Sleep-related memory consolidation in the psychosis spectrum phenotype.

Sleep and memory processing impairments range from mild to severe in the psychosis spectrum. Relationships between memory processing and sleep characteristics have been described for schizophrenia, including unaffected first-degree relatives, but they are less clear across other high-risk groups within the psychosis spectrum. In this study, we investigated high-risk individuals with accumulated risk-factors for psychosis and subthreshold symptoms. Out of 1898 screened individuals, 44 age- and sex-matched participants were sub-grouped into those with substantial environmental risk factors for psychosis and subthreshold psychotic symptoms (high-risk group) and those without these phenotypes (low-risk controls). Four groups (high/low risk, morning/evening training) were trained and tested in the laboratory for sustained attention, motor skill memory (finger-tapping task) and declarative memory (word-pair learning task) immediately after training, again after a night of EEG-recorded sleep at home or a period of daytime wakefulness, and again after 24 h from training. No differences in sustained attention or in memory consolidation of declarative and motor skill memory were found between groups for any time period tested. However, a group difference was found for rapid-eye movement (REM) sleep in relation to motor skill memory: the longer the total sleep time, particularly longer REM sleep, the greater the performance gain, which occurred only in high-risk individuals. In conclusion, our results suggest a gain in motor skill performance with sufficient sleep opportunity for longer REM sleep in high-risk individuals with subthreshold psychotic symptoms. Declarative memory did not benefit from sleep consolidation above or beyond that of the control group.

Different Effects of Sleep Deprivation and Torpor on EEG Slow-Wave Characteristics in Djungarian Hamsters.

It has been shown previously in Djungarian hamsters that the initial electroencephalography (EEG) slow-wave activity (power in the 0.5-4.0 Hz band; SWA) in non-rapid eye movement (NREM) sleep following an episode of daily torpor is consistently enhanced, similar to the SWA increase after sleep deprivation (SD). However, it is unknown whether the network mechanisms underlying the SWA increase after torpor and SD are similar. EEG slow waves recorded in the neocortex during sleep reflect synchronized transitions between periods of activity and silence among large neuronal populations. We therefore set out to investigate characteristics of individual cortical EEG slow waves recorded during NREM sleep after 4 h SD and during sleep after emergence from an episode of daily torpor in adult male Djungarian hamsters. We found that during the first hour after both SD and torpor, the SWA increase was associated with an increase in slow-wave incidence and amplitude. However, the slopes of single slow waves during NREM sleep were steeper in the first hour after SD but not after torpor, and, in contrast to sleep after SD, the magnitude of change in slopes after torpor was unrelated to the changes in SWA. Furthermore, slow-wave slopes decreased progressively within the first 2 h after SD, while a progressive increase in slow-wave slopes was apparent during the first 2 h after torpor. The data suggest that prolonged waking and torpor have different effects on cortical network activity underlying slow-wave characteristics, while resulting in a similar homeostatic sleep response of SWA. We suggest that sleep plays an important role in network homeostasis after both waking and torpor, consistent with a recovery function for both states.

Long-term history and immediate preceding state affect EEG slow wave characteristics at NREM sleep onset in C57BL/6 mice.

The dynamics of cortical activity across the 24-h day and at vigilance state transitions is regulated by an interaction between global subcortical neuromodulatory influences and local shifts in network synchrony and excitability. To address the role of long-term and immediate preceding history in local and global cortical dynamics, we investigated cortical EEG recorded from both frontal and occipital regions during an undisturbed 24-h recording in mice. As expected, at the beginning of the light period, under physiologically increased sleep pressure, EEG slow waves were more frequent and had higher amplitude and slopes, compared to the rest of the light period. Within discrete NREM sleep episodes, the incidence, amplitude and slopes of individual slow waves increased progressively after episode onset in both derivations by approximately 10-30%. Interestingly, at the beginning of NREM sleep episodes slow waves in the frontal and occipital derivations frequently occurred in isolation, as quantified by longer latencies between consecutive slow waves in the two regions. Notably, slow waves during the initial period of NREM sleep following REM sleep episodes were significantly less frequent, lower in amplitude and exhibited shallower slopes, compared to those that occurred in NREM episodes after prolonged waking. Moreover, the latencies between consecutive frontal and occipital NREM slow waves were substantially longer when they occurred directly after REM sleep compared to following consolidated wakefulness. Overall these data reveal a complex picture, where both time of day and preceding state contribute to the characteristics and dynamics of slow waves within NREM sleep. These findings suggest that NREM sleep initiates in a more "local" fashion when it occurs following REM sleep episodes as opposed to sustained waking bouts. While the mechanisms and functional significance of such a re-setting of brain state after individual REM sleep episodes remains to be investigated, we suggest that it may be an essential feature of physiological sleep regulation.

Normal sleep homeostasis and lack of epilepsy phenotype in GABA A receptor alpha3 subunit-knockout mice.

Thalamo-cortical networks generate specific patterns of oscillations during distinct vigilance states and epilepsy, well characterized by electroencephalography (EEG). Oscillations depend on recurrent synaptic loops, which are controlled by GABAergic transmission. In particular, GABA A receptors containing the alpha3 subunit are expressed predominantly in cortical layer VI and thalamic reticular nucleus (nRT) and regulate the activity and firing pattern of neurons in relay nuclei. Therefore, ablation of these receptors by gene targeting might profoundly affect thalamo-cortical oscillations. Here, we investigated the role of alpha3-GABA A receptors in regulating vigilance states and seizure activity by analyzing chronic EEG recordings in alpha3 subunit-knockout (alpha3-KO) mice. The presence of postsynaptic alpha3-GABA A receptors/gephyrin clusters in the nRT and GABA A-mediated synaptic currents in acute thalamic slices was also examined. EEG spectral analysis showed no difference between genotypes during non rapid-eye movement (NREM) sleep or at waking-NREM sleep transitions. EEG power in the spindle frequency range (10-15 Hz) was significantly lower at NREM-REM sleep transitions in mutant compared with wild-type mice. Enhancement of sleep pressure by 6 h sleep deprivation did not reveal any differences in the regulation of EEG activities between genotypes. Finally, the waking EEG showed a slightly larger power in the 11-13-Hz band in alpha3-KO mice. However, neither behavior nor the waking EEG showed alterations suggestive of absence seizures. Furthermore, alpha3-KO mice did not differ in seizure susceptibility in a model of temporal lobe epilepsy. Strikingly, despite the disruption of postsynaptic gephyrin clusters, whole-cell patch clamp recordings revealed intact inhibitory synaptic transmission in the nRT of alpha3-KO mice. These findings show that the lack of alpha3-GABA(A) receptors is extensively compensated for to preserve the integrity of thalamo-cortical function in physiological and pathophysiological situations.

Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice.

A recent hypothesis suggests that a major function of sleep is to renormalize synaptic changes that occur during wakefulness as a result of learning processes [G. Tononi, C. Cirelli, Sleep and synaptic homeostasis: a hypothesis, Brain Res. Bull. 62 (2003) 143-150; G. Tononi, C. Cirelli, Sleep function and synaptic homeostasis, Sleep Med. Rev. 10 (2006) 49-62]. Specifically, according to this synaptic homeostasis hypothesis, wakefulness results in a net increase in synaptic strength, while sleep is associated with synaptic downscaling. Since synaptic activity accounts for a large fraction of brain energy metabolism, one of the predictions of the hypothesis is that if synaptic weight increases in the course of wakefulness, cerebral metabolic rates should also increase, while the opposite would happen after a period of sleep. In this study we therefore measured brain metabolic rate during wakefulness and determined whether it was affected by the previous sleep-wake history. Three groups of mice in which behavioral states were determined by visual observation were subjected to 6h of sleep deprivation (SD). Group 1 was injected with 2-deoxyglucose (2-DG) 45 min before the end of SD, while Group 2 and Group 3 were injected with 2-DG after an additional period (2-3h) of waking or sleep, respectively. During the 45-min interval between 2-DG injection and sacrifice all mice were kept awake. We found that in mice that slept approximately 2.5h the 2-DG-uptake was globally decreased, on average by 15-20%, compared to the first two groups that were kept awake. On average, Group 2, which stayed awake approximately 2h more than Group 1, showed only a small further increase in 2-DG-uptake relative to Group 1. Moreover, the brain regions in which 2-DG-uptake increased the least when waking was prolonged by approximately 2h showed the most pronounced decrease in DG-uptake after sleep. The data are consistent with the prediction that sleep may reset cerebral metabolic rates to a lower level.

Handedness leads to interhemispheric EEG asymmetry during sleep in the rat.

Sleep electroencephalographic (EEG) slow-wave activity is increased after wakefulness and decreases during sleep. Regional sleep EEG differences are thought to be a consequence of activation of specific cortical neuronal circuits during waking. We investigated the relationship between handedness and interhemispheric brain asymmetry. Bilateral EEG recordings were obtained from the frontal and occipital cortex in rats with a clear paw preference in a food-reaching task (right, n = 5; left, n = 5). While still naïve to the task, no waking or sleep EEG asymmetry was present. During the food-reaching task, the waking EEG showed significant, substantial power increases in the frontal hemisphere contralateral to the dominant paw in the low theta range (4.5-6.0 Hz). Moreover, the non-REM sleep EEG following feeding bouts was markedly asymmetric, with significantly higher power in the hemisphere contralateral to the preferred paw in frequencies >1.5 Hz. No asymmetry was evident in the occipital EEG. Correlation analyses revealed a positive association between the hemispheric asymmetry during sleep and the degree of preferred use of the contralateral paw during waking in frequencies <9.0 Hz. Our findings show that handedness is reflected in specific, regional EEG asymmetry during sleep. Neuronal activity induced by preferential use of a particular forelimb led to a local enhancement of EEG power in frequencies within the delta and sigma ranges, supporting the hypothesis of use-dependent local sleep regulation. We conclude that inherent laterality is manifested when animals are exposed to complex behavioral tasks, and sleep plays a role in consolidating the hemispheric dominance of the brain.

Sleep homeostasis in the rat in the light and dark period.

Sleep is regulated by the interaction of a homeostatic (Process S) and a circadian component. The duration of prior wakefulness is the main factor influencing subsequent sleep duration and its intensity. We investigated in the rat whether the sleep-wake history before sleep deprivation (SD) contributes to the effects of sleep loss incurred during the SD. A 24-h baseline recording was followed by 6 h SD at light onset (SD-Light, n=7), or at dark onset (SD-Dark, n=8) and 18 h recovery. Both SDs led to a pronounced increase in slow wave activity (SWA, EEG power between 0.75 and 4.0 Hz) in NREM sleep and increased sleep consolidation. The prolongation of sleep episodes was associated with increased intra-episode SWA. The amount of waking before the SD correlated positively with the SWA increase during recovery, and SWA levels before SD were negatively correlated with their subsequent increase. The time-course of SWA (Process S) as well as of single frequency bins within the SWA band was successfully simulated based on vigilance-state distribution. The time constant of the exponential monotonic decay (Td) was higher for the 0.75-1.0 Hz bin compared to all remaining frequency bins of the SWA band, reflecting a slower process determining the slow EEG component during sleep. The data show that the homeostatic response after SD, consisting of increased sleep intensity and sleep consolidation is determined by a combination of SD and the preceding vigilance-state history. The slower dynamics of low frequency delta power compared to fast delta frequencies point to heterogeneity within the traditionally defined SWA band.

Alteration of behavior in mice by muscimol is associated with regional electroencephalogram synchronization.

We tested the hypothesis that the effects of GABAergic agonists on behavior and the electroencephalogram (EEG) result from an increased regional synchronization in cortical circuits. The relationship between regional EEG topography, EEG synchronization and alteration of behavior was investigated by administering male C57BL/6 mice (n=7) a high, 3 mg/kg i.p. dose of muscimol, a selective GABA(A) agonist. Parietal and frontal cortical EEG, electromyogram, infrared and running wheel activity were recorded for 3 h before and 9 h after injection. Muscimol consistently elicited biphasic behavioral changes. Initially, it induced a catalepsy-like state lasting 96.0+/-12.4 min. This state was followed by a hyperactivity period of 49.7+/-5.4 min, during which the mice engaged in vigorous wheel running. During catalepsy, the EEG exhibited high amplitude waves which showed a consistent phase relationship between the frontal and parietal derivation. Moreover, the typical regional differences between the EEG spectra of the two derivations were abolished, and a redistribution of EEG power toward lower frequencies (<3 Hz) occurred in both derivations. In contrast, during hyperactivity the parietal EEG was dominated by theta-activity (7-9 Hz), which is typical for running behavior, while high amplitude slow waves, resembling the normal non-rapid eye movement sleep EEG pattern, predominated in the frontal EEG. The data indicate that the GABAergic system is involved in the regulation of cortical synchronization of neuronal activity and suggest a link between regional EEG synchronization and behavioral states.

Sleep and rest regulation in young and old oestrogen-deficient female mice.

The effect of circulating oestrogen deficiency on sleep regulation and locomotor activity was investigated in aromatase cytochrome P450 deficient mice (ArKO) and wild-type (WT) controls. Sleep was recorded in 3-month old mice during a 24-h baseline day, 6-h sleep deprivation (SD) and 18-h recovery, and activity was recorded at the age of 3, 9 and 12 months. In mice deficient of oestrogen, the total amount of sleep per 24 h was the same as in WT controls. However, in ArKO mice, sleep was enhanced in the dark period at the expense of sleep in the light phase, and was more fragmented than sleep in WT mice. This redistribution of sleep resulted in a damped amplitude of slow-wave activity (SWA; power between 0.75-4.0 Hz) in non-rapid eye movement sleep across 24 h. After SD, the rebound of sleep and SWA was similar between the genotypes, suggesting that oestrogen deficiency does not affect the mechanisms maintaining the homeostatic balance between the amount of sleep and its intensity. Motor activity decreased with age in both genotypes and was lower in ArKO mice compared to WT at all three ages. After SD, the amount of rest in 3-month old WT mice increased above baseline and was more consolidated. Both effects were less pronounced in ArKO mice, reflecting the baseline differences between the genotypes. The results indicate that despite the pronounced redistribution of sleep and motor activity in oestrogen deficient mice, the basic homeostatic mechanisms of sleep regulation in ArKO mice remain intact.

The dynamics of spindles and EEG slow-wave activity in NREM sleep in mice.

A quantitative analysis of spindles and spindle-related EEG activity was performed in C57BL/6 mice. The hypothesis that spindles are involved in sleep regulatory mechanisms was tested by investigating their occurrence during 24 h and after 6 h sleep deprivation (SD; n = 7). In the frontal derivation distinct spindle events were characterized as EEG oscillations with a dominant frequency approximately at 11 Hz. Spindles were most prominent during NREM sleep and increased before NREM-REM sleep transitions. Whereas spindles increased concomitantly with slow wave activity (SWA, EEG power between 0.5 and 4.0 Hz) at the beginning of the NREM sleep episode, these measures showed an opposite evolution prior to the transition to REM sleep. The 24-h time course of spindles showed a maximum at the end of the 12-h light period, and was a mirror image of SWA in NREM sleep. After 6 h SD the spindles in NREM sleep were initially suppressed, and showed a delayed rebound. In contrast, spindles occurring immediately before the transition to REM sleep were enhanced during the first 2 h of recovery. The data suggest that spindles in NREM sleep may be involved in sleep maintenance, while spindles heralding the transition to REM sleep may be related to mechanisms of REM sleep initiation.

Interhemispheric coherence of the sleep electroencephalogram in mice with congenital callosal dysgenesis.

Regional differences in the effect of sleep deprivation on the sleep electroencephalogram (EEG) may be related to interhemispheric synchronization. To investigate the role of the corpus callosum in interhemispheric EEG synchronization, coherence spectra were computed in mice with congenital callosal dysgenesis (B1) under baseline conditions and after 6-h sleep deprivation, and compared with the spectra of a control strain (C57BL/6). In B1 mice coherence was lower than in controls in all vigilance states. The level of coherence in each of the three totally acallosal mice was lower than in the mice with only partial callosal dysgenesis. The difference between B1 and control mice was present over the entire 0.5-25 Hz frequency range in non-rapid eye movement sleep (NREM sleep), and in all frequencies except for the high delta and low theta band (3-7 Hz) in rapid eye movement (REM) sleep and waking. In control mice, sleep deprivation induced a rise of coherence in the Delta band of NREM sleep in the first 2 h of recovery. This effect was absent in B1 mice with total callosal dysgenesis and attenuated in mice with partial callosal dysgenesis. In both strains the effect of sleep deprivation dissipated within 4 h. The results show that EEG synchronization between the hemispheres in sleep and waking is mediated to a large part by the corpus callosum. This applies also to the functional changes induced by sleep deprivation in NREM sleep. In contrast, interhemispheric synchronisation of theta oscillations in waking and REM sleep may be mediated by direct interhippocampal connections.

Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat.

To test the theory that sleep is a regional, use-dependent process, rats were subjected to unilateral sensory stimulation during waking. This was achieved by cutting the whiskers on one side, in order to reduce the sensory input to the contralateral cortex. The animals were kept awake for 6 h in an enriched environment to activate the cortex contralateral to the intact side. Whiskers are known to be represented in the barrel field of the contralateral somatosensory cortex and their stimulation during exploratory behavior results in a specific activation of the projection area. In the 6 h recovery period following sleep deprivation, spectral power of the nonrapid eye-movement (NREM) sleep EEG in the 0.75-6.0 Hz range exhibited an interhemispheric shift towards the cortex that was contralateral to the intact whiskers. The results support the theory that sleep has a regional, use-dependent facet.

Long photoperiod restores the 24-h rhythm of sleep and EEG slow-wave activity in the Djungarian hamster (Phodopus sungorus).

Photoperiod influences the distribution of sleep and waking and electroencephalogram (EEG) power density in the Djungarian hamster. In an experimental procedure combining short photoperiod (SP) and low ambient temperature, the light-dark difference in the amount of sleep was decreased, and the changes in slow-wave activity (SWA) (mean EEG power density between 0.75 and 4.0 Hz) in nonrapid eye movement (NREM) sleep within 24 h were abolished. These findings, obtained in three different groups of animals, suggested that at the lower ambient temperature, the influence of the circadian clock on sleep-wake behavior was diminished. However, it remained unclear whether the changes were due to the photoperiod, ambient temperature, or both. Here, the authors show that EEG and electromyogram recordings in a single group of animals sequentially adapted to a short and long photoperiod (LP) at low ambient temperature (approximately 15 degrees C) confirm that EEG power is reduced in SP. Moreover, the nocturnal sleep-wake behavior and the changes in SWA in NREM sleep over 24 h were restored by returning the animals to LP and retaining ambient temperature at 15 degrees C. Therefore, the effects cannot be attributed to ambient temperature alone but are due to a combined effect of temperature and photoperiod. When the Djungarian hamster adapts to winter conditions, it appears to uncouple sleep regulation from the circadian clock.