The Dim Light Melatonin Onset (DLMO) across ages, methodologies and sex and its relationship with Morningness/Eveningness

The onset of melatonin secretion, the Dim Light Melatonin Onset or DLMO is a tool for determining the phase of the circadian timing system. While small studies have investigated the impacts of age and methods of calculating DLMO, there is no DLMO reference range. In the current study, the saliva DLMO from 121 published studies (3579 subjects) and plasma DLMO in 31 studies (818 subjects) in healthy control subjects (3 - 73 years) were analysed. In a subset of 53 papers (1749 subjects) individual saliva DLMO and MEQ scores were obtained from authors or mined from publications and a reference range was constructed. Saliva DLMO was earliest in children to 10 years of age and latest around 20 years of age and thereafter advanced with age by 30 minutes in the oldest subjects. Melatonin assay methods and DLMO calculation methods had little effect on the determination of the DLMO. Saliva DLMO was correlated (P < 0.001) with the MEQ score; lower MEQ scores were associated with later DLMO. MEQ scores increased with age, reflecting a tendency towards Morningness. An evaluation of 14 saliva DLMO studies of clinically diagnosed DSWPD patients (mean ages 20 to 31 years) revealed mean saliva DLMO within the reference range albeit at the late extreme. Peak plasma melatonin levels from 179 studies of healthy subjects revealed a high degree of variability within studies and age groups, but only a small decline between the 20 and 50 years and lowest levels after 70 years.David J. Kennawa

Physiological evidence consistent with reduced neuroplasticity in human adolescents born preterm

Preterm-born children commonly experience motor, cognitive, and learning difficulties that may be accompanied by altered brain microstructure, connectivity, and neurochemistry. However, the mechanisms linking the altered neurophysiology with the behavioral outcomes are unknown. Here we provide the first physiological evidence that human adolescents born preterm at or before 37 weeks of completed gestation have a significantly reduced capacity for cortical neuroplasticity, the key overall mechanism underlying learning and memory. We examined motor cortex neuroplasticity in three groups of adolescents who were born after gestations of ≤32 completed weeks (early preterm), 33–37 weeks (late preterm), and 38–41 weeks (term) using a noninvasive transcranial magnetic brain stimulation technique to induce long-term depression (LTD)-like neuroplasticity. Compared with term-born adolescents, both early and late preterm adolescents had reduced LTD-like neuroplasticity in response to brain stimulation that was also associated with low salivary cortisol levels. We also compared neuroplasticity in term-born adolescents with that in term-born young adults, finding that the motor cortex retains a relatively enhanced neuroplastic capacity in adolescence. These findings provide a possible mechanistic link between the altered brain physiology of preterm birth and the subsequent associated behavioral deficits, particularly in learning and memory. They also suggest that altered hypothalamic–pituitary–adrenal axis function due to preterm birth may be a significant modulator of this altered neuroplasticity. This latter finding may offer options in the development of possible therapeutic interventions

High-fat diet-induced obesity ablates gastric vagal afferent circadian rhythms

Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesityStephen J. Kentish, Andrew D. Vincent, David J. Kennaway, Gary A. Wittert, and Amanda J. Pag

Controlled-release melatonin implants delay puberty in rats without altering melatonin rhythmicity

There is increasing evidence that continuous availability of melatonin via implants can produce the same physiological changes in animals as timed administration of the hormone. The mechanisms underlying this apparent contradiction are not known. In an attempt to gain further understanding of the way continuous melatonin administration affects reproductive activity, the effects of melatonin implants on gonadal development and melatonin production were investigated in rats treated neonatally with testosterone. Five-day-old male rats maintained on a 12L:12D photoperiod were injected with 1 mg testosterone propionate to induce photo-responsiveness and implanted at 21 days of age with novel melatonin implants designed to raise the daytime blood melatonin concentration into the nighttime range, i.e., from less than 60 pM in the controls during the day to 380 +/- 33 pM in the implanted rats. Following 21 days treatment, seminal vesicle and ventral prostate weights of implanted rats were significantly less than the controls (27.0 +/- 1.9 vs. 18.5 +/- 1.5 mg/ 100 g BW (P = 0.003) and 33.8 +/- 2.1 vs. 26.7 +/- 2.2 mg/100 g BW (P = 0.02), respectively). To determine the effect of the implants upon melatonin production, urine was collected at hourly intervals during the last four days of the experiment and the hourly 6-sulphatoxymelatonin (aMT.6S) excretion rate was determined. Rats bearing melatonin implants maintained a rhythm of aMT.6S excretion in 12L:12D, which was indistinguishable from that in the control animals except for a raised daytime excretion of the metabolite. Following one cycle of urinary aMT.6S measurements in the light/dark cycle, the animals were released into constant darkness, with the implants still in place or after their removal four hours before darkness to evaluate the characteristics of the melatonin rhythm in the absence of masking effects of the light/dark cycle. The melatonin rhythm persisted in both control and implanted rats and no differences in the onset, offset, or amplitude could be determined. The results of this study indicate that, like many other mammals, for laboratory rats controlled continuous release of melatonin can mimic the effects of short daylength or timed melatonin administration. Despite the reproductive consequences of continuous melatonin delivery, the timing of endogenous melatonin production is unaffected

Effects of chronic agomelatine administration on the expression of a panel of genes in various brain areas of rats

Presentation P.2.d.019T.J. Varcoe, M. Salkeld, E. Mocaer, L. Seguin, D.J. Kennawa

A comparison of direct and spontaneous methods for assessing parental attributions

Recent studies have shown that intrauterine growth retardation or fetal distress in human infants is associated with a pronounced reduction in melatonin secretion during the first 3 months of life. It is not known whether these associations persist beyond infancy. We have therefore examined the relationship between birthsize and melatonin secretion in 159 men and women aged 20, born in Adelaide, South Australia. Melatonin secretion was estimated by analysing the overnight urinary excretion of 6-sulphatoxymelatonin. The overnight excretion ranged from 1.7 to 128.9 nmoles/subject, was higher in women than in men (46.5 vs 34.1 nmoles, P=0.003) and was significantly negatively correlated with the body mass index (P=0.006). Excretion correlated with both birthweight and ponderal index at birth (P=0.04 and P=0.01 respectively after adjustment for gestational age) and also fell with increased duration of gestation (P=0.007). The effects of adult body mass index added to that of low birthweight in predicting 6-sulphatoxymelatonin excretion. These data suggest that urinary 6-sulphatoxymelatonin excretion was impaired in adults who were growth restricted prenatally or were delivered after 40 weeks gestation

Simulated shift work during pregnancy does not impair progeny metabolic outcomes in sheep

Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non-litter bearing species. We therefore assessed postnatal growth from birth to adulthood, and body composition, glucose tolerance, insulin secretion and insulin sensitivity in pre-pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first 1/3 (SSW0-7: 11 males, 9 females), the first 2/3 (SSW0-14: 8 males, 11 females), or all (SSW0-21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre-pubertal progeny (12-14 weeks of age), adiposity, glucose tolerance and insulin secretion during an intravenous glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12-14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females (P = 0.031), and insulin sensitivity of SSW0-21 singleton females was 236% that of CON singleton female progeny (P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny.Kathryn L. Gatford, David J. Kennaway, Hong Liu, Christopher G. Schultz, Amy L. Wooldridge, Timothy R. Kuchel and Tamara J. Varco