Rapid Eye Movement Bout Research Articles

A predictive propensity measure to enter REM sleep.

During sleep periods, most mammals alternate multiple times between rapid-eye-movement (REM) sleep and non-REM (NREM) sleep. A common theory proposes that these transitions are governed by an "hourglass-like" homeostatic need to enter REM sleep that accumulates during the inter-REM interval and partially discharges during REM sleep. However, markers or mechanisms for REM homeostatic pressure remain undetermined. Recently, an analysis of sleep in mice demonstrated that the cumulative distribution function (CDF) of the amount of NREM sleep between REM bouts correlates with REM bout duration, suggesting that time in NREM sleep influences REM sleep need. Here, we build on those results and construct a predictive measure for the propensity to enter REM sleep as a function of time in NREM sleep since the previous REM episode. The REM propensity measure is precisely defined as the probability to enter REM sleep before the accumulation of an additional pre-specified amount of NREM sleep. Analyzing spontaneous sleep in mice, we find that, as NREM sleep accumulates between REM bouts, the REM propensity exhibits a peak value and then decays to zero with further NREM accumulation. We show that the REM propensity at REM onset predicts features of the subsequent REM bout under certain conditions. Specifically, during the light phase and for REM propensities occurring before the peak in propensity, the REM propensity at REM onset is correlated with REM bout duration, and with the probability of the occurrence of a short REM cycle called a sequential REM cycle. Further, we also find that proportionally more REM sleep occurs during sequential REM cycles, supporting a correlation between high values of our REM propensity measure and high REM sleep need. These results support the theory that a homeostatic need to enter REM sleep accrues during NREM sleep, but only for a limited range of NREM sleep accumulation.

Interictal spikes in Alzheimer's disease: Preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum

Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS.We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep.We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects.Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.

NREM–REM alternation complicates transitions from napping to non-napping behavior in a three-state model of sleep–wake regulation

The temporal structure of human sleep changes across development as it consolidates from the polyphasic sleep of infants to the single nighttime sleep episode typical in adults. Experimental studies have shown that changes in the dynamics of sleep need may mediate this developmental transition in sleep patterning, however, it is unknown how sleep architecture interacts with these changes. We employ a physiologically-based mathematical model that generates wake, rapid eye movement (REM) and non-REM (NREM) sleep states to investigate how NREM–REM alternation affects the transition in sleep patterns as the dynamics of the homeostatic sleep drive are varied. To study the mechanisms producing these transitions, we analyze the bifurcations of numerically-computed circle maps that represent key dynamics of the full sleep–wake network model by tracking the evolution of sleep onsets across different circadian (∼ 24 h) phases. The maps are non-monotonic and discontinuous, being composed of branches that correspond to sleep–wake cycles containing distinct numbers of REM bouts. As the rates of accumulation and decay of the homeostatic sleep drive are varied, we identify the bifurcations that disrupt a period-adding-like behavior of sleep patterns in the transition between biphasic and monophasic sleep. These bifurcations include border collision and saddle–node bifurcations that initiate new sleep patterns, period-doubling bifurcations leading to higher-order patterns of NREM–REM alternation, and intervals of bistability of sleep patterns with different NREM–REM alternations. Furthermore, patterns of NREM–REM alternation exhibit variable behaviors in different regimes of constant sleep–wake patterns. Overall, the sequence of sleep–wake behaviors, and underlying bifurcations, in the transition from biphasic to monophasic sleep in this three-state model is more complex than behavior observed in models of sleep–wake regulation that do not consider the dynamics of NREM–REM alternation. These results suggest that interactions between the dynamics of the homeostatic sleep drive and the dynamics of NREM–REM alternation may contribute to the wide interindividual variation observed when young children transition from napping to non-napping behavior.

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model.

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase-activating protein domains have been deleted (Syngap+/Δ-GAP ), we analysed the duration and occurrence of wake, non-rapid eye movement and rapid eye movement brain states during 6 h multi-electrode EEG recordings. We find that although Syngap+/Δ-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and non-rapid eye movement bouts are reduced and there is an increase in the average duration of both wake and non-rapid eye movement epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during non-rapid eye movement is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep abnormalities were mostly uncorrelated to the electrophysiological signature of absence seizures, spike and wave discharges, as was the imaginary coherence deficit. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/Δ-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high-connectivity instances between short-distance electrode pairs. Finally comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. This matched a significant reduction in connectivity during spindles when averaged regional comparisons were made. These data suggest that Syngap+/Δ-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP1 haploinsufficiency in humans.

A real-time sleep scoring framework for closed-loop sleep manipulation in mice.

Subtle changes in sleep architecture can accompany and be symptomatic of many diseases or disorders. In order to probe and understand the complex interactions between sleep and health, the ability to model, track, and modulate sleep in preclinical animal models is vital. While various methods have been described for scoring experimental sleep recordings, few are designed to work in real time - a prerequisite for closed-loop sleep manipulation. In the present study, we have developed algorithms and software to classify sleep in real time and validated it on C57BL/6 mice (n=8). Hidden Markov models of baseline sleep dynamics were fitted using an unsupervised algorithm to electroencephalogram (EEG) and electromyogram (EMG) data for each mouse, and were able to classify sleep in a manner highly concordant with manual scoring (Cohen's Kappa >75%) up to 3weeks after model construction. This approach produced reasonably accurate estimates of common sleep metrics (proportion, mean duration, and number of bouts). After construction, the models were used to track sleep in real time and accomplish selective rapid eye movement (REM) sleep restriction by triggering non-invasive somatosensory stimulation. During REM restriction trials, REM bout duration was significantly reduced, and the classifier continued to perform satisfactorily despite the disrupted sleep patterns. The software can easily be tailored for use with other commercial or customised methods of sleep disruption (e.g. stir bar, optogenetic stimulation, etc.) and could serve as a robust platform to facilitate closed-loop experimentation. The source code and documentation are freely available upon request from the authors.

Altered sleep architecture, rapid eye movement sleep, and neural oscillation in a mouse model of human chromosome 16p11.2 microdeletion.

Sleep abnormalities are common among children with neurodevelopmental disorders. The human chr16p11.2 microdeletion is associated with a range of neurological and neurobehavioral abnormalities. Previous studies of a mouse model of human chr16p11.2 microdeletion (chr16p11.2df/+) have demonstrated pathophysiological changes at the synapses in the hippocampus and striatum; however, the impact of this genetic abnormality on system level brain functions, such as sleep and neural oscillation, has not been adequately investigated. Here, we show that chr16p11.2df/+ mice have altered sleep architecture, with increased wake time and reduced time in rapid eye movement (REM) and non-REM (NREM) sleep. Importantly, several measurements of REM sleep are significantly changed in deletion mice. The REM bout number and the bout number ratio of REM to NREM are decreased in mutant mice, suggesting a deficit in REM-NREM transition. The average REM bout duration is shorter in mutant mice, indicating a defect in REM maintenance. In addition, whole-cell patch clamp recording of the ventrolateral periaqueductal gray (vlPAG)-projecting gamma-aminobutyric acid (GABA)ergic neurons in the lateral paragigantocellular nucleus of ventral medulla of mutant mice reveal that these neurons, which are important for NREM-REM transition and REM maintenance, have hyperpolarized resting membrane potential and increased membrane resistance. These changes in intrinsic membrane properties suggest that these projection-specific neurons of mutant mice are less excitable, and thereby may play a role in deficient NREM-REM transition and REM maintenance. Furthermore, mutant mice exhibit changes in neural oscillation involving multiple frequency classes in several vigilance states. The most significant alterations occur in the theta frequency during wake and REM sleep.

Altered sleep and EEG power in the P301S Tau transgenic mouse model.

ObjectiveSleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice.MethodsP301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining.ResultsP301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation.InterpretationOur results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models.

Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4–6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking “drive”.

REM Sleep Bout Duration and Frequency in PTSD

The few pharmacological treatments shown to be effective in reducing sleep disturbance in posttraumatic stress disorder (PTSD) might work through normalization of rapid eye movement (REM). However, evidence of REM sleep disturbance in PTSD has been inconsistent and the definition of REM bout has varied as well. In this study, we compared polysomnographic findings in adults with PTSD to both normal sleepers and insomniacs. We found no differences between those with and without PTSD on REM bout frequency or duration. We did, however, find gender differences within our PTSD sample as consistent with a previous review suggesting that males with PTSD are more likely to demonstrate REM sleep disturbance. Consensus on REM bout definition is needed, in addition to studies powered to detect gender differences.

Ischemic stroke selectively inhibits REM sleep of rats

Sleep disorders are important risk factors for stroke; conversely, stroke patients suffer from sleep disturbances including disruptions of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and a decrease in total sleep. This study was performed to characterize the effect of stroke on sleep architecture of rats using continuous electroencephalography (EEG) and activity monitoring. Rats were implanted with transmitters which enabled continuous real time recording of EEG, electromyography (EMG), and locomotor activity. Baseline recordings were performed prior to induction of either transient middle cerebral artery (MCA) occlusion or sham surgery. Sleep recordings were obtained for 60h after surgery to identify periods of wakefulness, NREM, and REM sleep before and after stroke. Spectral analysis was performed to assess the effects of stroke on state-dependent EEG. Finally, we quantified the time in wake, NREM, and REM sleep before and after stroke. Delta power, a measure of NREM sleep depth, was increased the day following stroke. At the same time, there was a significant shift in theta rhythms to a lower frequency during REM and wake periods. The awake EEG slowed after stroke over both hemispheres. The EEG of the ischemic hemisphere demonstrated diminished theta power specific to REM in excess of the slowing seen over the contralateral hemisphere. In contrast to rats exposed to sham surgery which had slightly increased total sleep, rats undergoing stroke experienced decreased total sleep. The decrease in total sleep after stroke was the result of dramatic reduction in the amount of REM sleep after ischemia. The suppression of REM after stroke was due to a decrease in the number of REM bouts; the length of the average REM bout did not change. We conclude that after stroke in this experimental model, REM sleep of rats is specifically and profoundly suppressed. Further experiments using this experimental model should be performed to investigate the mechanisms and consequences of REM suppression after stroke.

Association between the activation of MCH and orexin immunorective neurons and REM sleep architecture during REM rebound after a three day long REM deprivation

Rapid eye movement (REM) sleep rebound following REM deprivation using the platform-on-water method is characterized by increased time spent in REM sleep and activation of melanin-concentrating hormone (MCH) expressing neurons. Orexinergic neurons discharge reciprocally to MCH-ergic neurons across the sleep-wake cycle. However, the relation between REM architecture and the aforementioned neuropeptides remained unclear. MCH-ergic neurons can be divided into two subpopulations regarding their cocaine- and amphetamine-regulated transcript (CART) immunoreactivity, and among them the activation of CART-immunoreactive subpopulation is higher during the REM rebound. However, the possible role of stress in this association has not been elucidated.Our aims were to analyze the relationship between the architecture of REM rebound and the activation of hypothalamic MCH-ergic and orexinergic neurons. We also intended to separate the effect of stress and REM deprivation on the subsequent activation of subpopulations of MCH-ergic neurons. In order to detect neuronal activity, we performed MCH/cFos and orexin/cFos double immunohistochemistry on home cage, sleep deprived and sleep-rebound rats using the platform-on-water method with small and large (stress control) platforms. Furthermore, REM architecture was analyzed and a triple MCH/CART/cFos immunohistochemistry was also performed on the rebound groups in the same animals.We found that the activity of MCH- and orexin-immunoreactive neurons during REM rebound was positively and negatively correlated with the number of REM bouts, respectively. A negative reciprocal correlation was also found between the activation of MCH- and orexin-immunoreactive neurons during REM rebound. Furthermore, difference between the activation of CART-immunoreactive (CART-IR) and non-CART-immunoreactive MCH-ergic neuron subpopulations was found only after selective REM deprivation, it was absent in the large platform (stress control) rebound group.These results support the role of CART-IR subpopulation of MCH-ergic neurons and the inverse relationship of MCH and orexin in the regulation of REM sleep after REM sleep deprivation.

Olivo-cochlear inhibition during physostigmine-induced activity in the pontine reticular formation in the decerebrate cat

The physiological role of the olivo-cochlear pathway has been questioned recently because this pathway has never been shown to be operative under natural conditions. In this study, cochlear potentials were recorded differentially between a wire electrode placed on the round window and an indifferent electrode attached to the nuchal muscles in decerebrate, decerebellate cats. Physostigmine was used to induce bout of rapid eye movement (REM) sleep. REM bouts were verified by recording burst activity in the brain stem pontine reticular formation and the inhibition of lumbar monosynaptic reflexes. Intravenous physostigmine increased the inhibition of N 1 caused by direct electrical stimulation of the crossed olivo-cochlear bundle in the absence of REM. Olivo-cochlear system inhibition was also recruited during physostigmine-induced REM sleep. It is concluded that the brain stem reticular formation can activate the olivo-cochlear bundle and can thereby produce inhibition in the cochlea.