Sleep-promoting effects of cerebrospinal fluid from sleep-deprived goats.

Abstract

In 1913 Legendre and Pieron' reported that injection of cerebrospinal fluid (CSF) from a sleep-deprived dog into the cisterna magna of a normal animal induced sleep in the recipient for 2-6 hours following the injection. Recipients of fluid from normal dogs remained alert. The "hypnotoxic" factor was said to be nondialyzable and thermolabile. The Pieron phenomenon was reinvestigated in 1939 by Schnedorf and Ivy,2 who reported positive results in 9 out of 20 trials. The experimental conditions involved severe stress to both donor and recipient animals. Donor animals were deprived of sleep for 7-16 days and the technique of transferring relatively large quantities of CSF from donor to normal recipient without anesthesia undoubtedly involved severe trauma to the experimental animals. For these and other reasons, Schnedorf and Ivy questioned the relevance of the Pieron phenomenon to normal sleep, although they were convinced that the phenomenon was real.Monnier et al.3' 4 have recently reported that electrical stimulation of "sleep centers" in the thalamus of rabbits causes release of a dialyzable sleep-promoting factor in cerebral venous blood. The role of this substance in the initiation of normal sleep is unknown, as is its relation to the nondialyzable material described by Pieron. A humoral factor inducing sleep has also been postulated by Hayashi who reported that CSF obtained during the period of depression following convulsive seizures contains a factor which inhibits convulsions5 and promotes sleep6 when injected intraventricularly. Hayashi suggested that the active principle might be 4-amino-2-hydroxybutyrate or possibly 4-OH-butyrate.We have now conducted a new investigation of the Pieron phenomenon, taking advantage of new techniques which enable experiments to be carried out under more physiological conditions than were possible in the past. Crucial to our experiments is an abundant supply of CSF from goats which are provided with nylon guide tubes permanently implanted in occipital bone above the cisterna magna.7 8 CSF can be withdrawn repeatedly from each animal at the rate of 0.1 ml/minlute for many hours without the use of anesthesia and without causing the animals any apparent discomfort. For initial trials we prepared five cats with chronically implanted intraventricular cannulas of the Feldberg-Sherwood type.9 The ventricles of these animals were infused slowly (0.1 ml/min) with 1-3 ml of CSF from a normal goat or from the same goat which had been deprived of sleep for 72 hours. Cats which received fluid from sleep-deprived goats fell into a profound sleep or torpor which lasted 12-24 hours; the "sleep" appeared to be natural in the sense that the cats could be awakened by noise or handling, but reverted to sleep when left undisturbed. Some animals fell asleep during the infusion. Similar behavior was not observed when the same cats were infused with control CSF from the same (non-sleep-deprived) goats. These results supported Pieron's observations and indicated that the phenomenon was not specie...

Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain.

“…Glucose utilization reportedly increases in the choroid plexus during slow-wave sleep (22). The presence of the sleep-promoting substance(s) in the cerebrospinal fluid has been shown by a number of previous investigators and suggests that a humoral mechanism is critical in sleep regulation (23)(24)(25). PGD2 concentrations were selectively and markedly elevated in the cerebrospinal fluid of the advanced-stage patients of African sleeping sickness (26 …”

Biochemical Regulation of Sleep and Sleep Biomarkers

“…One of the first sleep promoting substances, called "Factor S" was isolated and purified at Harvard Medical School. 7 This substance progressively increased in the cerebral spinal fluid during sleep deprivation. In the 1980s, Factor S was chemically characterized as a muramyl peptide, a class of compounds previously known as immune adjuvants and as components of microbial cell walls.…”

Molecular Analysis of Sleep: Wake Cycles inDrosophila

“…This belief is based on experiments done many years ago in which cerebrospinal fluid extracted from sleep-deprived goats was shown to promote sleep in rested (i.e., nonsleep-deprived) controls (Pappenheimer et al 1967). The nature of the sleep-promoting molecules is not known, although attempts were made to purify such molecules (Pappenheimer et al 1975).…”