Neuromolecular mechanism of circadian rhythm sleep disorders
Disrupted circadian rhythm in blood pressure and nocturnal hypertension: New Target for Cardiovascular Protection

○Kazuomi Kario1
Division of Cardiovascular Medicine, Department of Medicine, Department of Sleep and Circadian Cardiology (SCC), Jichi Medical University School of Medicine (JMS)1

There is growing evidence that disrupted circadian rhythm in blood pressure (BP) is associated with hypertensive target organ damage and subsequent cardiovascular events, independently of 24-hr BP level in both hypertensive patients and community-dwelling normotensive subjects. There are 2 types of disrupted circadian BP rhythm. One is the extreme-dipper pattern with excess nocturnal BP falls, which is associated with exaggerated morning BP surge. Another is the non-dipper (diminished nocturnal BP fall)/riser (higher nocturnal BP than daytime BP) pattern with nocturnal hypertension.
In our JMS ABPM Study Wave 1 using ambulatory BP monitoring (ABPM), riser BP pattern was closely associated with stroke events independently of the 24-hr BP level, when compared with dipper pattern with normal circadian BP rhythm (Kario, et al. Hypertension 2001). Non-dipper/riser pattern is also associated with hypertensive target organ damage (Kario, et al. Hypertension 1996), including cardiac hypertrophy, chronic kidney disease, and subclinical cerebrovascular disease such as silent cerebral infarcts and deep white matter disease, and brain atrophy. Extreme-dipper pattern is also associated with silent cerebrovascular disease.
We are developing home BP monitoring (HBPM) which could measure sleep BP at home (Kario K. Hypertens Res 2013). In the J-HOP (Japan Morning Surge Home Blood Pressure) study, the HBPM-measured sleep BP was comparable to ABPM-measured sleep BP (Ishikawa, Kario, et al. Hypertension 2012). HBPM-measured sleep BP is associated with target organ damage independently of clinic BP and home BPs measured in the morning and in the evening.
Non-dipper/riser pattern is partly determined by increased circulating volume, autonomic nerve dysfunction, and poor sleep quality. Antihypertensive medication using antihypertensive drugs (angiotensin receptor blockades and diuretics), melatonin and its agonist, and renal sympathetic denervation partly restore disrupted circadian BP rhythm (Kario K. Hypertens Res 2013).
To achieve more effective prevention of cardiovascular disease, the "perfect 24-hr BP control" with restored circadian BP rhythm would be promising.
Molecular basis of jet-lag syndrome

○山口賀章1, 岡村均1
○Yoshiaki Yamaguchi1, Hitoshi Okamura1
Kyoto University Graduate School of Pharmaceutical Sciences1

Circadian clock in the body ticks the times even without the temporal cues from the environmental light dark cycle. Routinely we do not realize the existence of our internal body clock, since our clock oscillating system is in synchrony with environmental light dark cycle. However, we notice our own clock when we cross the time-zones in intercontinental or transmeridional travel by jet airplane, due to desynchrony between the internal clock and the external light-dark cycle. Acute desynchrony is accompanied by clinical symptoms such as daytime anergia, insomnia, and gastrointestinal disturbances. Not only this kind of temporal discomforts, jet-lag syndrome is now also common in our society as shift work or extended nighttime work. Actually, more than 27% of Japanese workers engage in shift work/nighttime work. Epidemiological studies have demonstrated that these shift workers are at increased risks of developing many chronic diseases including cancers, stroke, atherosclerosis, and depressed mood, as well as a variety of metabolic disturbances such as type 2 diabetes, obesity, and heart diseases. Indeed, experimental animal model of chronic jet-lag can induce variety of pathological symptoms including cardiomyopathy, accelerated tumor growth, and hastened death upon aging. Although many studies have been reported, until now, its physiological and molecular mechanism associated with jet-lag has not been fully clarified. In the present talk, we will demonstrate molecular, cellular, and physiological mechanisms of jet-lag from our experimental data using mice under the jet-lag paradigm.
Potential pathogenesis of Circadian Rhythm Sleep Disorders

○Akiko Hida1
国立精神・神経医療研究センター 精神保健研究所精神生理研究部1
NCNP National Institute of Mental Health Department of Psychophysiology1

Circadian clocks regulate daily rhythms of physiology and behavior such as the sleep-wake cycle, body temperature, and hormonal secretion in most organisms including humans. In mammals, the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus incorporates environmental information such as light-dark cycles and synchronizes phasing of clocks in peripheral cells, tissues and organs. The molecular mechanism of the circadian system involves transcriptional and translational negative feedback loops, and post-transcriptional and post-translational modifications of multiple clock genes. Advanced sleep phase type, delayed sleep phase type and non-entrained type of circadian rhythm sleep disorder (CRSD) are characterized by a persistent or recurrent disturbed sleep-wake pattern. CRSD is thought to result from malfunction/maladaptation of the circadian system. Evaluation of circadian phenotypes is indispensable to understanding the pathophysiology of CRSD. We evaluated rhythmic characteristics of physiological functions from healthy subjects in a laboratory environment free from external cues and masking effects. Also, we measured clock gene expression in primary fibroblast cells established from individual's skin biopsies using a luminescence reporter assay system and evaluated daily rhythms of luminescence in individual primary fibroblast cells. The period length of fibroblast in vitro rhythms correlated significantly with the preferred sleep-timings and chronotypes, while that of physiological in vivo rhythms did not correlate with these parameters. Our findings suggest that surrogate measurements using fibroblast cells derived from individual biopsies would be a useful tool for assessing individual circadian clock traits. Here, we have examined fibroblast in vitro rhythms in CRSD patients and will discuss the potential pathogenesis of CRSD.
Pathophysiological analysis of seasonal affective disorder using an animal model: photoperiodic regulation in serotonergic system and metabolism

○Shinobu Yasuo1
Kyushu University Faculty of Agriculture Animal & Mairne Bioresource Sciences1

Winter type of seasonal affective disorder (SAD), also known as winter depression, is characterized as a condition of regularly occurring depression in fall or winter with remission in the following spring or summer. Symptoms of SAD include hyperphagia, hypersomnia, daytime sleepiness, and carbohydrate craving. Clinical and epidemiological studies have suggested the disturbed brain serotonergic system and circadian clock system during winter, and the depressive symptoms significantly correlate with short photoperiod and less sunshine. However, the pathophysiological mechanisms of SAD remain elusive because of a lack of appropriate animal models; most laboratory mice strains are deficient of melatonin, an important photoperiodic signal, due to a truncation in melatonin synthetic enzyme, and thus lost the seasonality in their reproduction. Recently, we have reported that hypothalamic-pituitary-adrenal axis of mice strongly responded to the photoperiod despite of nonresponse of reproductive axis. Furthermore, they exhibited a clear response to photoperiod and light intensity in the immobility time in forced swimming test, serotonin and its precursor tryptophan contents in brain, and glucose homeostasis, which are all associated with symptoms of SAD. Photoperiod also regulated plasma amino acid balance that relates to the transport of tryptophan into brain as well as metabolic functions of organs. Immobility time in forced swimming test was reduced by bright light treatment, an effective treatment for SAD. The mice model will provide a powerful tool to address the mechanisms underlying the link between seasons and mood-related functions.
Why sleep is undisturbed or disturbed by micturition?

○兼松明弘1, 根来宏光2, 小川修2
○Akihiro Kanematsu1, Hiromitsu Negoro2, Osamu Ogawa2
兵庫医科大学泌尿器科学講座1, 京都大・院・泌尿器2
Hyogo Medical University Department of Urology1, Dept Urol, Kyoto Univ Grad Med, Kyoto2

In healthy humans, kidneys produce more urine and urinary bladder keeps more urine while awake than while asleep, resulting in a dramatically decreased micturition frequency during the sleep time. Disruption of this cycle is seen in nocturnal enuresis, i.e. involuntary loss of urine during sleep, experienced by 5-15% of school children, and in nocturia, i.e. waking up for micturition during sleep time experienced by more than 60% of elderly people over 60 years old. Nocturnal enuresis and nocturia share common features, nocturnal polyuria and decreased sleeping-time bladder capacity, both disturbance of biological rhythm in kidney and bladder. Such rhythm is not exclusive for humans. Rodents are nocturnal animals and their sleep-awake cycle is opposite from humans in the light-dark cycles. They also urinate less frequently in sleep (light) cycle than in awake (dark) cycle. In mice, this rhythm is maintained under constant dark condition, suggesting that micturition is a circadian event. Recent progress in molecular chronobiology using rodents as model animals revealed that circadian clock exists, not only in the brain, but also in the kidney and bladder. Micturition rhythm is generated not only by neural and hormonal control from the central nervous system, but also by autonomous genetic cycle of kidneys and bladder. In the kidneys, genetic circadian oscillation is seen with molecules associated with regulation of water reabsorption or electrolytes. In the bladder, Connexin 43 (Cx43) coding gap junction protein, is a determinant of functional bladder capacity. Cx43 protein in mouse bladder increases during awake (dark) cycle, and decreases during sleep (light) cycle, and Rev-erbα, a component of the clock, controls this oscillation by cyclically activating Cx43 promoter. These findings provide novel chronobiological perspective for micturition rhythm and warrants translational research for enuresis and nocturia.

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