Biology subjects

Vyazovskiy, V. V.

Publications and source records attributed to Vyazovskiy, V. V..

At least 19 recordsLinked to original sources

bioRxiv2026

Enhancing cortical electrophysiological signatures of sleep overrides ER stress responses in sleep-deprived mice

Sleep deprivation (SD) triggers characteristic changes in the cortical electroencephalogram (EEG) during waking and sleep, as well as upregulating molecular signatures of neuronal activity, synaptic plasticity, and endoplasmic reticulum (ER) stress. This includes the induction of the unfolded protein response (UPR), the primary marker and adaptive mechanism of ER stress. Yet how cortical neuronal activity during SD contributes to the induction of these molecular signatures remains unknown. Here we investigate whether manipulating cortical activity during SD with a physiological stimulation paradigm (flickering light stimulation, FLS) affects the induction of the UPR. As expected, SD alone upregulated activity-dependent and UPR-related genes in cortex and led to increased EEG slow-wave activity (SWA) during subsequent NREM sleep, an electrophysiological signature of sleep need. Delivering FLS during SD, however, prevented the upregulation of activity- and UPR-related genes while inducing an additional increase in SWA during subsequent sleep. Further analysis of neuronal firing revealed that FLS induced brief neuronal silent (OFF) periods in awake animals during stimulation, thereby shifting cortical activity towards a brain state resembling sleep. These findings suggest that physiological manipulation of cortical activity during waking is sufficient to dissociate molecular signatures of ER stress from electrophysiological markers of sleep pressure. We propose that global sleep wake history and cortical network dynamics differentially regulate activity-dependent transcription and the accumulation of sleep pressure.

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bioRxiv2026

Coordinated Brain-Heart Dynamics During Human NREM Sleep

Communication between the brain and cardiovascular system is increasingly recognized as a fundamental determinant of health, yet the mechanisms coordinating neural and cardiac rhythms remain poorly understood. Sleep provides a unique physiological state for investigating neurovisceral integration because cortical slow oscillations (SOs), thalamocortical sleep spindles, and autonomic activity undergo profound reorganization during non-rapid eye movement (NREM) sleep. We analyzed overnight high-density electroencephalography and electrocardiography recordings from 30 healthy adults and quantified interactions among SOs, sleep spindles, cardiac R-peaks, heart rate variability (HRV), spectral slope, and Lempel-Ziv complexity. To assess integrated brain-heart coordination, we developed a Joint Phase-Amplitude Coupling (JPAC) metric that quantifies the corelation between SO phase-dependent modulation of spindle amplitude and cardiac timing. SO-spindle coupling showed the expected fronto-central distribution but was not significantly related to autonomic or cortical state markers. In contrast, SO-R-peak coupling and JPAC systematically tracked physiological state. Stronger JPAC was associated with higher high-frequency HRV, steeper spectral slopes, and lower neural complexity, indicating enhanced coupling during synchronized, parasympathetically dominated NREM sleep. These findings demonstrate coordinated organization of cortical, thalamocortical, and cardiac rhythms within a common oscillatory framework and identify NREM sleep as a state and potential treatment target of large-scale neurovisceral integration.

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bioRxiv2026

Sleep immediately after noise overexposure worsens tinnitus in mice

Subjective tinnitus is the most common auditory phantom perception in the absence of an acoustic stimulus yet there is no cure nor widely effective treatment to date. Previously, we suggested that sleep may contribute to tinnitus development after a triggering event, such as noise overexposure (NOE). Here, we investigated the effect of natural sleep on tinnitus development following NOE in mice. One group of mice was kept awake for 6 hours immediately after NOE, whereas a control group could sleep ad libitum. Tinnitus and hearing loss were assessed before and after NOE by determining gap prepulse inhibition of the acoustic startle reflex (GPIAS) and by recording auditory brainstem responses (ABRs). Only mice that were allowed to sleep in the first six hours after NOE developed a significant change in the GPIAS ratio one week after NOE, indicative of tinnitus. Habituation to the startle stimulus was largely similar between both groups, except that at eight weeks after NOE, when GPIAS ratio had returned to baseline levels in both groups, the sleep deprived group showed less habituation to the startle stimulus. Notably, animals in neither group showed significantly elevated ABR thresholds after NOE, yet the control group showed signs of elevated evoked activity in the auditory brainstem one week after NOE. These findings demonstrate that sleep early after noise overexposure may amplify subsequent tinnitus development. Our results suggest that sleep represents a temporal window that may be harnessed for potential modulation or mitigation of noise-induced hearing loss and tinnitus-related impairments.

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bioRxiv2026

Opposing intrinsic and synaptic plasticity mechanisms stabilize altered cortical networks during sleep deprivation

Sleep deprivation alters brain activity and impairs performance, yet many aspects of behaviour are preserved in this state. In the cortex for example, sleep deprivation increases neuronal firing rates and low-frequency oscillatory activity, but cortical circuits continue to process information. Recent work has implicated synaptic inhibition in these changes, with sleep deprivation causing cortical GABAA receptor (GABAAR) signalling to become depolarizing due to changes in chloride gradients that determine the GABAAR reversal potential (EGABAAR). The impact in the intact brain remains unclear, however, as both the degree and effects of EGABAAR changes depend on network activity and intrinsic properties of neurons. To address this, we perform in vivo gramicidin recordings from cortical pyramidal neurons in sleep-deprived mice. We reveal that synaptic EGABAAR is depolarised to values sufficient to support bona fide excitatory GABAAR signalling, through combined network-dependent and cell-autonomous effects. In the face of this depolarizing drive, cortical neurons engage spike threshold adaptation mechanisms that limit their excitability. These opposing effects stabilise activity in simulations of sleep-deprived cortical networks and reproduce the increased firing rates and low-frequency oscillatory activity. This interplay between intrinsic and synaptic mechanisms may help maintain network stability during sleep deprivation, while reducing flexibility for subsequent adaptation.

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bioRxiv2026

Is torpor a quiescent state? Periodic motility and transient brain activation during daily torpor in Djungarian hamsters

Torpor is a hypometabolic state employed by many mammalian and non-mammalian species to cope with harsh environments. When exposed to a short photoperiod, Djungarian hamsters (Phodopus sungorus) enter daily torpor with body temperatures dropping to as low as 15{degrees}C. Despite the widely-held notion that torpor is a form of deep sleep, torpid animals are not completely inactive but exhibit occasional movements reflected in an increase in EMG tone. Little is known about these EMG events during torpor and whether they have a functional role during the torpid state. We here analysed EEG, EMG, and brain temperature data from Djungarian hamsters, and used an automatic detection algorithm to identify periods of EMG activation during spontaneous daily torpor. The hamsters exhibited regular periods of motility that were invariably initiated during a decline in brain temperature and were followed by a brain temperature increase. The frequency of EMG events exhibited a negative correlation with brain temperature, such that lower brain temperature was associated with a higher frequency of EMG events. In addition, EMG events were associated with a pronounced increase in EEG power, especially between 9.5-15.5 Hz, which often started with an EEG pattern similar to an evoked potential preceding the increase in the EMG activity. On the contrary, micro-arousals during normothermic NREM sleep were associated with a decrease in EEG power, a decrease in brain temperature and were of shorter duration than torpor EMG events, indicating that the two phenomena may serve different purposes. We speculate that periodic motility associated with increased brain activity during torpor may play a role in thermoregulation, and help retain vigilance to potentially mitigate predation risk during this hypometabolic state.

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bioRxiv2025

Bidirectional modulation of sleep and wakefulness via prefrontal cortical chemogenetics

The cortex is now recognised as a key regulator of sleep. It remains unclear, however, how sleep is affected by changes in cortical activity over different spatial scales. For instance, sleep states are associated with global changes in activity across cortex, but sleep pressure is associated with local variations in cortical activity. Here we use chemogenetic manipulations of a single neuronal population to determine how sleep reflects the spatial scale of cortical activity. Global inhibition of Rbp4-Cre+ neurons increases sleep, but also produces abnormal brief-awakenings and reduces electroencephalogram slow-wave activity, a marker of sleep intensity. In contrast, local inhibition/excitation of Rbp4-Cre+ neurons in the prefrontal but not occipital cortex increases sleep/wake, respectively, whilst preserving normal sleep architecture and electrophysiological features. We conclude that globally altering cortical activity may induce unphysiological sleep due to conflicting sleep-regulatory signals, while locally modulating prefrontal cortex affords bidirectional sleep regulation that leaves naturalistic features intact.

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bioRxiv2025

Increased slow wave activity in response to sleep deprivation is highest immediately after micro-arousals

Non-rapid eye movement (NREM) sleep is not uniform but characterized by brief intrusions of wake-like brain activity, known as micro-arousals or brief awakenings. Although micro-arousals are an inherent feature of both human and animal sleep, knowledge about the neural correlates of micro-arousals across the cortical column is sparse. We here developed an algorithm for automatic detection of micro-arousals based on EMG activity and used it to explore how micro-arousals modulate laminar neural activity in the motor cortex, and how this relationship is affected by sleep pressure in mice. Our analysis showed that micro-arousals were associated with a general suppression of local field potential (LFP) power across the cortical column. Slow wave activity (SWA, 1-4 Hz) immediately after micro-arousals was tightly correlated with sleep pressure and even surpassed average SWA levels during NREM sleep in sleep deprived animals. In addition, analysis of single-channel firing showed that some channels exhibited increased activity immediately prior to micro-arousals, while others exhibited decreased activity. This study provides new insights into the neural mechanisms underlying micro-arousals and identifies a new link between micro-arousals and sleep homeostasis.

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bioRxiv2024

Cortical layer 6b mediates state-dependent changes in brain activity and effects of orexin on waking and sleep

One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least-studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally "silenced", during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-silenced mice showed a slowing of theta frequency (6-9 Hz) during wake and REM sleep, and a marked reduction of total EEG power, especially in NREM sleep. The infusion of orexin A increased wakefulness in both genotypes, but subsequent levels of EEG slow-wave activity during NREM sleep were lower in L6b-silenced animals in the occipital derivation. In summary, these results demonstrate a role for cortical L6b in state-dependent brain oscillations and in the response to orexinergic neurotransmission. Our findings provide new insights in functions of L6b neurons and could inform the understanding of abnormal regulation of brain states in neurodevelopmental and psychiatric disorders.

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bioRxiv2024

Cortical evoked activity is modulated by the sleep state in a ferret model of tinnitus. A case study.

Subjective tinnitus is a phantom auditory perception in the absence of an actual acoustic stimulus. It affects 15% of the global population and can be associated with disturbed sleep, poor mental health and quality of life. To date, there is no effective treatment for tinnitus. We used adult ferrets exposed to mild noise trauma as an animal model of tinnitus. We assessed the phantom percept using two operant paradigms sensitive to tinnitus, silent gap detection and silence detection, before and up to six months after the mild acoustic trauma. The integrity of the auditory brainstem was assessed over the same period using auditory brainstem response recordings. Following noise overexposure, ferrets developed lasting, frequency-specific impairments in operant behaviour and evoked brainstem activity. To explore the interaction between sleep and tinnitus, in addition to tracking the behavioural markers of noise-induced tinnitus and hearing impairment after noise overexposure, we evaluated sleep-wake architecture and spontaneous and auditory-evoked EEG activity across vigilance states. Behavioural performance and auditory-evoked activity measurements after noise overexposure suggested distinct degrees of tinnitus and hearing impairment between individuals. Animals that developed signs of tinnitus consistently developed sleep impairments, suggesting a link between the emergence of noise-induced tinnitus and sleep disruption. However, neural markers of tinnitus were reduced during sleep, suggesting that sleep may transiently mitigate tinnitus. These results reveal the importance of sleep-wake states in tinnitus and suggest that understanding the neurophysiological link between sleep and tinnitus may provide a new angle for research into the causes of phantom percepts and inform future treatments.

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bioRxiv2023

Metaplasticity of cortical glutamatergic LTP by diurnal intracellular chloride dynamics

Neural plasticity varies depending on the time of day and preceding sleep-wake history. It is unclear however, how diurnal changes in cellular physiology modulate a neurons propensity to exhibit synaptic plasticity. Recently it has been shown that cortical pyramidal neurons exhibit diurnal changes in their transmembrane chloride gradients, which shift the equilibrium potential for GABAA receptors (EGABAA). Here we demonstrate that diurnal EGABAA affects membrane potential dynamics and glutamatergic long-term potentiation (LTP) elicited by high-frequency spiking activity in pyramidal neurons of mouse cortex. More depolarized EGABAA values associated with the active period facilitate LTP induction by promoting residual depolarization during synaptically-evoked spiking. Diurnal differences in LTP can be reversed by switching the EGABAA-dependent effects on membrane potential dynamics, either by direct current injection or pharmacologically altering EGABAA. These findings identify EGABAA as a metaplastic regulator of glutamatergic synaptic potentiation, which has implications for understanding synaptic plasticity during waking and sleep.

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bioRxiv2023

Oscillatory-Quality of sleep spindles: from properties to function

Sleep spindles are traditionally defined as 10-15Hz thalamo-cortical oscillations typical of NREM sleep. While substantial heterogeneity in the appearance or spatio-temporal dynamics of spindle events is well recognised, the physiological relevance of the underlying fundamental property - the oscillatory strength - has not been studied. Here we introduce a novel metric called oscillatory Quality (o-Quality), which is derived by fitting an auto-regressive model to short segments of electrophysiological signals, recorded from the cortex in mice, to identify and calculate the damping of spindle oscillations. We find that the o-Quality of spindles varies markedly across cortical layers and regions and reflects the level of synchrony within and between cortical networks. Furthermore, the o-Quality of spindles varies as a function of sleep-wake history, determines the strength of coupling between spindles and slow waves, and influences the responsiveness to sensory stimulation during sleep. Thus, the o-Quality emerges as a metric that, for the first time, directly links the spatio-temporal dynamics of sleep spindles with their functional role.

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bioRxiv2023

Deficient synaptic neurotransmission results in a persistent sleep-like cortical activity across vigilance states in mice

Growing evidence suggests that brain activity during sleep, as well as sleep regulation, are tightly linked with synaptic function and network excitability at the local and global levels. We previously reported that a mutation in synaptobrevin 2 (Vamp2) in restless (rlss) mice results in a marked increase of wakefulness and suppression of sleep, in particular REM sleep (REMS) as well as increased consolidation of sleep and wakefulness. In the current study, using finer-scale in vivo electrophysiology recordings, we report that spontaneous cortical activity in rlss mice during NREM sleep (NREMS) is characterised by an occurrence of abnormally prolonged periods of complete neuronal silence (OFF-periods), often lasting several seconds, similar to the burst suppression pattern typically seen under deep anaesthesia. Increased incidence of prolonged network OFF-periods was not specific to NREMS, but also present in REMS and wake in rlss mice. Slow-wave activity (SWA) was generally increased in rlss mice, while higher frequencies including theta-frequency activity were decreased, further resulting in diminished differences between vigilance states. The relative increase in SWA after sleep deprivation was attenuated in rlss mice, suggesting either that rlss mice experience persistently elevated sleep pressure, or, alternatively, that the intrusion of sleep-like patterns of activity into awake state diminishes the accumulation of sleep drive. We propose that deficit in global synaptic neurotransmitter release leads to state inertia, reflected in an abnormal propensity of brain networks to enter and remain in a persistent default state resembling coma or deep anaesthesia.

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bioRxiv2022

"Paradoxical wakefulness" induced by psychedelic 5-methoxy-N,N-dimethyltryptamine in mice

Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of arousal. Here, we performed chronic electrophysiological recordings from the cortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We observed an acute induction of a dissociated state of arousal, characterised by prominent sleep-like slow waves in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was markedly suppressed, similar to the effect of conventional antidepressants. We argue that the occurrence of a dissociated brain state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics -- from dream-like hallucinations to reopening of the critical period for plasticity.

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bioRxiv2022

Detection of neuronal OFF periods as low amplitude neural activity segments

During non-rapid eye movement sleep (NREM), synchronised neuronal activity is reflected in a specific neural oscillation observed in neocortical electrophysiological signals: a low frequency component characterised by depth-positive/surface-negative potentials known as slow waves, corresponding to alternating periods of high (ON period) and low (OFF period) spiking activity. Often overlooked in favour of slow waves, there is an interest in understanding how neuronal silencing during OFF periods leads to the generation of slow waves and whether this relationship changes between cortical layers. The foremost issue in detecting population OFF periods is the absence of a formal, widely adopted definition. Here, we grouped segments of high frequency neural activity containing spikes, recorded from the neocortex, on the basis of amplitude and asked whether the population of low amplitude (LA) segments displayed the expected characteristics of OFF periods. We corroborate previous studies showing that LA segments in neural activity signals are a uniquely identifiable structure with distinct characteristics from the surrounding signal that identify them as OFF periods including NREM sleep predominance and association with a local field potential (LFP) slow wave. In addition, we attribute new characteristics to these segments not previously associated with OFF periods: vigilance-state-dependent duration and duration-dependent homeostatic response. This could suggest that ON/OFF periods are currently underdefined, and their appearance is less binary than previously considered, instead representing a continuum.

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bioRxiv2022

Neuronal-spiking-based closed-loop stimulationduring cortical ON and OFF states in freely moving mice

The slow oscillation (SO) is a central neuronal dynamic during sleep and is generated by alternating periods of high and low neuronal activity (ON and OFF states). Mounting evidence causally links the SO to sleeps functions, and it has recently become possible to manipulate the SO non-invasively and phase-specifically. These developments represent promising clinical avenues, but they also highlight the importance of improving our understanding of how ON/OFF states affect incoming stimuli and what role they play in neuronal plasticity. Most studies using closed-loop stimulation rely on the electroencephalogram (EEG) and local field potential (LFP) signals, which reflect neuronal ON and OFF states only indirectly. Here we develop an online detection algorithm based on spiking activity recorded from laminar arrays in mouse motor cortex. We find that online detection of ON and OFF states reflects specific phases of spontaneous LFP SO. Our neuronal-spiking-based closed-loop procedure offers a novel opportunity for testing the functional role of SO in sleep-related restorative processes and neural plasticity.

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bioRxiv2022

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye-movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21 or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.

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bioRxiv2021

Somnotate: A robust automated sleep stage classifier that exceeds human performance and identifies ambiguous states in mice

Electrophysiological recordings from freely behaving animals are a widespread and powerful mode of investigation in sleep research. These recordings generate large amounts of data that require sleep stage annotation (polysomnography), in which the data is parcellated according to three vigilance states: awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. Manual and computational annotation methods currently ignore intermediate states because the classification features become ambiguous. However, these intermediate states contain important information regarding vigilance state dynamics. Here, we present a new classifier, "Somnotate", which produces automated annotation accuracies that exceed human expert performance on mouse electrophysiological data, is robust to errors in the training data, compatible with different recording configurations, and maintains high performance during experimental interventions. Somnotate is a probabilistic classifier based on a combination of linear discriminant analysis (LDA) with a hidden Markov model (HMM). A unique feature of Somnotate is that it quantifies and reports the certainty of its annotations, enabling the experimenter to identify ambiguous recording periods in a principled manner. We leverage this feature to identify epochs that exhibit intermediate vigilance states, revealing that many of these cluster around state transitions, whereas others correspond to failed attempts to transition. We show that the success rates of different transitions can be experimentally manipulated and explain previously observed sleep patterns. Somnotate can thus facilitate the study of sleep stage transitions and offers new insight into the mechanisms underlying sleep-wake dynamics. Author summaryTypically, the three different vigilance states - awake, REM sleep, and non-REM sleep - exhibit distinct features that are readily recognised in electrophysiological recordings. However, particularly around vigilance state transitions, epochs often exhibit features from more than one state. These intermediate vigilance states pose challenges for existing manual and automated classification methods, and are hence often ignored. Here, we present Somnotate - an open-source, highly accurate and robust sleep stage classifier, which supports research into intermediate states and sleep stage dynamics. Somnotate quantifies and reports the certainty of its annotations, enabling the experimenter to identify abnormal epochs in a principled manner. We use this feature to identify intermediate states and to detect unsuccessful attempts to switch between vigilance states. This provides new insights into the mechanisms of vigilance state transitions in mice, and creates new opportunities for future experiments.

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bioRxiv2021

Light-regulated SIK1 remodels the synaptic phosphoproteome to induce sleep

The sleep and circadian systems act in concert to regulate sleep-wake timing, yet the molecular mechanisms that underpin their interaction to induce sleep remain unknown. Synaptic protein phosphorylation, driven by the kinase SIK3, correlates with sleep pressure, however it is unclear whether these phosphoproteome changes are causally responsible for inducing sleep. Here we show that the light-dependent activity of SIK1 controls the phosphorylation of a subset of the brain phosphoproteome to induce sleep in a manner that is independent of sleep pressure. By uncoupling phosphorylation and sleep induction from sleep pressure, we establish that synaptic protein phosphorylation provides a causal mechanism for the induction of sleep under different environmental contexts. Furthermore, we propose a framework that details how the salt-inducible kinases regulate the synaptic phosphoproteome to integrate exogenous and endogenous stimuli, thereby providing the molecular basis upon which the sleep and circadian systems interact to control the sleep-wake cycle.

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