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Welcome to OXION, Universities of Oxford, Cambridge, London and MRC Harwell
Sleep homeostasis during daytime food entrainment in mice.
Twenty-four hour rhythms of physiology and behavior are driven by the environment and an internal endogenous timing system. Daily restricted feeding (RF) in nocturnal rodents during their inactive phase initiates food anticipatory activity (FAA) and a reorganization of the typical 24-hour sleep-wake structure. Here, we investigate the effects of daytime feeding, where food access was restricted to 4 hours during the light period ZT4-8 (Zeitgeber time; ZT0 is lights on), on sleep-wake architecture and sleep homeostasis in mice. Following 10 days of RF, mice were returned to ad libitum feeding. To mimic the spontaneous wakefulness associated with FAA and daytime feeding, mice were then sleep deprived between ZT3-6. Although the amount of wake increased during FAA and subsequent feeding, total wake time over 24 hours remained stable as the loss of sleep in the light phase was compensated for by an increase in sleep in the dark phase. Interestingly, sleep that followed spontaneous wake episodes during the dark period and the extended period of wake associated with FAA, exhibited lower levels of slow-wave activity (SWA) when compared to baseline or after sleep deprivation, despite a similar duration of waking. This suggests an evolutionary mechanism of reducing sleep drive during negative energy balance to enable greater arousal for food-seeking behaviors. However, the total amount of sleep and SWA accumulated during the 24 hours was similar between baseline and RF. In summary, our study suggests that despite substantial changes in the daily distribution and quality of wake induced by RF, sleep homeostasis is maintained.
Environment shapes sleep patterns in a wild nocturnal primate.
Among primates, the suborder Haplorhini is considered to have evolved a consolidated monophasic sleep pattern, with diurnal species requiring a shorter sleep duration than nocturnal species. Only a few primate species have been systematically studied in their natural habitat where environmental variables, including temperature and light, have a major influence on sleep and activity patterns. Here we report the first sleep study on a nocturnal primate performed in the wild. We fitted seven wild Javan slow lorises (Nycticebus javanicus) in West Java, Indonesia with accelerometers that collected activity data, and installed climate loggers in each individual's home range to collect ambient temperature readings (over 321 days in total). All individuals showed a strictly nocturnal pattern of activity and displayed a striking synchronisation of onset and cessation of activity in relation to sunset and sunrise. The longest consolidated rest episodes were typically clustered near the beginning and towards the end of the light period, and this pattern was inversely related to daily fluctuations of the ambient temperature. The striking relationship between daily activity patterns, light levels and temperature suggests a major role of the environment in shaping the daily architecture of waking and sleep. We concluded that well-known phenotypic variability in daily sleep amount and architecture across species may represent an adaptation to changes in the environment. Our data suggest that the consolidated monophasic sleep patterns shaped by environmental pressures observed in slow lorises represent phylogenetic inertia in the evolution of sleep patterns in humans.
In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy.
AIMS: The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice. METHODS AND RESULTS: Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy. CONCLUSIONS: MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.
Modulation of recognition memory performance by light and its relationship with cortical EEG theta and gamma activities.
Acute exposure to light exerts widespread effects on physiology, in addition to its key role in photoentrainment. Although the modulatory effect of light on physiological arousal is well demonstrated in mice, its effect on memory performance is inconclusive, as the direction of the effect depends on the nature of the behavioural task employed and/or the type of stimulus utilised. Moreover, in all rodent studies that reported significant effects of light on performance, brain activity was not assessed during the task and thus it is unclear how brain activity was modulated by light or the exact relationship between light-modulated brain activity and performance. Here we examine the modulatory effects of light of varying intensities on recognition memory performance and frontoparietal waking electroencephalography (EEG) in mice using the spontaneous recognition memory task. We report a light-intensity-dependent disruptive effect on recognition memory performance at the group level, but inspection of individual-level data indicates that light-intensity-dependent facilitation is observed in some cases. Using linear mixed-effects models, we then demonstrate that EEG fast theta (θ) activity at the time of encoding negatively predicts recognition memory performance, whereas slow gamma (γ) activity at the time of retrieval positively predicts performance. These relationships between θ/γ activity and performance are strengthened by increasing light intensity. Thus, light modulates θ and γ band activities involved in attentional and mnemonic processes, thereby affecting recognition memory performance. However, extraneous factors including the phase of the internal clock at which light is presented and homeostatic sleep pressure may determine how photic input is translated into behavioural performance.
Effects of circadian misalignment on sleep in mice.
Circadian rhythms and sleep-wake history determine sleep duration and intensity, and influence subsequent waking. Previous studies have shown that T cycles - light-dark (LD) cycles differing from 24 h - lead to acute changes in the daily amount and distribution of waking and sleep. However, little is known about the long-term effects of T cycles. Here we performed continuous 10 day recording of electroencephalography (EEG), locomotor activity and core body temperature in C57BL/6 mice under a T20 cycle, to investigate spontaneous sleep and waking at baseline compared with when the circadian clock was misaligned and then re-aligned with respect to the external LD cycle. We found that the rhythmic distribution of sleep was abolished during misalignment, while the time course of EEG slow wave activity (1-4 Hz) was inverted compared to baseline. Although the typical light-dark distribution of NREM sleep was re-instated when animals were re-aligned, slow wave activity during NREM sleep showed an atypical increase in the dark phase, suggesting a long-term effect of T cycles on sleep intensity. Our data show that circadian misalignment results in previously uncharacterised long-term effects on sleep, which may have important consequences for behaviour.
Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity.
Sleep homeostasis manifests as a relative constancy of its daily amount and intensity. Theoretical descriptions define 'Process S', a variable with dynamics dependent on global sleep-wake history, and reflected in electroencephalogram (EEG) slow wave activity (SWA, 0.5-4 Hz) during sleep. The notion of sleep as a local, activity-dependent process suggests that activity history must be integrated to determine the dynamics of global Process S. Here, we developed novel mathematical models of Process S based on cortical activity recorded in freely behaving mice, describing local Process S as a function of the deviation of neuronal firing rates from a locally defined set-point, independent of global sleep-wake state. Averaging locally derived Processes S and their rate parameters yielded values resembling those obtained from EEG SWA and global vigilance states. We conclude that local Process S dynamics reflects neuronal activity integrated over time, and global Process S reflects local processes integrated over space.
