Neurobiology of Sleep and Circadian Rhythms最新文献

Circadian entrainment to the solar light:dark schedule is thought to be maintained by a simple photon counting method. According to this hypothesis, the pacemaker adjusts the phase of the body’s endogenous rhythms in accordance to the intensity and duration with which it encounters a perceived twilight signal. While previous data have generally supported the hypothesis, more recent analysis has codified other factors besides irradiance that influence the magnitude of resetting responses to light delivered within the same phase of the circadian cycle. In particular, the frequency with which light is alternated with darkness, or whether it’s packaged in millisecond flashes versus continuous blocks, can significantly alter the dose-response relationship. Here, we used a drosophilid model to test whether circadian photon-counting trends can be broken with light administration protocols spanning just 15 minutes. In the early part of the delay zone, a 15-min continuous light pulse was fragmented until it could no longer produce a full-magnitude shift of the flies’ locomotor activity rhythms. The remaining exposure was then reorganized along various fractionation schemes that employed pulses with different widths and interstimulus intervals. Our results suggest that the pacemaker integrates the phase-shifting effects of equiluminous light differently depending on the stimulus pattern with which light is made available. For example, despite having fewer photons, certain ratios of light and darkness could be optimized on a timescale of seconds and minutes so as to achieve pacemaker resetting close to par with steady luminance. These data provide further evidence that the circadian pacemaker’s responses to light entail more than photon counting and motivate continued discussion on how phototherapy can be best optimized in clinical practice to improve conditions linked to circadian impairment.

Chronic cocaine use has been associated with sleep disturbances, both during active use periods and during withdrawal and abstinence. Acute cocaine also increases waking at the expense of slow wave sleep and Rapid Eye Movement in non-human subjects. However, the effects of acute cocaine on sleep/waking activity in mice, a rodent model commonly used in both sleep and addiction research due to its high genetic tractability, has yet to be investigated. Sleep/waking activity was measured via polysomnography following IP administration of three doses of cocaine (3.6, 9.6, 18 mg/kg) and vehicle control in male C57BL/6 mice. Cocaine dose-dependently increased sleep latency, increased waking time and increased fast EEG activity within waking. Increases in waking occurred primarily during the first hour following injection, followed by rebound SWS sleep. Sleep/waking activity normalized within a 24-hour period. As with humans and other rodents, cocaine dose dependently reduces sleep in a wildtype strain of mice commonly used in reward and addiction research.

In mammals, daily rhythms in behavior and physiology are under control of an endogenous clock or pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN assures an optimal temporal organization of internal physiological process and also synchronizes rhythms in physiology and behavior to the cyclic environment. The SCN receives direct light input from the retina, which is capable of resetting the master clock and thereby synchronizes internally driven rhythms to the external light-dark cycle. In keeping with its function as a clock and pacemaker, the SCN appears to be well buffered against influences by other stimuli and conditions that contain no relevant timing information, such as acute stressors. On the other hand, it has been suggested that chronic forms of stress may have gradually accumulating effects that can disturb normal clock function and thereby contribute to stress-related disorders. Therefore, in the present study we investigated whether chronic intermittent social stress affects the endogenous period and phase of the free-running activity rhythm in mice. Adult male mice were maintained in constant dim red light conditions and exposed to a daily 20 min social defeat stress session for 10 consecutive days, either during the first half of their activity phase or the first half of their resting phase. The overall amount of running wheel activity was strongly suppressed during the 10 days of social defeat, to about 50% of the activity in non-defeated control mice. Activity levels gradually normalized during post-defeat recovery days. Despite the strong suppression of activity in defeated animals, the endogenous free-running circadian period of the activity rhythm and the phase of activity onset were not affected. These findings are thus in agreement with earlier studies suggesting that the circadian pacemaker in the SCN that is driving the rhythmicity in activity is well-protected against stress. Even severe social defeat stress for 10 consecutive days, which has a major effect on the levels of activity, does not affect the pace of the endogenous clock.

Melatonin deficiency has been proposed to underlie higher risks for cardiovascular and several other diseases in humans experiencing prolonged shiftwork. However, melatonin secretion has not been monitored longitudinally during consecutive shifts of the light:dark (LD) cycles in the same individuals (animals or humans) and the extent of melatonin deficiency is unknown in individuals experiencing consecutive LD shifts. We investigated the effect of consecutive LD shifts on melatonin secretion in adult F344 rats using continuous online pineal-microdialysis. The rats were entrained to the 12 h:12 h LD cycle before the shifts. The LD cycle was then advanced (n=5) or delayed (n=4) for six hours every four days for four consecutive times. The rats exhibited marked asymmetry in response to delay or advance LD shifts. While rats exposed to the repeated LD delay shifts always exhibited melatonin secretion throughout the entire periods, repeated LD advance shifts suppressed nocturnal melatonin secretion for several consecutive days in the middle of the 3-week period. Moreover, melatonin offset after LD delay and melatonin onset after LD advance determined the rate of circadian pacemaker reentrainment. Additionally, melatonin offset was phase locked at the new dark/light junctions for days following LD advance. These data demonstrate that chronic LD shifts are deleterious to melatonin rhythms, and that this effect is much more pronounced during advance shifts. These data may enhance our understanding of impact of LD shifts on our circadian timing system and benefit better design of shiftwork schedules to avoid melatonin disruption.

In the early 1980s Jeff Hall and Michael Rosbash at Brandeis University and Mike Young at Rockefeller University set out to isolate the period (per) gene, which was recovered in a revolutionary genetic screen by Ron Konopka and Seymour Benzer for mutants that altered circadian behavioral rhythms. Over the next 15 years the Hall, Rosbash and Young labs made a series of groundbreaking discoveries that defined the molecular timekeeping mechanism and formed the basis for them being awarded the 2017 Nobel Prize in Physiology or Medicine. Here the authors recount their experiences as post-docs in the Hall, Rosbash and Young labs from the mid-1980s to the mid-1990s, and provide a perspective of how basic research conducted on a simple model system during that era profoundly influenced the direction of the clocks field and established novel approaches that are now standard operating procedure for studying complex behavior.

Sleep is regulated by a homeostatic and a circadian process. Together these two processes determine most aspects of sleep and related variables like sleepiness and alertness. The two processes are known to be able to work independently, but also to both influence sleep and sleep related variables in an additive or more complex manner. The question remains whether the two processes are directly influencing each other.

The present review summarizes evidence from behavioural and electroencephalographic determined sleep, electrophysiology, gene knock out mouse models, and mathematical modelling to explore whether sleep homeostasis can influence circadian clock functioning and vice versa.

There is a multitude of data available showing parallel action or influence of sleep homeostatic mechanisms and the circadian clock on several objective and subjective variables related to sleep and alertness. However, the evidence of a direct influence of the circadian clock on sleep homeostatic mechanisms is sparse and more research is needed, particularly applying longer sleep deprivations that include a second night.

The strongest evidence of an influence of sleep homeostatic mechanisms on clock functioning comes from sleep deprivation experiments, demonstrating an attenuation of phase shifts of the circadian rhythm to light pulses when sleep homeostatic pressure is increased. The data suggest that the circadian clock is less susceptible to light when sleep pressure is high.

The available data indicate that a strong central clock will induce periods of deep sleep, which in turn will strengthen clock function. Both are therefore important for health and wellbeing. Weakening of one will also hamper functioning of the other. Shift work and jet lag are situations where one tries to adapt to zeitgebers in a condition where sleep is compromised. Adaptation to zeitgebers may be improved by introducing nap schedules to reduce sleep pressure, and through that increasing clock susceptibility to light.

The central aim of this study was to investigate hormones as a predictor of individual vulnerability or resiliency on emotion processing tasks following one night of sleep restriction. The restriction group was instructed to sleep 3 a.m.–7 a.m. (13 men, 13 women in follicular phase, 10 women in luteal phase of menstrual cycle), and a control group slept 11 p.m.–7 a.m. (12 men, 12 follicular women, 12 luteal women). Sleep from home was verified with actigraphy. Saliva samples were collected on the evening prior to restriction, and in the morning and afternoon following restriction, to measure testosterone, estradiol, and progesterone. In the laboratory, event-related potentials (ERPs) were recorded during presentation of images and faces to index neural processing of emotional stimuli. Compared to controls, sleep-restricted participants had a larger amplitude Late Positive Potential (LPP) ERP to positive vs neutral images, reflecting greater motivated attention towards positive stimuli. Sleep-restricted participants were also less accurate categorizing sad faces and exhibited a larger N170 to sad faces, reflecting greater neural reactivity. Sleep-restricted luteal women were less accurate categorizing all images compared to control luteal women, and progesterone was related to several outcomes. Morning testosterone in men was lower in the sleep-restricted group compared to controls; lower testosterone was associated with lower accuracy to positive images, a greater difference between positive vs neutral LPP amplitude, and lower accuracy to sad and fearful faces. In summary, women higher in progesterone and men lower in testosterone were more vulnerable to the effects of sleep restriction on emotion processing tasks. This study highlights a role for sex and sex hormones in understanding individual differences in vulnerability to sleep loss.

Heart rate variability (HRV) is a reliable technique to evaluate autonomic activity and shows marked changes across a night of sleep. Previous nighttime sleep findings report changes in HRV during non-rapid eye movement sleep (NREM), which have been associated with cardiovascular health benefits. Daytime sleep, however, has been linked with both positive and negative cardiovascular outcomes. Yet, no studies have directly compared HRV profiles during an ecologically-valid daytime nap in healthy, well-rested adults to that of nighttime sleep. Using a within-subjects design, 32 people took a daytime nap and slept overnight in the lab at least one week apart; both sleep sessions had polysomnography, including electrocardiography (ECG), recorded. We measured inter-beat intervals (RR), total power (TP), low frequency power (LF; .04–.15 Hz), and high frequency power (HF; .15–.40 Hz) components of HRV during NREM and rapid eye movement (REM) sleep. Compared to the nap, we found longer RR intervals and decreased heart rate during the night for both Stage 2 and SWS and increased TP, LF and HF power during nighttime Stage 2 sleep only; however, no differences in the LFHF ratio or normalized HF power were found between the nap and the night. Also, no differences in REM sleep between the nap and night were detected. Similar relationships emerged when comparing the nap to one cycle of nighttime sleep. These findings suggest that longer daytime naps, with both SWS and REM, may provide similar cardiovascular benefits as nocturnal sleep. In light of the on-going debate surrounding the health benefits and/or risks associated with napping, these results suggest that longer daytime naps in young, healthy adults may support cardiac down-regulation similar to nighttime sleep. In addition, napping paradigms may serve as tools to explore sleep-related changes in autonomic activity in both healthy and at-risk populations.

The mammalian circadian and sleep-wake systems are closely aligned through their coordinated regulation of daily activity patterns. Although they differ in their anatomical organization and physiological processes, they utilize overlapping regulatory mechanisms that include an assortment of proteins and molecules interacting within the extracellular space. These extracellular factors include proteases that interact with soluble proteins, membrane-attached receptors and the extracellular matrix; and cell adhesion molecules that can form complex scaffolds connecting adjacent neurons, astrocytes and their respective intracellular cytoskeletal elements. Astrocytes also participate in the dynamic regulation of both systems through modulating neuronal appositions, the extracellular space and/or through release of gliotransmitters that can further contribute to the extracellular signaling processes. Together, these extracellular elements create a system that integrates rapid neurotransmitter signaling across longer time scales and thereby adjust neuronal signaling to reflect the daily fluctuations fundamental to both systems. Here we review what is known about these extracellular processes, focusing specifically on areas of overlap between the two systems. We also highlight questions that still need to be addressed. Although we know many of the extracellular players, far more research is needed to understand the mechanisms through which they modulate the circadian and sleep-wake systems.

Millions of people worldwide are required to work when their physiology is tuned for sleep. By forcing wakefulness out of the body’s normal schedule, shift workers face numerous adverse health consequences, including gastrointestinal problems, sleep problems, and higher rates of some diseases, including cancers. Recent studies have developed protocols to simulate shift work in rodents with the intention of assessing the effects of night-shift work on subsequent sleep (Grønli et al., 2017). These studies have already provided important contributions to the understanding of the metabolic consequences of shift work (Arble et al., 2015; Marti et al., 2016; Opperhuizen et al., 2015) and sleep-wake-specific impacts of night-shift work (Grønli et al., 2017). However, our understanding of the causal mechanisms underlying night-shift-related sleep disturbances is limited. In order to advance toward a mechanistic understanding of sleep disruption in shift work, we model these data with two different approaches. First we apply a simple homeostatic model to quantify differences in the rates at which sleep need, as measured by slow wave activity during slow wave sleep (SWS) rises and falls. Second, we develop a simple and novel mathematical model of rodent sleep and use it to investigate the timing of sleep in a simulated shift work protocol (Grønli et al., 2017). This mathematical framework includes the circadian and homeostatic processes of the two-process model, but additionally incorporates a stochastic process to model the polyphasic nature of rodent sleep. By changing only the time at which the rodents are forced to be awake, the model reproduces some key experimental results from the previous study, including correct proportions of time spent in each stage of sleep as a function of circadian time and the differences in total wake time and SWS bout durations in the rodents representing night-shift workers and those representing day-shift workers. Importantly, the model allows for deeper insight into circadian and homeostatic influences on sleep timing, as it demonstrates that the differences in SWS bout duration between rodents in the two shifts is largely a circadian effect. Our study shows the importance of mathematical modeling in uncovering mechanisms behind shift work sleep disturbances and it begins to lay a foundation for future mathematical modeling of sleep in rodents.