Molecular insights into human daily behavior

Brown, Steven A.; Kunz, Dieter; Dumas, Amelie; Westermark, Pål O.; Vanselow, Katja; Tilmann-Wahnschaffe, Amely; Herzel, Hanspeter; Kramer, Achim

doi:10.1073/pnas.0707772105

Cited by 246 publications

(264 citation statements)

References 32 publications

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“…Second, alteration in circadian processes in peripheral pacemakers as noted here may not necessarily reflect changes in central processes (the key regulators of behaviour) and thus we make no claims that the oral mucosa is a proxy for the SCN. Having said this, it is worth noting that the characteristics of molecular rhythms in skin fibroblasts 25 and in hair follicles 23 do correlate with behavioural measures of the subjects from whom the samples were derived, as they do in our present study (correlations between clock gene chronometrics and actigraphic period).…”

Section: Clock Gene Rhythmsmentioning

confidence: 63%

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

et al. 2011

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Attention-deficit hyperactivity disorder (ADHD) in adults is associated with impaired sleep, and it has been postulated that this impairment may contribute to the psychopathology of this common condition. One key driver of sleep/wake cycles is the circadian system, which at the molecular level consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological and behavioural outputs with a near 24 h periodicity. We set out to examine circadian rhythms at the behavioural, endocrine and molecular levels in ADHD. Adults with ADHD as well as age-and sex-matched controls were recruited. Circadian rhythms were measured by means of actigraphy for the determination of gross motor patterns, by self-sampling of oral mucosa for assessment of rhythmic expression of the clock genes BMAL1 and PER2, and by estimation of salivary cortisol and melatonin levels. Actigraphic analysis revealed significant diurnal and nocturnal hyperactivity in the ADHD group, as well as a significant shorter period of best fit for the locomotor circadian rhythm in ADHD. BMAL1 and PER2 showed circadian rhythmicity in controls with this being lost in the ADHD group. Cortisol rhythms were significantly phase delayed in the ADHD group. These findings indicate that adult ADHD is accompanied by significant changes in the circadian system, which in turn may lead to decreased sleep duration and quality in the condition. Further, modulation of circadian rhythms may represent a novel therapeutic avenue in the management of ADHD.

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Section: Clock Gene Rhythmsmentioning

confidence: 63%

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

et al. 2011

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“…These two methods are therefore complementary for detecting circadian rhythm disorders. Our metabolite timetable method may provide a good platform for the initial screening of body-time abnormality caused by either abnormal environments or genetic differences, because our method is minimally invasive and less labor intensive compared with the conventional method or biopsy adopted in Brown et al (61,62). Moreover, the metabolite timetable method can track the transient dynamics of internal body time, which cannot be detected by conventional time-course sampling method.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to abnormal environments, genetic differences such as familial advanced sleep phase syndrome (FASPS) also cause changes in the internal body time of individuals (58-60). Brown et al recently developed a method to potentially detect the circadian rhythm disorders caused by genetic differences (61,62). They collected skin samples from human subjects, cultured these cells, and transfected them with a clock-controlled reporter to characterize the features of the molecular clock in these tissues.…”

Section: Discussionmentioning

confidence: 99%

Human blood metabolite timetable indicates internal body time

Kasukawa

Sugimoto

Hida

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

168

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A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, moleculartimetable method with human blood enables highly optimized and personalized medicine.metabolomics | circadian rhythm | liquid chromatography mass spectrometry | diagnostic tool M any organisms possess a molecular time-keeping mechanism, a circadian clock, which has endogenous, self-sustained oscillations with a period of about 24 h. Circadian regulation of cell activity occurs in diverse biological processes such as electrical activity, gene/protein expression, and concentration of ions and substances (1, 2). In mammals, for example, several clock genes regulate circadian gene expression in central and peripheral clock tissues (3-9), as well as metabolites in the blood (10-15). Reflecting circadian regulation of such processes, the potency and toxicity of administered drugs depends on an individual's body time (BT) (16)(17)(18)(19)(20)(21)(22). Drug delivery according to body time improves the outcome of pharmacotherapy by maximizing potency and minimizing toxicity (23), and administrating drugs at an inappropriate body time can result in severe side effects (22). For example, rhythm disturbances were induced by administration of IFN-α during the early active phase in mice, although unaffected during the early rest phase (22); and the time of administration of two anticancer drugs, adriamycin (6:00 AM) and cisplatin (6:00 PM), made a lower toxicity effect than its antiphasic administration (24). However, several reports showed that internal body time varies by 5-6 h in healthy humans (25, 26) and as much as 10-12 h in shift workers without forced entrainments (27,28). Therefore, for efficient application of body-time drug delivery or "chronotherapy" (16-20) in a clinical setting, a simple and robust method for estimating an individual's internal body time is needed.Additionally, the timing of food intake may contribute to weight gain (29) and metabolic disease (30) because energy regulation and circadian rhythms are molecularly and physiologically intertwined (31-41). For example, mice fed a high-fat diet during a 12-h light phase gain significantly more ...

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“…As reported by Brown et al, the second step can be performed by monitoring the activity of a clock-regulated reporter gene transfected into primary-cultured fibroblasts obtained from the skin (24). By using this method, they have already succeeded in characterizing human chronotypes (25). However, because skin biopsy is burdensome to patients, another similar method may need to be developed without this type of biopsy.…”

Section: Correlation Between Human Behavioral Rhythms and Circadian Cmentioning

confidence: 99%

Noninvasive method for assessing the human circadian clock using hair follicle cells

Akashi

Soma

Yamamoto

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

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A thorough understanding of the circadian clock requires qualitative evaluation of circadian clock gene expression. Thus far, no simple and effective method for detecting human clock gene expression has become available. This limitation has greatly hampered our understanding of human circadian rhythm. Here we report a convenient, reliable, and less invasive method for detecting human clock gene expression using biopsy samples of hair follicle cells from the head or chin. We show that the circadian phase of clock gene expression in hair follicle cells accurately reflects that of individual behavioral rhythms, demonstrating that this strategy is appropriate for evaluating the human peripheral circadian clock. Furthermore, using this method, we indicate that rotating shift workers suffer from a serious time lag between circadian gene expression rhythms and lifestyle. Qualitative evaluation of clock gene expression in hair follicle cells, therefore, may be an effective approach for studying the human circadian clock in the clinical setting.circadian rhythm | clock gene | shift work | jet lag | chronotherapy C ircadian behavioral and physiological rhythms are driven by autonomous oscillation of clock gene expression (1-3). Thus, a clear understanding of the circadian core clock requires a thorough examination of the rhythmic expression of clock genes. As evidenced by the correlation between circadian dysfunction and the incidence of pathological diseases such as sleep disorders, metabolic syndromes, and cancer (4-7), newer strategies for monitoring clock gene expression in humans are necessary for preventing circadian rhythm-related diseases. Furthermore, medical evaluation of circadian rhythm disorders, basic research on shift work and jet lag, and chronopharmacological applications also require effective strategies for studying human clock gene expression. However, currently there is no established simple and accurate method for detecting human circadian clock gene expression. This is underscored by the fact that despite the identification of major mammalian clock genes from 1997 to 1999 (8-14), there are only about 10 studies reporting the basic research and clinical application of human clock gene expression in vivo (15,16). The lack of an established method for evaluating circadian clock gene expression has markedly impeded the progress for studying human circadian rhythms. Circadian clock gene expression is detectable not only in the central circadian pacemaker, the suprachiasmatic nucleus, but also in almost all peripheral tissues. The circadian clock is a cell-autonomous system, and numerous cell-autonomous peripheral clocks are synchronized and governed by the suprachiasmatic nucleus (17,18). These findings suggest that it is possible to characterize the human circadian clock by determining clock gene mRNA expression in peripheral tissues. In previous reports, white blood cells or oral mucosa samples were used for the detection of human clock gene expression, although these methods have several potential is...

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Molecular insights into human daily behavior

Cited by 246 publications

References 32 publications

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

Human blood metabolite timetable indicates internal body time

Noninvasive method for assessing the human circadian clock using hair follicle cells

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