Sleep homeostasis and the function of sleep.

A considerable number of hypothetical functions of sleep have been proposed, but none of the hypotheses under active consideration has gained enough experimental support to convince a preponderance of sleep researchers. Some researchers even question whether we should expect to identify one primary function of sleep, given the multitude of physiological processes that are affected by sleep. But we do know that sleep is homeostatically regulated, and we have discovered a great deal about the physiological mechanisms underlying sleep homeostasis. Other homeostatically regulated behaviors have one or a small number of functions, and those functions are closely linked to the homeostatic control mechanisms for those process. We can therefore apply what is already known about sleep homeostasis to test and evaluate hypothesized functions of sleep. It should be possible to trace the connections between the cellular and molecular basis of a hypothesized function and the cellular and molecular mechanisms underlying homeostatic responses to sleep deprivation. Hypothesized functions that do not plausibly admit of such connections can reasonably be rejected. Four current hypotheses suggesting that the function of sleep is to assist in the process of activity-dependent synaptic reorganization are critiqued to demonstrate how what is known about sleep homeostasis can be used to assess hypothesized functions of sleep.

An automated system for recording and analysis of sleep in mice.

Significant differences in many aspects of sleep/wake activity among inbred strains of mice suggest genetic influences on the control of sleep. A number of genetic techniques, including transgenesis, random and targeted mutagenesis, and analysis of quantitative trait loci may be used to identify genetic loci. To take full advantage of these genetic approaches in mice, a comprehensive and robust description of behavioral states has been developed. An existing automated sleep scoring algorithm, designed for sleep analysis in rats, has been examined for acceptability in the analysis of baseline sleep structure and the response to sleep deprivation in mice. This algorithm was validated in three inbred strains (C57BL/6J, C3HeB/FeJ, 129X1/SvJ) and one hybrid line (C57BL/6J X C3HeB/FeJ). Overall accuracy rates for behavioral state detection (mean+/-SE) using this system in mice were: waking, 98.8%+/-0.4; NREM sleep, 97.1%+/-0.5; and REM sleep, 89.7%+/-1.4. Characterization of sleep has been extended to include measurements of sleep consolidation and fragmentation, REM sleep latency, and delta density decline with sleep. An experimental protocol is suggested for acquiring baseline sleep data for genetic studies. This sleep recording protocol, scoring, and analysis system is designed to facilitate the understanding of genetic basis of sleep structure.

Astrocyte glucose metabolism under normal and pathological conditions in vitro.

Astrocytes in primary culture produce lactate. The net production of lactate from glucose requires that the carbon flux through glycolysis exceed the carbon flux to CO2. This study investigates the control and function of this 'excess' glycolysis in astrocyte cultures. Blockade of glycolysis was found to have minimal effects on astrocyte ATP and function if other substrates for oxidative metabolism were available. In contrast, selective blockade of oxidative metabolism reduced adenosine triphosphate (ATP) levels and slowed glutamate uptake despite a marked increase in glycolytic rate. Acidosis suppressed both glucose utilization and lactate production but had minimal effects on ATP levels. Acidosis in combination with blockade of oxidative metabolism blunted the increase in glycolytic rate and accentuated ATP depletion relative to oxidative blockade alone. These studies suggest that glycolysis in astrocyte cultures is regulated by factors other than energy demand, and that the capacity of glycolysis to support astrocyte metabolism during hypoxia is markedly pH dependent.

Stimulation of A1 adenosine receptors mimics the electroencephalographic effects of sleep deprivation.

N6-Cyclopentyladenosine (CPA), an A1 adenosine receptor agonist, increased EEG slow-wave activity in nonREM sleep when administered either systemically (0.1-3 mg/kg) or intracerebroventricularly (3.5-10 micrograms) in the rat. The power spectrum of EEG changes (as calculated by Fourier analysis) matched that produced by total sleep deprivation in the rat. The effects of CPA on the nonREM-sleep EEG were dose-dependent. These findings suggest that adenosine is an endogenous mediator of sleep-deprivation induced increases in EEG slow-wave activity, and therefore that increased adenosine release is a concomitant of accumulation of sleep need and may be involved in homeostatic feedback control of sleep expression.

Apamin, a selective SK potassium channel blocker, suppresses REM sleep without a compensatory rebound.

To determine the role of neuronal potassium conductance in rapid-eye-movement (REM)-sleep homeostasis, we have administered small doses of apamin (2-5 ng), a selective blocker of the calcium-dependent SK potassium channel, injected into the lateral ventricle in rats, and characterized the resultant effects on REM-sleep expression. Apamin produces a dose-dependent reduction in REM-sleep expression without an increase in the frequency of attempts to enter REM sleep, suggesting that accumulation of REM-sleep propensity is suppressed. The vast majority (84-95%) of lost REM sleep is not recovered 40 h after apamin administration. These findings suggest that accumulation of REM-sleep propensity is linked to the increased neuronal potassium conductance in nonREM sleep.

Monoaminergic and cholinergic modulation of REM-sleep timing in rats.

The effects on sleep structure of systemic administration of benchmark cholinergic, serotonergic, and noradrenergic antagonists (QNB, ritanserin, metergoline, and prazosin) were characterized in rats using a new technique for identifying transitions (NRTs) from non-REM (NREM) sleep to REM sleep. In agreement with previous studies, all agents tested reduced REM-sleep expression (by 36-86%). In addition, the serotonergic and noradrenergic antagonists reduced NRT frequency (by 58-81%). The cholinergic antagonist QNB had no effect on NRT frequency. These findings suggest that blockade of serotonergic or noradrenergic receptors increases the interval between REM-sleep episodes, perhaps reducing the rate of accumulation of REM-sleep propensity. Blockade of cholinergic receptors, by contrast, decreases REM-sleep expression by interfering with REM-sleep maintenance, not by modulating REM-sleep timing. These conclusions are contrary to the predictions of a number of published models of REM-sleep timing.

Does the function of REM sleep concern non-REM sleep or waking?

We have hypothesized that REM sleep is functionally and homeostatically related to NREM sleep rather than to waking. In other words, REM sleep rather than to waking. In other words, REM sleep occurs in response to NREM-sleep expression and compensates for some process that takes place during NREM sleep. Under normal conditions, the need for REM sleep does not accrue during waking. The primary basis for this hypothesis is the fact that REM-sleep expression is a function of prior NREM-sleep expression. That is, REM sleep follows NREM sleep within sleep periods, REM-sleep episodes occur at intervals determined by the amount of NREM-sleep time elapsed, and total time spent in REM sleep is consistently about 1/4 of prior NREM-sleep time, regardless of how much time is spent in NREM sleep. Our experimental tests of the hypothesis support it. (1) REM-sleep propensity accumulates quite rapidly during a 2-hr interval spent predominantly in NREM sleep. (2) The timing of individual REM-sleep episodes is controlled homeostatically, by accumulation within NREM sleep of a propensity for REM sleep. The NREM sleep-related model of REM-sleep regulation (Fig. 1) explains a number of phenomena of REM-sleep expression, including the frequent and periodic occurrence of REM-sleep episodes throughout sleep periods, that have been accommodated by the waking-related model but are not functionally accounted for by it. In our opinion, the NREM sleep-related model of REM-sleep regulation recommends itself partly by its simplicity. According to the waking-related model, two independent and competing sleep propensities accumulate during waking and are discharged in two distinct sleep states that perform different waking-related recovery processes. One behaviour, sleep, is thought to perform two independent and competing functions that alternate at regular intervals. In the NREM sleep-related model of REM-sleep regulation, sleep debt simply reflects a need for NREM sleep. That is, the cerebrally less activated state of NREM sleep enables some form of restoration made necessary by the cerebrally activated state of waking. Periodic occurrence of REM-sleep episodes is explained without postulating an oscillatory mechanism to gate expression of NREM sleep versus REM sleep. In assessing the comparative merits of the waking-related and NREM sleep-related models of REM-sleep regulation, one should consider the influence of time-worn habits of thought.(ABSTRACT TRUNCATED AT 400 WORDS)

REM-sleep propensity accumulates during 2-h REM-sleep deprivation in the rest period in rats.

Two-hour, highly-selective, rest-period, rapid-eye-movement (REM)-sleep deprivation (RD) was performed on rats to characterize the time-course of the homeostatic response to REM-sleep loss. RD caused a dramatic and progressive increase in the frequency of attempts to enter REM sleep, suppressed non-REM sleep EEG delta power, and (in late rest period trials) was followed by a rebound increase in REM-sleep expression.

REM-sleep timing is controlled homeostatically by accumulation of REM-sleep propensity in non-REM sleep.

Sleep structure in the rat was characterized during uninterrupted full-day recordings using an analytic procedure that identifies rapid eye movement (REM) sleep episodes based on REM-sleep-onset electroencephalograph phenomena, hence independently of REM-sleep duration. The data were used to determine whether REM-sleep timing is controlled homeostatically or by an oscillatory mechanism. The findings and conclusions are that 1) non-REM (NREM) sleep episode duration is positively correlated with prior REM-sleep episode duration, suggesting that REM-sleep expression is permissive of NREM sleep; 2) mean NREM-sleep episode duration decreases after repeated brief REM-sleep episodes (< 30 s), also suggesting that discharge of REM-sleep propensity is essential for NREM-sleep expression; 3) REM-sleep episode duration is independent of prior sleep history, suggesting that REM-sleep maintenance is controlled by factors other than accumulated REM-sleep propensity; 4) brief REM-sleep episodes occur progressively more frequently over the course of the NREM-sleep interval between sustained REM-sleep episodes (> 30 s), suggesting that REM-sleep propensity increases progressively within episodes of NREM sleep; and 5) the diurnal cycle of REM-sleep expression primarily reflects modulation in the efficiency of REM-sleep maintenance. These findings support the hypothesis that REM-sleep timing is controlled by accumulation of REM-sleep propensity during NREM sleep.

Scoring transitions to REM sleep in rats based on the EEG phenomena of pre-REM sleep: an improved analysis of sleep structure.

Algorithms for scoring sleep/waking states and transitions to REM sleep (NRTs) in rats are presented and validated. Both algorithms are based on electroencephalographic (EEG) power in delta (0.5-4.0 Hz), theta (6-9 Hz) and sigma (10-14 Hz) frequency bands, and electromyogram (EMG) intensity. Waking is scored when EMG intensity is high or (sigma power).(theta power) is low. Nonrapid eye movement (NREM) sleep is scored in nonwaking epochs having high (delta power)/(theta power). Rapid eye movement (REM) sleep is scored in nonwaking epochs having low (delta power)/(theta power). NRTs are identified by the EEG phenomena of the pre-REM sleep phase of NREM sleep. Algorithms are validated by comparison with records scored independently by two investigators based on visual examination of EEGs and EMGs. The sleep/waking-state scoring algorithm produces greater than 90% agreement with visual scoring. The NRT-scoring algorithm produces 88-92% agreement with visual scoring. Scoring NRTs based on the phenomena of the pre-REM sleep phase of NREM sleep, instead of relying solely on REM sleep expression for identification of REM sleep onset, reveals a significant population of brief REM sleep episodes that are ignored by most sleep cycle analyses and allows independent quantification of REM sleep timing and maintenance.