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Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex.

ABSTRACT: Studies using self-report and physiological markers of circadian rhythmicity have demonstrated sex differences in a number of circadian attributes including morningness-eveningness, entrained phase, and intrinsic period. However, these sex differences have not been examined at the level of the molecular clock and not in human cerebral cortex. The authors tested the hypothesis that there are detectable daily rhythms of clock gene expression in human cerebral cortex and that there are significant sex differences in the timing of these rhythms. The expression levels of 3 clock genes-PER2, PER3, and ARNTL1-were quantified in samples of dorsolateral prefrontal cortex from 490 deceased individuals in 2 cohort studies of older individuals, the Religious Orders Study and the Rush Memory and Aging Project, using mRNA microarray data. Clock gene expression at death was parameterized as a function of time of death using cosine curves and was examined for sex differences in the phase of these curves. Significant daily variation was seen in the expression of PER2 (p = 0.004), PER3 (p = 0.003), and ARNTL1 (p = 0.0005). PER2/3 expression peaked at 10:38 (95% confidence interval [CI], 09:20-11:56) and 10:44 (95% CI, 09:29-11:59), respectively, and ARNTL1 expression peaked in antiphase to this at 21:23 (95% CI, 20:16-22:30). The timing of the expression of all 3 genes was significantly earlier in women than in men (PER2 6.8 h, p = 0.002; PER3 5.5 h, p = 0.001; ARNTL1 4.7 h, p = 0.007). Daily rhythms of clock gene expression are present in human cerebral cortex and can be inferred from postmortem samples. Moreover, these rhythms are relatively delayed in men compared with women.

SUBMITTER: Lim AS

PROVIDER: S-EPMC3774838 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex.

Lim Andrew S P AS Myers Amanda J AJ Yu Lei L Buchman Aron S AS Duffy Jeanne F JF De Jager Philip L PL Bennett David A DA

Journal of biological rhythms 20130401 2

Studies using self-report and physiological markers of circadian rhythmicity have demonstrated sex differences in a number of circadian attributes including morningness-eveningness, entrained phase, and intrinsic period. However, these sex differences have not been examined at the level of the molecular clock and not in human cerebral cortex. The authors tested the hypothesis that there are detectable daily rhythms of clock gene expression in human cerebral cortex and that there are significant ...[more]

PMID: 23606611

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Project description:BackgroundThe consequences of the earth's daily rotation have led to 24-h biological rhythms in most organisms. Even some parasites are known to have daily rhythms, which, when in synchrony with host rhythms, can optimise their fitness. Understanding these rhythms may enable the development of control strategies that take advantage of rhythmic vulnerabilities. Recent work on protozoan parasites has revealed 24-h rhythms in gene expression, drug sensitivity and the presence of an intrinsic circadian clock; however, similar studies on metazoan parasites are lacking. To address this, we investigated if a metazoan parasite has daily molecular oscillations, whether they reveal how these longer-lived organisms can survive host daily cycles over a lifespan of many years and if animal circadian clock genes are present and rhythmic. We addressed these questions using the human blood fluke Schistosoma mansoni that lives in the vasculature for decades and causes the tropical disease schistosomiasis.ResultsUsing round-the-clock transcriptomics of male and female adult worms collected from experimentally infected mice, we discovered that ~ 2% of its genes followed a daily pattern of expression. Rhythmic processes included a stress response during the host's active phase and a 'peak in metabolic activity' during the host's resting phase. Transcriptional profiles in the female reproductive system were mirrored by daily patterns in egg laying (eggs are the main drivers of the host pathology). Genes cycling with the highest amplitudes include predicted drug targets and a vaccine candidate. These 24-h rhythms may be driven by host rhythms and/or generated by a circadian clock; however, orthologs of core clock genes are missing and secondary clock genes show no 24-h rhythmicity.ConclusionsThere are daily rhythms in the transcriptomes of adult S. mansoni, but they appear less pronounced than in other organisms. The rhythms reveal temporally compartmentalised internal processes and host interactions relevant to within-host survival and between-host transmission. Our findings suggest that if these daily rhythms are generated by an intrinsic circadian clock then the oscillatory mechanism must be distinct from that in other animals. We have shown which transcripts oscillate at this temporal scale and this will benefit the development and delivery of treatments against schistosomiasis.

Project description:Circadian clocks in many brain regions and peripheral tissues are entrained by the daily rhythm of food intake. Clocks in one or more of these locations generate a daily rhythm of locomotor activity that anticipates a regular mealtime. Rats and mice can also anticipate two daily meals. Whether this involves 1 or 2 circadian clocks is unknown. To gain insight into how the circadian system adjusts to 2 daily mealtimes, male rats in a 12∶12 light-dark cycle were fed a 2 h meal either 4 h after lights-on or 4 h after lights-off, or a 1 h meal at both times. After 30 days, brain, blood, adrenal and stomach tissue were collected at 6 time points. Multiple clock genes from adrenals and stomachs were assayed by RT-PCR. Blood was assayed for corticosterone and ghrelin. Bmal1 expression was quantified in 14 brain regions by in situ hybridization. Clock gene rhythms in adrenal and stomach from day-fed rats oscillated in antiphase with the rhythms in night-fed rats, and at an intermediate phase in rats fed twice daily. Corticosterone and ghrelin in 1-meal rats peaked at or prior to the expected mealtime. In 2-meal rats, corticosterone peaked only prior the nighttime meal, while ghrelin peaked prior to the daytime meal and then remained elevated. The olfactory bulb, nucleus accumbens, dorsal striatum, cerebellum and arcuate nucleus exhibited significant daily rhythms of Bmal1 in the night-fed groups that were approximately in antiphase in the day-fed groups, and at intermediate levels (arrhythmic) in rats anticipating 2 daily meals. The dissociations between anticipatory activity and the peripheral clocks and hormones in rats anticipating 2 daily meals argue against a role for these signals in the timing of behavioral rhythms. The absence of rhythmicity at the tissue level in brain regions from rats anticipating 2 daily meals support behavioral evidence that circadian clock cells in these tissues may reorganize into two populations coupled to different meals.

Dataset Information

Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex.

Publications

Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex.

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