Bright light exposure during simulated night work improves cognitive flexibility

Under embargo until: 2023-03-28Night work leads to sleepiness and reduced vigilant attention during work hours, and bright light interventions may reduce such effects. It is also known that total sleep deprivation impairs cognitive flexibility as measured by reversal learning tasks. Whether night work impairs reversal learning task performance or if bright light can mitigate reversal learning deficits during night work is unclear. In this counterbalanced crossover study (ClinicaTrials.gov Identifier NCT03203538), young healthy individuals completed a reversal learning task twice during each of three consecutive simulated night shifts (23:00–07:00 h). The night shifts were performed in a laboratory under a full-spectrum (4000 K) bright light (~900 lx) and a standard light (~90 lx) condition. Reversal learning task performance was reduced towards the end of the night shifts (04:50 h), compared to the first part of the night shifts (00:20 h) in both light conditions. However, with bright light, the reversal learning task performance improved towards the end of the night shifts, compared to standard light. The study shows that bright light may mitigate performance deficits on a reversal learning task during night work and implies that bright light interventions during night work may be beneficial not only for vigilant attention but also for cognitive flexibility.acceptedVersio

Blue-enriched white light improves performance but not subjective alertness and circadian adaptation during three consecutive simulated night shifts

Use of blue-enriched light has received increasing interest regarding its activating and performance sustaining effects. However, studies assessing effects of such light during night work are few, and novel strategies for lighting using light emitting diode (LED) technology need to be researched. In a counterbalanced crossover design, we investigated the effects of a standard polychromatic blue-enriched white light (7000 K; ∼200 lx) compared to a warm white light (2500 K), of similar photon density (∼1.6 × 1014 photons/cm2/s), during three consecutive simulated night shifts. A total of 30 healthy participants [10 males, mean age 23.3 (SD = 2.9) years] were included in the study. Dependent variables comprised subjective alertness using the Karolinska Sleepiness Scale, a psychomotor vigilance task (PVT) and a digit symbol substitution test (DSST), all administered at five time points throughout each night shift. We also assessed dim-light melatonin onset (DLMO) before and after the night shifts, as well as participants’ opinion of the light conditions. Subjective alertness and performance on the PVT and DSST deteriorated during the night shifts, but 7000 K light was more beneficial for performance, mainly in terms of fewer errors on the PVT, at the end of the first- and second- night shift, compared to 2500 K light. Blue-enriched light only had a minor impact on PVT response times (RTs), as only the fastest 10% of the RTs were significantly improved in 7000 K compared to 2500 K light. In both 7000 and 2500 K light, the DLMO was delayed in those participants with valid assessment of this parameter [n = 20 (69.0%) in 7000 K light, n = 22 (78.6%) in 2500 K light], with a mean of 2:34 (SE = 0:14) and 2:12 (SE = 0:14) hours, respectively, which was not significantly different between the light conditions. Both light conditions were positively rated, although participants found 7000 K to be more suitable for work yet evaluated 2500 K light as more pleasant. The data indicate minor, but beneficial, effects of 7000 K light compared to 2500 K light on performance during night work. Circadian adaptation did not differ significantly between light conditions, though caution should be taken when interpreting these findings due to missing data. Field studies are needed to investigate similar light interventions in real-life settings, to develop recommendations regarding illumination for night workers.publishedVersio

Mathematical modeling of sleep state dynamics in a rodent model of shift work

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

Shift in Food Intake and Changes in Metabolic Regulation and Gene Expression during Simulated Night-Shift Work:A Rat Model

Night-shift work is linked to a shift in food intake toward the normal sleeping period, and to metabolic disturbance. We applied a rat model of night-shift work to assess the immediate effects of such a shift in food intake on metabolism. Male Wistar rats were subjected to 8 h of forced activity during their rest (ZT2-10) or active (ZT14-22) phase. Food intake, body weight, and body temperature were monitored across four work days and eight recovery days. Food intake gradually shifted toward rest-work hours, stabilizing on work day three. A subgroup of animals was euthanized after the third work session for analysis of metabolic gene expression in the liver by real-time polymerase chain reaction (PCR). Results show that work in the rest phase shifted food intake to rest-work hours. Moreover, liver genes related to energy storage and insulin metabolism were upregulated, and genes related to energy breakdown were downregulated compared to non-working time-matched controls. Both working groups lost weight during the protocol and regained weight during recovery, but animals that worked in the rest phase did not fully recover, even after eight days of recovery. In conclusion, three to four days of work in the rest phase is sufficient to induce disruption of several metabolic parameters, which requires more than eight days for full recovery.publishedVersio

No Escaping the Rat Race: Simulated Night Shift Work Alters the Time-of-Day Variation in BMAL1 Translational Activity in the Prefrontal Cortex

Millions of people worldwide work during the night, resulting in disturbed circadian rhythms and sleep loss. This may cause deficits in cognitive functions, impaired alertness and increased risk of errors and accidents. Disturbed circadian rhythmicity resulting from night shift work could impair brain function and cognition through disrupted synthesis of proteins involved in synaptic plasticity and neuronal function. Recently, the circadian transcription factor brain-and-muscle arnt-like protein 1 (BMAL1) has been identified as a promoter of mRNA translation initiation, the most highly regulated step in protein synthesis, through binding to the mRNA “cap”. In this study we investigated the effects of simulated shift work on protein synthesis markers. Male rats (n = 40) were exposed to forced activity, either in their rest phase (simulated night shift work) or in their active phase (simulated day shift work) for 3 days. Following the third work shift, experimental animals and time-matched undisturbed controls were euthanized (rest work at ZT12; active work at ZT0). Tissue lysates from two brain regions (prefrontal cortex, PFC and hippocampus) implicated in cognition and sleep loss, were analyzed with m7GTP (cap) pull-down to examine time-of-day variation and effects of simulated shift work on cap-bound protein translation. The results show time-of-day variation of protein synthesis markers in PFC, with increased protein synthesis at ZT12. In the hippocampus there was little difference between ZT0 and ZT12. Active phase work did not induce statistically significant changes in protein synthesis markers at ZT0 compared to time-matched undisturbed controls. Rest work, however, resulted in distinct brain-region specific changes of protein synthesis markers compared to time-matched controls at ZT12. While no changes were observed in the hippocampus, phosphorylation of cap-bound BMAL1 and its regulator S6 kinase beta-1 (S6K1) was significantly reduced in the PFC, together with significant reduction in the synaptic plasticity associated protein activity-regulatedcytoskeleton-associated protein (Arc). Our results indicate considerable time-of-day and brain-region specific variation in cap-dependent translation initiation. We concludethat simulated night shift work in rats disrupts the pathways regulating the circadian component of the translation of mRNA in the PFC, and that this may partly explain impaired waking function during night shift work

The early life condition: Importance for sleep, circadian rhythmicity, behaviour and response to later life challenges

Early life environment has a vast impact on development and adult functioning. Optimal brain development depends not only on genetic programming but also on specific external stimuli, where mother-infant relationships play an important role. In rats, through maternal presence and active care, important stimuli are provided which influence the development of behaviour and basic physiological functions in the offspring such as sleep, circadian rhythms and stress-regulating mechanisms. Events in early life can define the development of the offspring, and depending on the events’ timing and duration, may induce long-term positive or negative consequences. If the events are adverse they may induce enhanced vulnerability to stress exposure later in life. Clinical studies have revealed a close link between adverse early life events and development of affective disorders in adulthood. Underlying mechanisms are commonly studied using experimental models of early life adverse events based on daily separations of infant rats from their mothers for periods longer than considered natural, in comparison to other more natural early life conditions. The main aim of this study was to investigate three early life conditions in rats, long maternal separations (LMS), brief maternal separations (BMS) or non-handling (NH), and their consequences in adulthood on: brain activity, sleep, circadian rhythms, levels of corticosterone, affective-like behaviour and cognitive performance. Effects of early life conditions in combination with exposure to chronic mild stress (CMS) in adulthood were also investigated. Such a combination, which yields a potentially high etiological and construct validity, has not received great attention in the preclinical literature. Paper I investigated the consequences on brain activity measured by electroencephalogram (EEG) power and sleep in adult LMS and BMS offspring. As an effect of early life condition, adult LMS offspring showed lower EEG power recorded from the frontal cortical structures during both sleep and wakefulness, compared to BMS offspring. The quality of slow wave sleep (SWS) differed as a consequence of maternal separation. LMS offspring showed more deep SWS but lower power of delta waves and a slower reduction of the sleep pressure compared to BMS offspring. Exposure to CMS led to similar reductions in EEG power during sleep and wakefulness and affected reduction of sleep pressure in both groups. Compared to BMS offspring, the lower EEG power was still present in LMS offspring who also showed longer total sleep time and an indication of higher pressure for rapid eye movement (REM) sleep. In Paper II, the consequences on circadian rhythmicity of body temperature, locomotor activity and heart rate were investigated in adult LMS and BMS offspring. As an effect of early life condition, LMS offspring showed a delayed circadian peak of body temperature compared to BMS offspring. Investigation of all other parameters showed that circadian rhythms of body temperature, locomotor activity and heart rate were similar between adult LMS and BMS offspring. The stronger impact of CMS exposure in LMS offspring was evident in stronger and longer lasting reduction of body temperature compared to BMS offspring. The degree of mothers’ active care was reflected in the degree of hypothermia in LMS offspring. More active nursing following maternal separation moderated the severity of hypothermia. In Paper III, consequences of three early life conditions, LMS, BMS and NH were investigated measuring levels of corticosterone, affective-like behaviour and cognitive performance. LMS offspring displayed higher basal level of corticosterone than BMS offspring and both NH and LMS offspring showed poor cognitive performance measured by lower object exploration compared to BMS offspring. NH also showed lower pre-pulse inhibition than LMS and BMS offspring. These results reflect adverse consequences of both LMS and the condition with constant presence of the mother. There were no differences in affective-like behaviour between the three early life conditions. Exposure to CMS induced an anhedonic-like state in all offspring. An initially high level of corticosterone was not further elevated by CMS in LMS offspring, whereas they explored objects less compared to BMS offspring. Upon CMS exposure, both BMS and NH offspring increased their object exploration. A positive effect of CMS in NH offspring was also indicated by increased habituation and pre-pulse inhibition in acoustic startle test. The present study describes consequences of different early life conditions (LMS, BMS or NH) on adulthood functioning and different consequences of exposure to chronic stressors in adulthood. Overall, the results indicate that exposure to LMS during early life may have adverse consequences for brain functioning as reflected in measures of brain activity and cognitive performance. Results in BMS offspring confirm that brief separations early in life may provide a “toughening up” effect in adulthood. Exposure to CMS affected brain activity in both LMS and BMS offspring. More severe impact was observed on cognitive performance and thermoregulatory response in the LMS offspring; importantly, active maternal care reduced the negative consequence of CMS. Brain activity was not assessed in the NH offspring, while the results on cognitive performance suggest adverse consequences of early life condition with the constant presence of the mother. However, remarkably, the results indicate that adult exposure to chronic mild stressors mimicking daily hassles in humans may produce a positive effect in NH offspring. Overall, the present findings reveal that different experiences and hence different developmental conditions during early life may have consequences for adulthood brain functioning

Sleep homeostasis and night work: a polysomnographic study of daytime sleep following three consecutive simulated night shifts

Purpose: Millions of people work at times that overlap with the habitual time for sleep. Consequently, sleep often occurs during the day. Daytime sleep is, however, characterized by reduced sleep duration. Despite preserved time spent in deep NREM sleep (stage N3), daytime sleep is subjectively rated as less restorative. Knowledge on how night work influences homeostatic sleep pressure is limited. Therefore, we aimed to explore the effect of three consecutive simulated night shifts on daytime sleep and markers of sleep homeostasis. Patients and Methods: We performed continuous EEG, EMG and EOG recordings in the subjects’ home setting for one nighttime sleep opportunity, and for the daytime sleep opportunities following three consecutive simulated night shifts. Results: For all daytime sleep opportunities, total sleep time was reduced compared to nighttime sleep. While time spent in stage N3 was preserved, sleep pressure at sleep onset, measured by slow wave activity (1– 4 Hz), was higher than nighttime sleep and higher on day 3 than on day 1 and 2. Elevated EEG power during daytime sleep was sustained through 6 h of time in bed. Slow wave energy was not significantly different from nighttime sleep after 6 h, reflecting a less efficient relief of sleep pressure. Conclusion: Adaptation to daytime sleep following three consecutive simulated night shifts is limited. The increased homeostatic response and continuation of sleep pressure relief even after 6 h of sleep, are assumed to reflect a challenge for appropriate homeostatic reduction to occur.publishedVersio

Early and Later Life Stress Alter Brain Activity and Sleep in Rats

Exposure to early life stress may profoundly influence the developing brain in lasting ways. Neuropsychiatric disorders associated with early life adversity may involve neural changes reflected in EEG power as a measure of brain activity and disturbed sleep. The main aim of the present study was for the first time to characterize possible changes in adult EEG power after postnatal maternal separation in rats. Furthermore, in the same animals, we investigated how EEG power and sleep architecture were affected after exposure to a chronic mild stress protocol. During postnatal day 2–14 male rats were exposed to either long maternal separation (180 min) or brief maternal separation (10 min). Long maternally separated offspring showed a sleep-wake nonspecific reduction in adult EEG power at the frontal EEG derivation compared to the brief maternally separated group. The quality of slow wave sleep differed as the long maternally separated group showed lower delta power in the frontal-frontal EEG and a slower reduction of the sleep pressure. Exposure to chronic mild stress led to a lower EEG power in both groups. Chronic exposure to mild stressors affected sleep differently in the two groups of maternal separation. Long maternally separated offspring showed more total sleep time, more episodes of rapid eye movement sleep and higher percentage of non-rapid eye movement episodes ending in rapid eye movement sleep compared to brief maternal separation. Chronic stress affected similarly other sleep parameters and flattened the sleep homeostasis curves in all offspring. The results confirm that early environmental conditions modulate the brain functioning in a long-lasting way

Physical Exercise and Serum BDNF Levels : Accounting for the Val66Met Polymorphism in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) expression, which can be measured in blood serum, has been found to increase with aerobic exercise. The link between BDNF level, physical exercise, and genetic status (Val66Met polymorphism) has not been well researched in older adults. OBJECTIVE: To investigate the possible link between BDNF expression, acute aerobic exercise, and the Val66Met polymorphism in older adults. METHOD: Twenty-three healthy older adults participated in one session of acute aerobic exercise. Their serum BDNF levels were measured both at baseline and post exercise. Saliva samples were collected to identify each individual's genetic status. RESULTS: At baseline, the individuals' mean serum BDNF level was 16.03 ng/mL (Val66Val = 15.89 ng/mL; Val66Met = 16.34 ng/mL); post exercise, the individuals' mean serum BDNF level was 16.81 ng/mL (Val66Val = 16.14 ng/mL; Val66Met = 18.34 ng/mL). CONCLUSION: One session of acute aerobic exercise significantly increased the individuals' mean serum BDNF level. Males had higher BDNF levels than females. There was a significant interaction between gender and BDNF expression post exercise and a significant between-group effect of gender. The Val66Met carriers had a more positive response to the acute aerobic exercise compared with the Val66Val carriers, although without a significant difference between the two groups