The circadian clock orchestrates many aspects of human physiology, and disruption of this clock has been implicated in various pathologies, ranging from cancer to metabolic syndrome and diabetes. Although there is evidence that metabolism and the circadian clockwork are intimately linked on a transcriptional level, whether these effects are directly under clock control or are mediated by the rest-activity cycle and the timing of food intake is unclear. To answer this question, we conducted an unbiased screen in human subjects of the metabolome of blood plasma and saliva at different times of day. To minimize indirect effects, subjects were kept in a 40-h constant routine of enforced posture, constant dim light, hourly isocaloric meals, and sleep deprivation. Under these conditions, we found that ∼15% of all identified metabolites in plasma and saliva were under circadian control, most notably fatty acids in plasma and amino acids in saliva. Our data suggest that there is a strong direct effect of the endogenous circadian clock on multiple human metabolic pathways that is independent of sleep or feeding. In addition, they identify multiple potential small-molecule biomarkers of human circadian phase and sleep pressure.metabolomics | LC/GC-MS | metabolite profiling | sleep-wake regulation T he circadian clock has been shown to modulate many aspects of behavior and physiology (1). It is thought to be an important regulator of metabolism, and disruption of the clock and sleep is associated with obesity, metabolic syndrome, and type 2 diabetes, as well as other disorders (2-4). In the last decade, ample data on the circadian transcriptome (5, 6) and the even larger circadian proteome (7) have been compiled. These datasets are directly dependent on the genome of a particular species and cannot be compared easily between model systems. However, changes in physiology and metabolism governed by these genes and proteins ultimately affect the abundance of small metabolites that are quite conserved among species and fewer in number (50-fold fewer than transcripts and 500-fold fewer than proteins).The relationship between metabolism and the clock is not unidirectional, and the two processes are intertwined (8). For example, metabolic status feeds back to the clock, so that feeding behavior directly entrains molecular clock function (9). Likewise, obesity is correlated with poor sleep (2), and in mice 80% of circadian transcription in the brain is dependent on the rest-activity cycle (10). Given these feedback mechanisms, it is unclear what proportion of circadian metabolic control is directly clockregulated and what proportion is controlled by circadian restactivity and food intake.In plants, the metabolome approach has been used to characterize the effects of clock disruption on general metabolism (11). The circadian metabolome also has been characterized in CBA/N mice, and ∼20% of the recorded molecules were found to vary in abundance with time of day (12). Similarly, the urine and saliva metabolomes of human subjects diff...

The maturation of sleep regulatory systems during adolescence in combination with psychosocial and societal pressures culminate in a "Perfect Storm" of short and ill-timed sleep and the associated consequences for many youngsters. This model, first described by Carskadon in 2011, guides our current thinking of adolescent sleep behavior. Since the original description, the field has moved forward with remarkable pace, and this review aims to summarize recent progress and describe how this new work informs our understanding of sleep regulation and sleep behavior during this developmental time frame.

Sleep is a core behavior of adolescents, consuming up to a third or more of each day. As part of this special issue on the adolescent brain, we review changes to sleep behaviors and sleep physiology during adolescence with a particular focus on the sleeping brain. We posit that brain activity during sleep may provide a unique window onto adolescent cortical maturation and compliment waking measures. In addition, we review how sleep actively supports waking cognitive functioning in adolescence. Though this review is focused on sleep in healthy adolescents, the striking comorbidity of sleep disruption with nearly all psychiatric and developmental disorders (for reviews see 1,2) further highlights the importance of understanding the determinants and consequences of adolescent sleep for the developing brain. Figure 1 illustrates the overarching themes of our review, linking brain development, sleep development, and behavioral outcomes.

The aim of this descriptive analysis was to examine sleep timing, circadian phase, and phase angle of entrainment across adolescence in a longitudinal study design. Ninety-four adolescents participated; 38 (21 boys) were 9–10 years (“younger cohort”) and 56 (30 boys) were 15–16 years (“older cohort”) at the baseline assessment. Participants completed a baseline and then follow-up assessments approximately every six months for 2.5 years. At each assessment, participants wore a wrist actigraph for at least one week at home to measure self-selected sleep timing before salivary dim light melatonin onset (DLMO) phase – a marker of the circadian timing system – was measured in the laboratory. Weekday and weekend sleep onset and offset and weekend-weekday differences were derived from actigraphy. Phase angles were the time durations from DLMO to weekday sleep onset and offset times. Each cohort showed later sleep onset (weekend and weekday), later weekend sleep offset, and later DLMO with age. Weekday sleep offset shifted earlier with age in the younger cohort and later in the older cohort after age 17. Weekend-weekday sleep offset differences increased with age in the younger cohort and decreased in the older cohort after age 17. DLMO to sleep offset phase angle narrowed with age in the younger cohort and became broader in the older cohort. The older cohort had a wider sleep onset phase angle compared to the younger cohort; however, an age-related phase angle increase was seen in the younger cohort only. Individual differences were seen in these developmental trajectories. This descriptive study indicated that circadian phase and self-selected sleep delayed across adolescence, though school-day sleep offset advanced until no longer in high school, whereupon offset was later. Phase angle changes are described as an interaction of developmental changes in sleep regulation interacting with psychosocial factors (e.g., bedtime autonomy).

This longitudinal analysis highlights asymmetrical frequency-specific declines in sleep EEG spectral power with early adolescent maturation, which may reflect early signs of the cortical synaptic pruning in the healthy adolescent.