21st Century COE Program Human Nutritional Science on Stress Control
Research Aim
Dr. Takeda's Labo
Dr. Terao's Labo
Dr. Miyamoto's Labo
Dr. Nakaya's Labo
Dr. Rokutan's Labo
Dr. Chuman's Labo
Dr. Kaji's Labo
Dr. Ohmori's Labo
Dr. Sei's Labo
Dr. Sei's Labo
Prof. Hiroyoshi Sei
Department of Integrative Physiology
Hiroyoshi Sei (Professor), Sachiko Chikahisa (Assistant Professor), and *Kazuyoshi Kitaoka (COE Researcher)

Dr. Kazuyoshi Kitaoka has now been employed as an assistant professor of Dept of Physiology

Sleep is vulnerable to stress. Many of patients with depression have sleep disorder such as insomnia.On the other hand, sleep loss itself is, conversely, considered to be a stress for neurons. As hypnotics have a variety of embarrassing side effects, food factors that can control sleep have lately attracted considerable attention. Recently, we have found that peroxisome proliferators- activated receptor (PPAR) -alpha contributes to sleep regulation, especially on the circadian phase of sleep-wake rhythm. We have also found the novel physiological role of vitamin A on the sleep regulation. Deficiency of vitamin A induces a decrease of EEG delta power during non-REM sleep. We have now noticed that the nutritional factors play important physiological roles on the higher brain function, such as sleep.
[Role of PPAR-alpha on sleep and body temperature regulation]
Peroxisome proliferators- activated receptors (PPARs) are ligandĖactivated transcription factors belonging to the nuclear receptor family. PPAR-alpha, the isoform of PPARs, play a role in lipid metabolism. The ligand of PPAR-alpha is endogeneous fatty acids. Beyond metabolic effects, recent study showed that PPAR-alpha is involved in circadian clock control. It is reported that mice treated with bezafibrate, which is an anti-hyperlipidemic PPAR-alpha ligand, showed phase-advanced locomotor activity (1). We examined whether chronic bezafibrate treatment would alter sleep and body temperature rhythm and sleep construction.
Mice (ICR) were fed with a control diet for two weeks, and were recorded body temperature, electroencephalogram and electromyogram for 48 h, under light- dark (LD) conditions. Body temperature was measured by using a telemetric device (DSI, USA). After the baseline recording, these mice were fed with bezafibrate containing diet (0.5%) for two weeks, and then same recordings were carried out. Furthermore, the recordings were again performed after 5 weeks of recovery period.
Acrophase of rhythm for body temperature was about 2-h advanced after 2-week feeding of bezafibrate in comparison with the baseline (Fig). Sleep-wake rhythm were also phase-advanced for about 3 hrs. Furthermore, bezafibrate treatment increased the EEG delta power (0.8ĀE.0 Hz) in non-rapid eye movement (NREM) sleep compared to the baseline. The advanced acrophase of body temperature and sleep-wake rhythm and increased delta power by feeding with bezafibrate were returned to the baseline level after 5 weeks feeding with control diet.
These data suggest that chronic bezafibrate treatment could advance a sleep-wake and body temperature rhythm as seen in locomotor activity, and PPAR-alpha might be involved in the regulation of delta wave during NREM sleep. Molecular mechanism of the interaction between daily life rhythm and obesity or metabolic syndrome has become a target of our research.
Body temperature
  1. Shirai H, etal.: PPARalpha is a potential therapeutic target of drugs to treat circadian rhythm sleep disorders. Biochem Biophys Res Commun. 357(3):679-82, 2007.
[Novel role of vitamin A as an enhancer of EEG delta wave during sleep enhancer]
By mapping of the genes, recent report has suggested that vitamin A (retinol and its derivatives) is genetically involved in the electroencephalogram (EEG) delta oscillation during sleep (1). Activity in the delta range is a measure of NREM-sleep depth and consolidation. It is considered to be a reliable indicator of time spent awake and has been proposed to reflect a homeostatic need for sleep.
The actions of retinolís metabolites are primarily mediated by nuclear retinoid receptor proteins termed retinoic acid receptors (RAR) and retinoid X receptors (RXR). These receptors are members of the steroid receptor family and essentially they function as transcription factors (2). Deficits in retinoid signaling may contribute to the pathology of Alzheimerís disease, schizophrenia and depression. Recently, it has been noticed that the retinoid signaling may also be required for several aspects of adult brain function (2).
Fig.1We are now attempting to clarify the mechanism of retinoic acid signaling on the regulation of delta oscillation. First, we recorded sleep and spontaneous activity and quantified striatal monoamines in mice fed a vitamin A-deficient (VAD) diet for four weeks. VAD mice demonstrated a significant decrease in the delta oscillation of the EEG (Fig.1). However, 6-hour sleep deprivation caused the recovery of the delta oscillation in VAD mice to a level similar to that of the control, indicating that the neural mechanism involved in delta oscillation may not be directly impaired by VAD feeding. VAD also caused the decrease of spontaneous activity throughout 24-hour period (Fig.2).
Furthermore, DOPAC, a metabolite of dopamine, was decreased significantly in the striatal tissue of VAD mice.
These results suggest that the vitamin A is, at least partially and indirectly, involved in the delta oscillation during NREM sleep and spontaneous activity. The vitamin A may play its role on sleep through the striatal dopaminergic function. We are now investigating the effect of antagonist for RAR and/or RXR on the sleep regulation.
Fig.2 (open circle: control, closed circle: VAD)
  1. Maret S, etal.: Retinoic acid signaling affects cortical synchrony during sleep. Science 310, 111-3, 2005.
  2. Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Prog Neurobiol. 75(4):275-93, 2005.
  1. Oishi K, Ohkura N, Sei H, Matsuda J, Ishida N. CLOCK regulates the circadian rhythm of kaolin-induced writhing behavior in mice. Neuroreport. 18(18):1925-1928, 2007
  2. Miyazaki K, Wakabayashi M, Chikahisa S, Sei H, Ishida N. PER2 controls circadian periods through nuclear localization in the suprachiasmatic nucleus. Genes Cells. 12(11):1225-34, 2007
  3. Kitaoka K, Hattori A, Chikahisa S, Miyamoto K, Nakaya Y, Sei H. Vitamin A deficiency induces a decrease in EEG delta power during sleep in mice. Brain Res. 1150:121-30, 2007
  4. Chikahisa S, Sano A, Kitaoka K, Miyamoto K, Sei H. Anxiolytic effect of music depends on ovarian steroid in female mice. Behav Brain Res. 179(1):50-9, 2007
  5. Sei H, Oishi K, Sano A, Seno H, Ohmori T, Morita Y, Ishida N. Clock mutant mice with Jcl/ICR background shows an impaired learning ability in water maze, but not in passive avoidance, at the beginning of dark phase. Congenit Anom (Kyoto). 46(2):81-5, 2006

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