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The humoral theory of sleep regulation, the concept that sleep and wakefulness are induced and regulated by a hormone-like chemical substance rather than by a neural network, was initially proposed by Kuniomi Ishimori of Nagoya, Japan, and independently and concurrently by the French neuroscientist Henri Piéron of Paris, in the first decade of the twentieth century. They took samples of cerebrospinal fluid (CSF) from sleep-deprived dogs and infused them into the brains of normal dogs. The recipient dogs soon fell asleep. Thus these researchers became the first to demonstrate the existence of endogenous sleep-promoting substances. However, the chemical nature of these sleep substance(s) was not identified. During the following 90 years, more than 30 so-called endogenous sleep and wake substances were reported by numerous investigators to exist in the brain, CSF, urine, and other organs and tissues of animals. For example, delta-sleep-inducing peptide, muramyl peptides, uridine, oxidized glutathione, and vitamin B12 have been proposed as endogenous somnogenic substances. The detailed account of these substances is described in an excellent treatise by Inoué (1989). During the early 1980s, Professor Jouvet and his colleagues in Lyon also found a sleep-inducing factor produced by the periventricular structures including the choroid plexus in the central nervous system (CNS) of cats (Bobillier et al., 1982; Jouvet et al., 1983).
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