Depression in adolescent boys is characterized by more evenly distributed SWA through the night as compared to healthy subjects, and we showed for the first time that this pattern of SWA distribution is associated with severity of depressive symptoms. These findings suggest that homeostatic regulation of sleep may be impaired in adolescent depression.

Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC) and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

Study Objective: Adverse early-life events induce behavioral psychopathologies and sleep changes in adulthood. In order to understand the molecular level mechanisms by which the maltreatment modifies sleep, valid animal models are needed. Changing pups between mothers at early age (cross-fostering) may satisfyingly model adverse events in human childhood. Methods: Cross-fostering (CF) was used to model mild early-life stress in male and female Wistar rats. Behavior and BDNF gene expression in the basal forebrain (BF), cortex, and hypothalamus were assessed during adolescence and adulthood. Spontaneous sleep, sleep homeostasis, and BF extracellular adenosine levels were assessed in adulthood. Results: CF rats demonstrated increased number of REM sleep onsets in light and dark periods of the day. Total REM and NREM sleep duration was also increased during the light period. While sleep homeostasis was not severely affected, basal level of adenosine in the BF of both male and female CF rats was lower than in controls. CF did not lead to considerable changes in behavior. Conclusions: Even when the consequences of adverse early-life events are not observed in tests for anxiety and depression, they leave a molecular mark in the brain, which can act as a vulnerability factor for psychopathologies in later life. Sleep is a sensitive indicator for even mild early-life stress.

Objectives: This study aimed to test the hypothesis that sleep and depression have independent effects on brain development and plasticity in adolescents, and that these changes are reflected in changes in the epigenome. Methods: Participants were 17 medication-free adolescent boys (age 16.05 ± 0.80 years, mean ± standard deviation (SD); eight cases with depression and sleep symptoms, nine healthy controls). Sleep was assessed by polysomnography recordings and the Pediatric Daytime Sleepiness Scale (PDSS) and Athens Insomnia Scale (AIS). Participants underwent a clinical evaluation. DNA methylation of blood leukocytes was measured by Illumina 450K array, and Ingenuity Pathway analysis was applied to identify the most significant pathways with differentially methylated positions (DMPs). Secondary analysis of the identified loci included linear correlations between methylation and the subjectively rated scales of sleep, depression and sleep microarchitecture. Results: Due to small sample size, we found no genome-wide significant differences in methylation between cases and controls. However, pathway analysis identified the synaptic long-term depression (LTD) canonical pathway (p ¼ 0.00045) when the best 500 DMPs from the original caseecontrol design were included. A flattened dissipation of slow wave sleep, tiredness and depression severity values correlated with five of 10 sites from the LTD pathway (IGF1R, PLAG16, PLA2R1, PPP2C5 and ERK12) in the secondary analysis when the caseecontrol status was controlled for. Conclusion: Among adolescents, depressive disorder with sleep symptoms is associated with a distinctive epigenetic pattern of DNA methylation in blood leukocytes. The enrichment of DMPs on genes related to synaptic LTD emphasizes the role of sleep in synaptic plasticity and the widespread physiological consequences of disturbed sleep.