Distribution of prostaglandin D receptor(green) in the mouse brain The VLPO (sleep center) and TMN (wake center) are shown indicated by color overlays. Pathway of prostaglandin synthesis in the trypanosome

Outline We sleep every day. We probably spend one-third to one-fourth of our lifetime sleeping. Despite the fact that sleeping is a risky behavior, humans and all other animals sleep. Even mice, which occupy a position at a lower level in the food chain and are always surrounded by their enemies, sleep. However, there are no answers to questions "Why do animals sleep?" and "What is occurring in the brain during sleep?" Today's life is stressful. It is also an age of globalization with information exchanges beyond the fence of time. The number of people working or travelling all over the world at night is increasing. A lack of sleep affects our judgment and concentration, which in turn lowers work efficiency and increases the risk of accidents. It has also been noticed that the incidence of sleep disturbance is increasing with general population aging. Sufferers of insomnia mostly take sleeping medications, which can cause non-physiological sleep or even coma since they have been developed by changing the composition of tranquilizers. Today people need drugs that induce naturalistic sleep without adverse reactions. Such drugs cannot be developed unless sleep is understood scientifically. There are two kinds of sleep: non-REM sleep (slow-wave sleep) and REM sleep (paradoxical sleep). Non-REM sleep corresponds to nearly complete stoppage of cerebral activity. REM sleep is characterized by systemic weakness and dreaming with brain activity. These two kinds of sleep occur repeatedly at given intervals to form our sleep. Modern science has made it possible to quantify sleep by subjective numerical data from electroencephalograms. "As we stay awake more, we become increasingly sleepy. " Taking notice of this well-known phenomena, Dr. Kuniomi Ishimori of Japan and Dr. Henri Pieron of France independently found in the beginning of the 20th century that a dog falls asleep when receiving an intracerebral injection of cerebrospinal fluid from another dog kept without sleep for a long time, and foresaw the presence of "sleep-substances" that accumulate in the brain while awake. Of the several dozen sleep-promoting substances thus far reported, prostaglandin (PG) D2, the primary subject of our investigation at the Molecular Behavioral Biology Department, is now accepted as the most potent endogenous sleep-promoting substance, with its mechanism of action most extensively characterized at the molecular level. PGD2 is produced at high levels in the brain-wrapping arachnoid and the ventral choroid plexus and secreted into the cerebrospinal fluid, after which it circulates in the brain as a sleep hormone. PGD2 also acts on PGD2 receptors, which is localized in the arachnoid of the forebrain fundus to activate the sleep center and selectively induce non-REM sleep, and has an important role in the recovery of fatigue. In other words, the sleeping brain is comprised of cerebral parenchyma, whereas the sleep-inducing brain is comprised of membrane tissue, brain-surrounding spaces such as ventricles and subarachnoid cavity, and cerebrospinal fluid, etc., contained therein. Aiming at elucidating the molecular mechanism of sleep-wake regulation, this department has conducted investigations of PGD2 and PGE2 awaking hormone that exhibits a biological activity opposite to that of PGD2, using a new approach called sleep analysis in gene-manipulated mice. Data from these studies are expected to provide a basis for the development of better drugs that ensure comfortable and high-quality sleep and waking as needed by modern people. Research Activities We have found that naturalistic sleep is induced when prostaglandin D2 (PGD2), the principal prostaglandin produced in the central nervous system, is administered into the brains of animal. The sleep induced by PGD2 has been shown to be identical to physiological sleep as evidenced by electroencephalograms and animal behavioral observation. We have also demonstrated that the enzyme for the production of PGD2 in the brain is localized in the arachnoid membrane of the brain. We aim to continue to investigate the function of this enzyme and the cellular changes caused by PGD2 during sleep. Elucidation of the mechanism of sleep-wake regulation, an essential behavior of all organisms, would deepen the understanding of various nervous or mental phenomena, including mood, affection, cognition, memory, and learning, and would contribute to the improvement of clinical practice in neurology and psychiatry and all other aspects of our society. PGD2 is also known to be a mediator of allergic responses, but this PGD2 is synthesized by the action of an enzyme other than the enzyme that produces PGD2 in the central nervous system. We have succeeded in crystallizing both enzymes and have analyzed their structures. We have also successfully created mice expressing high levels of these enzymes. These achievements are of paramount importance in designing and assessing new anti-doze drugs and anti-allergic drugs with low rates of adverse reactions. Furthermore, we have been studying prostaglandin generating system of parasite protozoa which causes "Sleepy Sick." Research Subjects Elucidation of the signal transduction mechanism behind sleep induced by prostaglandin D2. Elucidation of the tissue distribution and cellular localization of prostaglandin D synthase. Elucidation of the regulatory mechanism for the prostaglandin D synthase gene. Elucidation of the three-dimensional structure of prostaglandin D synthase through crystallographic analysis.