Sleep debt accumulates during wakefulness, leading to increased slow wave activity (SWA) during sleep, an encephalographic marker for sleep need. The use-dependent demands of prior wakefulness increase sleep SWA locally. However, the circuitry and molecular identity of this \"local sleep\" remain unclear. Using pharmacology and optogenetic perturbations together with transcriptomics, we find that cortical brain-derived neurotrophic factor (BDNF) regulates SWA via the activation of tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We map BDNF/TrkB-induced sleep SWA to layer 5 (L5) pyramidal neurons of the cortex, independent of neuronal firing per se. Using mathematical modeling, we here propose a model of how BDNF\'s effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Proteomic analysis further reveals that TrkB activation enriches ubiquitin and proteasome subunits. Together, our study reveals that local SWA control is mediated by BDNF-TrkB-CREB signaling in L5 excitatory cortical neurons.

Slow-wave sleep (SWS), characterized by slow oscillations (SOs, <1Hz) of alternating active and silent states in the thalamocortical network, is a primary brain state during Non-Rapid Eye Movement (NREM) sleep. In the last two decades, the traditional view of SWS as a global and uniform whole-brain state has been challenged by a growing body of evidence indicating that SO can be local and can coexist with wake-like activity. However, the mechanisms by which global and local SOs arise from micro-scale neuronal dynamics and network connectivity remain poorly understood. We developed a multi-scale, biophysically realistic human whole-brain thalamocortical network model capable of transitioning between the awake state and SWS, and we investigated the role of connectivity in the spatio-temporal dynamics of sleep SO. We found that the overall strength and a relative balance between long and short-range synaptic connections determined the network state. Importantly, for a range of synaptic strengths, the model demonstrated complex mixed SO states, where periods of synchronized global slow-wave activity were intermittent with the periods of asynchronous local slow-waves. An increase in the overall synaptic strength led to synchronized global SO, while a decrease in synaptic connectivity produced only local slow-waves that would not propagate beyond local areas. These results were compared to human data to validate probable models of biophysically realistic SO. The model producing mixed states provided the best match to the spatial coherence profile and the functional connectivity estimated from human subjects. These findings shed light on how the spatio-temporal properties of SO emerge from local and global cortical connectivity and provide a framework for further exploring the mechanisms and functions of SWS in health and disease.

An increase in ambient temperature leads to an increase in sleep. However, the mechanisms behind this phenomenon remain unknown. This study aimed to investigate the role of microglia in the increase of sleep caused by high ambient temperature. We confirmed that at 35 °C, slow-wave sleep was significantly increased relative to those observed at 25 °C. Notably, this effect was abolished upon treatment with PLX3397, a CSF1R inhibitor that can deplete microglia, while sleep amount at 25 °C was unaffected. These observations suggest that microglia play a pivotal role in modulating the homeostatic regulation of sleep in response to the fluctuations in ambient temperature.

OBJECTIVE: To compare the effect of stage 3 fragmentation and the paradoxical phase of night sleep on melatonin (MT) secretion, and to evaluate the effects of changes in autonomic balance and activation reactions that occur in the orthodox and paradoxical phases of sleep.
METHODS: Fifteen healthy men participated in three sessions: with stage 3 fragmentation, with fragmentation of paradoxical sleep, and in a control experiment in which sleep was not disturbed. In each experiment, 7 saliva samples were collected in the evening, at night and in the morning and the MT content was determined. Heart rate variability was analyzed using an electrocardiogram and autonomic balance was assessed.
RESULTS: Sleep fragmentation was accompanied by activation reactions and reduced the duration of stage 3 and paradoxical phase sleep by 50% and 51% in the corresponding sessions. Fragmentation of paradoxical sleep also led to an increase in the duration of night wakefulness. Sleep disturbances caused an increase in MT secretion in the second half of the night and in the morning, especially pronounced in sessions with fragmentation of paradoxical sleep, in which upon awakening MT was 1.8 times higher than in the control. Stage 3 fragmentation was accompanied by increased sympathetic activation, while fragmentation of paradoxical sleep did not cause autonomic shifts. The subjects were divided into 2 clusters: with high and low MT in night and morning saliva samples. In all sessions, subjects with high MT had 1.7-2 times longer duration of night wakefulness; in sessions with fragmentation, they had significantly more activations in the paradoxical phase of sleep.
CONCLUSIONS: Night sleep disturbances cause an increase in MT secretion, especially pronounced during the fragmentation of the paradoxical phase. An increase in MT levels does not depend on changes in autonomic balance and is apparently associated with activation of the serotonergic system, which accompanies disturbances in the depth and continuity of sleep.
UNASSIGNED: Сравнить влияние на секрецию мелатонина (МТ) фрагментации 3-й стадии и парадоксальной фазы ночного сна, а также оценить эффекты изменений вегетативного баланса и реакций активации, возникающих в ортодоксальной и парадоксальной фазах сна.
UNASSIGNED: Пятнадцать здоровых мужчин участвовали в трех экспериментах: с фрагментацией 3-й стадии, с фрагментацией парадоксального сна, и в контрольном, в котором сон не нарушался. В каждом эксперименте вечером, ночью и утром собирали 7 проб слюны и определяли содержание МТ. По электрокардиограмме анализировали вариабельность сердечного ритма и оценивали вегетативный баланс.
UNASSIGNED: Фрагментация сна сопровождалась реакциями активации и снизила продолжительность 3-й стадии и парадоксальной фазы сна на 50 и 51% в соответствующих экспериментах. Фрагментация парадоксального сна привела также к увеличению продолжительности ночного бодрствования. Нарушения сна вызывали рост секреции МТ во второй половине ночи и утром, особенно выраженный в экспериментах с фрагментацией парадоксального сна, в которых при пробуждении МТ был в 1,8 раза выше, чем в контроле. Фрагментация 3-й стадии сопровождалась усилением симпатической активации, тогда как фрагментация парадоксального сна не вызывала вегетативных сдвигов. Испытуемые разделились на 2 кластера: с высоким и низким МТ в ночных и утренних пробах слюны. Испытуемые с высоким МТ имели во всех экспериментах в 1,7—2 раза большую продолжительность ночного бодрствования, в экспериментах с фрагментацией у них было значительно больше активаций в парадоксальной фазе сна.
UNASSIGNED: Нарушения ночного сна вызывают рост секреции МТ, особенно выраженный при фрагментации парадоксальной фазы. Повышение уровня МТ не зависит от изменений вегетативного баланса и, по-видимому, связано с активацией серотонинергической системы, сопровождающей нарушение глубины и непрерывности сна.

Sleep spindles are one of the prominent EEG oscillatory rhythms of non-rapid eye movement sleep. In the memory consolidation, these oscillations have an important role in the processes of long-term potentiation and synaptic plasticity. Moreover, the activity (spindle density and/or sigma power) of spindles has a linear association with learning performance in different paradigms. According to the experimental observations, the sleep spindle activity can be improved by closed loop acoustic stimulations (CLAS) which eventually improve memory performance. To examine the effects of CLAS on spindles, we propose a biophysical thalamocortical model for slow oscillations (SOs) and sleep spindles. In addition, closed loop stimulation protocols are applied on a thalamic network. Our model results show that the power of spindles is increased when stimulation cues are applied at the commencing of an SO Down-to-Up-state transition, but that activity gradually decreases when cues are applied with an increased time delay from this SO phase. Conversely, stimulation is not effective when cues are applied during the transition of an Up-to-Down-state. Furthermore, our model suggests that a strong inhibitory input from the reticular (RE) layer to the thalamocortical (TC) layer in the thalamic network shifts leads to an emergence of spindle activity at the Up-to-Down-state transition (rather than at Down-to-Up-state transition), and the spindle frequency is also reduced (8-11 Hz) by thalamic inhibition.

OBJECTIVE: Encephalitis with anti-N-methyl-d-aspartate receptor antibodies (anti-NMDARe) is a rare disorder characterized by cognitive impairment, psychosis, seizures, and abnormal movements. Abnormal behaviors during REM sleep have not been described in anti-NMDARe.
METHODS: Patients were monitored by video-polysomnography on a first night followed by multiple sleep latency tests and 18 hours of bed rest.
RESULTS: Two patients with anti-NMDARe developed during the acute and postacute phase parasomnias including REM sleep behavior disorder and continuous finalistic quiet gesturing during a mixed N2/R sleep. The parasomnia disorder was improved by gabapentin and clonazepam.
CONCLUSIONS: Video-polysomnography avoids misdiagnosing these parasomnia behaviors for seizure or movement disorders and allows adequate treatment.

Idling brain activity has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the idling brain can create novel ideas. Here, we show that cortical offline activity is both necessary and sufficient for building unlearned inferential knowledge from previously acquired information. In a transitive inference paradigm, male C57BL/6J mice gained the inference 1 day after, but not shortly after, complete training. Inhibiting the neuronal computations in the anterior cingulate cortex (ACC) during post-learning either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep, but not wakefulness, disrupted the inference without affecting the learned knowledge. In vivo Ca2+ imaging suggests that NREM sleep organizes the scattered learned knowledge in a complete hierarchy, while REM sleep computes the inferential information from the organized hierarchy. Furthermore, after insufficient learning, artificial activation of medial entorhinal cortex-ACC dialog during only REM sleep created inferential knowledge. Collectively, our study provides a mechanistic insight on NREM and REM coordination in weaving inferential knowledge, thus highlighting the power of idling brain in cognitive flexibility.

Memory consolidation relies in part on the reactivation of previous experiences during sleep. The precise interplay of sleep-related oscillations (slow oscillations, spindles and ripples) is thought to coordinate the information flow between relevant brain areas, with ripples mediating memory reactivation. However, in humans empirical evidence for a role of ripples in memory reactivation is lacking. Here, we investigated the relevance of sleep oscillations and specifically ripples for memory reactivation during human sleep using targeted memory reactivation. Intracranial electrophysiology in epilepsy patients and scalp EEG in healthy participants revealed that elevated levels of slow oscillation - spindle activity coincided with the read-out of experimentally induced memory reactivation. Importantly, spindle-locked ripples recorded intracranially from the medial temporal lobe were found to be correlated with the identification of memory reactivation during non-rapid eye movement sleep. Our findings establish ripples as key-oscillation for sleep-related memory reactivation in humans and emphasize the importance of the coordinated interplay of the cardinal sleep oscillations.

BACKGROUND: A compelling hypothesis about attention-deficit/hyperactivity disorder (ADHD) etiopathogenesis is that the ADHD phenotype reflects a delay in cortical maturation. Slow-wave activity (SWA) of non-rapid eye movement (NREM) sleep electroencephalogram (EEG) is an electrophysiological index of sleep intensity reflecting cortical maturation. Available data on ADHD and SWA are conflicting, and developmental differences, or the effect of pharmacological treatment, are relatively unknown.
METHODS: We examined, in samples (Mage = 16.4, SD = 1.2), of ever-medicated adolescents at risk for ADHD (n = 18; 72% boys), medication-naïve adolescents at risk for ADHD (n = 15, 67% boys), and adolescents not at risk for ADHD (n = 31, 61% boys) matched for chronological age and controlling for non-ADHD pharmacotherapy, whether ADHD pharmacotherapy modulates the association between NREM SWA and ADHD risk in home sleep.
RESULTS: Findings indicated medication-naïve adolescents at risk for ADHD exhibited greater first sleep cycle and entire night NREM SWA than both ever-medicated adolescents at risk for ADHD and adolescents not at risk for ADHD and no difference between ever-medicated, at-risk adolescents, and not at-risk adolescents.
CONCLUSIONS: Results support atypical cortical maturation in medication-naïve adolescents at risk for ADHD that appears to be normalized by ADHD pharmacotherapy in ever-medicated adolescents at risk for ADHD. Greater NREM SWA may reflect a compensatory mechanism in middle-later adolescents at risk for ADHD that normalizes an earlier occurring developmental delay.

Memories benefit from sleep1, and the reactivation and replay of waking experiences during hippocampal sharp-wave ripples (SWRs) are considered to be crucial for this process2. However, little is known about how these patterns are impacted by sleep loss. Here we recorded CA1 neuronal activity over 12 h in rats across maze exploration, sleep and sleep deprivation, followed by recovery sleep. We found that SWRs showed sustained or higher rates during sleep deprivation but with lower power and higher frequency ripples. Pyramidal cells exhibited sustained firing during sleep deprivation and reduced firing during sleep, yet their firing rates were comparable during SWRs regardless of sleep state. Despite the robust firing and abundance of SWRs during sleep deprivation, we found that the reactivation and replay of neuronal firing patterns was diminished during these periods and, in some cases, completely abolished compared to ad libitum sleep. Reactivation partially rebounded after recovery sleep but failed to reach the levels found in natural sleep. These results delineate the adverse consequences of sleep loss on hippocampal function at the network level and reveal a dissociation between the many SWRs elicited during sleep deprivation and the few reactivations and replays that occur during these events.