According to the synaptic homeostasis hypothesis (SHY), sleep serves to renormalize synaptic connections that have been potentiated during the prior wake phase due to ongoing encoding of information. SHY focuses on glutamatergic synaptic strength and has been supported by numerous studies examining synaptic structure and function in neocortical and hippocampal networks. However, it is unknown whether synaptic down-regulation during sleep occurs in the hypothalamus, i.e., a pivotal center of homeostatic regulation of bodily functions including sleep itself. We show that sleep, in parallel with the synaptic down-regulation in neocortical networks, down-regulates the levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the hypothalamus of rats. Most robust decreases after sleep were observed at both sites for AMPARs containing the GluA1 subunit. Comparing the effects of selective rapid eye movement (REM) sleep and total sleep deprivation, we moreover provide experimental evidence that slow-wave sleep (SWS) is the driving force of the down-regulation of AMPARs in hypothalamus and neocortex, with no additional contributions of REM sleep or the circadian rhythm. SWS-dependent synaptic down-regulation was not linked to EEG slow-wave activity. However, spindle density during SWS predicted relatively increased GluA1 subunit levels in hypothalamic synapses, which is consistent with the role of spindles in the consolidation of memory. Our findings identify SWS as the main driver of the renormalization of synaptic strength during sleep and suggest that SWS-dependent synaptic renormalization is also implicated in homeostatic control processes in the hypothalamus.

Melatonin (MLT) is an important circadian signal for sleep regulation, but the neural circuitries underlying the sleep-promoting effects of MLT are poorly understood. The paraventricular thalamus (PVT) is a critical thalamic area for wakefulness control and expresses MLT receptors, raising a possibility that PVT neurons may mediate the sleep-promoting effects of MLT. Here, we found that MLT receptors were densely expressed on PVT neurons and exhibited circadian-dependent variations in C3H/HeJ mice. Application of exogenous MLT decreased the excitability of PVT neurons, resulting in hyperpolarization of membrane potential and reduction of action potential firing. MLT also inhibited the spontaneous activity of PVT neurons at both population and single-neuron levels in freely behaving mice. Furthermore, pharmacological manipulations revealed that local infusion of exogeneous MLT into the PVT promoted non-rapid eye movement (NREM) sleep and increased NREM sleep duration, whereas MLT receptor antagonists decreased NREM sleep. Moreover, we found that selectively knocking down endogenous MLT receptors in the PVT decreased NREM sleep and correspondingly increased wakefulness, with particular changes shortly after the onset of the dark or light phase. Taken together, these results demonstrate that PVT is an important target of MLT for promoting NREM sleep.

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.

BACKGROUND: Depression and sleep disturbances are commonly seen non-motor symptoms in patients with Parkinson\'s disease (PD). This study used polysomnography to examine the relationship between mild-moderate depression in PD and sleep characteristics, particularly slow wave activities (SWA).
METHODS: 59 PD patients were split into two groups: nd-PD (n = 27) (patients with PD without depression) and d-PD (n = 32) (patients with PD with mild-moderate depression). Their clinical features, polysomnography parameters, and demographics were evaluated. Early and late sleep SWA spectrum densities and overnight SWA decline in different brain regions were particularly analyzed.
RESULTS: Non-rapid eye movement 3 (N3) sleep duration and percentage were greater in the d-PD group. N3 percentage was linked to depression (p = 0.014). During late sleep, higher SWA (0.5-4Hz) in the frontal and central regions, higher low-SWA (0.5-2Hz) in the whole brain, central and occipital regions, and higher high-SWA (2-4Hz) in the frontal region was observed in the d-PD group. During early sleep, there was also higher low-SWA (0.5-2Hz) in the occipital region. Patients in d-PD group exhibited reduced overnight high-SWA (2-4Hz) decline (Δhigh-SWA) in the whole brain and occipital regions. Δhigh-SWA(2-4Hz) in the occipital region were associated with depression (p = 0.049).
CONCLUSIONS: PD patients with mild-moderate depression have impaired slow wave sleep, exhibiting as increased N3 sleep, SWA, and reduced overnight SWA decline. This implies that synaptic strength reduction during sleep and impaired synaptic homeostasis regulation may be associated with depression in PD. Reduced overnight high-SWA decline in the occipital region may serve as a novel electrophysiological biomarker for indicating depression in PD.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

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.