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Krone, L. B.

Publications and source records attributed to Krone, L. B..

10 recordsLinked to original sources

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

A role for the cortex in sleep-wake regulation

The cortex and subcortical circuitry are thought to play distinct roles in the generation of sleep oscillations and global control of vigilance states. Here we silenced a subset of cortical layer 5 pyramidal and dentate gyrus granule cells in mice using a cell-specific ablation of the key t-SNARE protein SNAP25. We found a marked increase in wakefulness accompanied by a reduced rebound of EEG slow-wave activity after sleep deprivation. Our data illustrates an important role for the cortex in both global state control and sleep homeostasis.

neuroscience↗