Irene Tobler

Revision as of 13:14, 17 May 2007

Sleep Homeostasis

Definition

Homeostasis refers to regulatory mechanisms that maintain the constancy of the physiology of organisms.

The term can be applied to sleep: Sleep has a regulatory system enabling organisms to compensate for the loss of sleep or surplus sleep.

The daily sleep-wake cycle, typical for humans, and the polyphasic sleep-wake cycles in animals are regulated by two a

• homeostatic mechanism and • the circadian system

The two main regulated variables are

• sleep intensity and • to a lesser extent, sleep duration (or the amount of sleep)

The homeostatic system regulates sleep intensity, while the circadian clock regulates the timing of sleep.

The intensity component of sleep is slow-wave activity (its level correlates negatively with the threshold to arouse subjects or animals). Slow-wave activity is defined as EEG power of slow waves in the frequency range of approximately 0.5 – 4.0 or 4.5 Hz.

Brief history of the concept

The general concept of homeostasis dates back to two pioneers:

• Claude Bernard (1813-1978) a professor of Physiology at the College of France and the Sorbonne in Paris, and

• Walter Cannon (1871-1945) (Cannon, 1939), Professor at Harvard University. Both men engaged in physiology, Bernard defining a “milieu interieur” and Cannon, coining the term homeostasis.

Alexander Borbély, a Swiss pharmacologist and sleep researcher who began his research of sleep by studying sleep regulation in laboratory rats under diverse controlled conditions (Borbély, Neuhaus, 1979) applied the concept of homeostasis to sleep regulation. Sleep homeostasis: regulated balance between sleep and waking. Homeostatic mechanisms counteract deviations from an average “reference level” of sleep (Borbély, 1980).

Based on his seminal experiments, Borbély postulated a two-process model of sleep homeostasis (Borbély 1980), and extended his concept to human sleep (Borbély, Baumann, Brandeis …1981; Borbély 1982). Later, Serge Daan, Domien Beersma from the University of Groningen and Alexander Borbély, formulated a quantitative model (Daan et al, 1984). This collaborative work led to the formulation of a simple model, the “two-process model of sleep regulation” which inspired many researches to test its tenets as well as its applicability to human sleep disorders: A Process S, the homeostatic process, increases as an exponential saturating function during waking and decreases as an exponential function during nonREM sleep (sleep is subdivided into rapid-eye movement sleep, REM sleep and nonREM sleep). Slow-wave activity is the marker for the decrease of Process S.

Seminal experimental data demonstrating the existence of sleep homeostasis

Early experiments had shown that sleep deprivation has major effects on the homeostatic regulation of sleep, but has only minor effects or no effect on the circadian pacemaker. Sleep deprivation invariably leads to an increase in slow-wave activity during sleep. The potential confound that the sleep deprivation induced activation can be stressful, and therefore unspecific factors not directly related to the loss of sleep could be responsible for the increase of slow-waves during recovery sleep was excluded in many studies:

For example, early experiments in two different rat strains (Al Rechtschaffen, Chicago and Alexander Borbély, Zurich) showed that doubling the rotation rate of a slowly turning cylinder used to sleep deprive the animals had no additional effect on recovery, and that rats which had no circadian organization of their sleep-wake cycle still showed a compensatory increase of slow waves during recovery from the sleep deprivation (Tobler, Gross, Borbély, 19xx).

The evolutionary advantage of developing an intensity dimension of sleep, provided sleep with a relative independence from the circadian system allowing organisms a more flexible adaptation to changes in sleep, than the strictly controlled timing of sleep within the time constraints set by the circadian pacemaker.

Elegant experiments in human subjects:

1. Healthy young men slept at different times of day while their sleep was being recorded. A higher level of EEG slow-waves occurred the later in the day they took their nap or in other words, the longer they had been awake since ending last night’s sleep (Dijk, Beersma, Daan, 1987).

2. Similarly, persons taking a 2-h nap in the evening, simulating what often occurs during a normal day when people fall asleep when relaxing after coming home from work, had a lower level of slow-waves during the subsequent nights sleep (Werth et al, xx).

These studies demonstrated a predictable increase of “sleep pressure” as a function of the duration of the previous waking interval.

The polyphasic sleep-wake cycle of animals is an ideal feature of animal sleep to examine whether keeping animals awake, in this case many different mouse strains, hamsters, rats, squirrels and even cats, for a varying amount of hours, leads to a predictable change in sleep intensity (Reviewed in Tobler, 2005). It did, and the results obtained in the different species were consistent.

Later studies extended the variables reflecting sleep homeostasis:

• Very short awakenings from sleep (“brief awakenings”), typical for most animals, decrease when sleep intensity is high (Franken et al, 199x). • Sleep fragmentation decreases in humans as sleep intensity increases.

Species similarities/differences

Animals ranging from mammals to birds and even to invertebrates show compensatory mechanisms after sleep loss (Tobler, 2005). The first such demonstration was in cockroaches and later in scorpions (Tobler, 2005). However, the strict relationship between the amount of sleep lost and the degree of compensation has been demonstrated for a few mammals, such as rats, mice, hamsters, squirrels and humans and the fruit fly. Especially the discovery that also insects do compensate for the loss of sleep, inspired research on sleep regulation in thousands of mutants of the fruit fly Drosophila, where the genetic mechanisms of the compensatory process can be investigated (cross reference).

Neuronal mechanisms underlying sleep homeostasis

Sleep deprivation causes behavioral, physiological and molecular changes. Despite considerable knowledge about the neuronal mechanisms enabling the transition from wakefulness to sleep (cross reference), and the synchronization of EEG waves in the cortex (cross reference), we still do not fully understand the mechanisms leading to the intensity increase. A common belief was the existence of a sleep factor (or perhaps several sleep factors) accumulating during waking and dissipating during sleep. Many neurotransmitters and neuropeptides must be involved in sleep regulation, but one such substance, adenosine, a neurotransmitter is more and more at the center of attention. Manipulating the adenosine system leads to changes in sleep (review xx). Especially an adenosine antagonist, caffeine, is the world-wide most popular wakefulness inducing and maintaining substance.

Open questions and perspectives

It is still unresolved whether REM sleep has a homeostatic regulatory component of its own. REM sleep loss does lead to an increase in the tendency to enter REM sleep, and its loss is compensated up to a certain extent, with some species differences. However, in contrast to nonREM sleep which has an intensity dimension, there is no evidence for an intensity dimension of REM sleep.

Recent experiments used exquisite, selective manipulations activating specific brain regions during sleep. In rats and mice, cutting whiskers on one side of the snout and encouraging spontaneous stimulation of the remaining whiskers by placing the animals in an enriched environment, led to a selective increase of slow waves over the stimulated brain region during sleep (Vyazowskiy et al, 19xx). An early study in humans showed a similar selective increase in slow-waves over the “stimulated hemisphere” during sleep, after one hand had been vibrated previously for several hours (Kattler et al, xxx). Recordings making use of EEG topography, placing 256 electrodes on the heads of subjects and subjecting them to a motor learning task before sleep, led to a selective increase of slow-waves over the particular brain region where neurons had been stimulated during the rotation task (Huber et al., 2000). The studies in the rat were developed further, showing a correlation between increases in the brain derived nerve growth factor BDNF during sleep and spontaneous exploratory waking activities. These studies pursue the hypothesis that sleep may be rescaling neurons and synapses according to their previous use (Tononi and Cirelli, 2006).

Cannon WB: The Wisdom of the Body, New York, WW Norton, 1939

Borbély, Neuhaus, 1979

Borbély, 1980

Borbély, Baumann, Brandeis …1981

Borbély 1982

Daan et al, 1984

Friedmann, Al Rechtschaffen xxx

(Tobler, Gross, 19xx)

Dijk, Beersma, Daan, 1987

Werth et al, xx nap paper

Tobler, 2005

Franken et al, 199x brief awakenings neg correlation

review xx adenosine

caffeine

Vyazowskiy et al, 19xx

Kattler et al, xxx

Huber et al., 2000

Tononi and Cirelli, 2006