parallel fibers may translate into the formation of synapses converging on the same branched spine, which may be especially effective in driving Purkinje cells to fire. By contrast, sleep may promote the off-line pruning of branched synapses that were formed due to spurious coincidences.

Diagnostic difficulties with central nervous system actinomycosis.

When faced with expanding brain lesions of unknown origin showing a ring-shaped enhancement on post-contrast imaging, we use definite criteria to direct further investigation and distinguish among a number of possible diagnostic hypotheses. However, a correct diagnosis may be difficult in some cases, especially when dealing with less frequent conditions. This is the case of actinomycosis, a highly treatable but insidious infection for which nowadays there may be a low level of attention. Brain localization is associated with a significant morbidity and may represent a true diagnostic pitfall. Here we report the difficulties encountered with a case of central nervous system actinomycosis.

Synaptic plasticity modulates autonomous transitions between waking and sleep states: insights from a Morris-Lecar model.

The transitions between waking and sleep states are characterized by considerable changes in neuronal firing. During waking, neurons fire tonically at irregular intervals and a desynchronized activity is observed at the electroencephalogram. This activity becomes synchronized with slow wave sleep onset when neurons start to oscillate between periods of firing (up-states) and periods of silence (down-states). Recently, it has been proposed that the connections between neurons undergo potentiation during waking, whereas they weaken during slow wave sleep. Here, we propose a dynamical model to describe basic features of the autonomous transitions between such states. We consider a network of coupled neurons in which the strength of the interactions is modulated by synaptic long term potentiation and depression, according to the spike time-dependent plasticity rule (STDP). The model shows that the enhancement of synaptic strength between neurons occurring in waking increases the propensity of the network to synchronize and, conversely, desynchronization appears when the strength of the connections become weaker. Both transitions appear spontaneously, but the transition from sleep to waking required a slight modification of the STDP rule with the introduction of a mechanism which becomes active during sleep and changes the proportion between potentiation and depression in accordance with biological data. At the neuron level, transitions from desynchronization to synchronization and vice versa can be described as a bifurcation between two different states, whose dynamical regime is modulated by synaptic strengths, thus suggesting that transition from a state to an another can be determined by quantitative differences between potentiation and depression.

Sleep quality relates to emotional reactivity via intracortical myelination.

A good quality and amount of sleep are fundamental to preserve cognition and affect. New evidence also indicates that poor sleep is detrimental to brain myelination. In this study, we test the hypothesis that sleep quality and/or quantity relate to variability in cognitive and emotional function via the mediating effect of interindividual differences in proxy neuroimaging measures of white matter integrity and intracortical myelination. By employing a demographically and neuropsychologically well-characterized sample of healthy people drawn from the Human Connectome Project (n = 974), we found that quality and amount of sleep were only marginally linked to cognitive performance. In contrast, poor quality and short sleep increased negative affect (i.e. anger, fear, and perceived stress) and reduced life satisfaction and positive emotionality. At the brain level, poorer sleep quality and shorter sleep duration related to lower intracortical myelin in the mid-posterior cingulate cortex (p = 0.038), middle temporal cortex (p = 0.024), and anterior orbitofrontal cortex (OFC, p = 0.034) but did not significantly affect different measures of white matter integrity. Finally, lower intracortical myelin in the OFC mediated the association between poor sleep quality and negative emotionality (p < 0.05). We conclude that intracortical myelination is an important mediator of the negative consequences of poor sleep on affective behavior.