Neuroanatomy and neurochemistry of sleep

Sleep is regulated by homeostatic and circadian factors, and the regulation of sleep of mammals shares many molecular properties with the rest state of submammalian species. Several brain structures take part in waking: the basal forebrain, posterior and lateral hypothalamus, and nuclei in the tegmentum and pons. Active sleep mechanisms are located to the preoptic/anterior hypothalamic area. In addition to acetylcholine and monoamines, glutamate and hypocretin/orexin are important waking factors. Gamma-aminobutyric acid and several peptide factors, including cytokines, growth hormone-releasing hormone and prolactin, are related to sleep promotion. Adenosine is an important homeostatic sleep factor acting in basal forebrain and preoptic areas through A1 and A2A receptors. Prolonged waking activates inducible nitric oxide synthase in the basal forebrain, which through energy depletion causes adenosine release and recovery sleep. Numerous genes have been found differentially displayed in waking compared with sleep, and they relate to neural transmission, synaptic plasticity, energy metabolism and stress protection. The genetic background of a few sleep disorders has been solved.     

Sleep in the tortoiseKinosternon sp.

Summary Individuals ofKinosternon sp., previously confined to laboratory conditions, were chronically implanted with electrodes for electroencephalogram, electro-oculogram and electrocardiogram recording. Behavioral states of waking and sleep were clearly observed. Two sleep stages were present: quiet sleep and REM or active sleep. Electrical cerebral activity was polymorphic and irregular. EEG frequencies declined and amplitudes diminished with sleep. Arrhythmic spikes occurred during behavioral sleep and declined with waking. Heart rate decreased when passing from wakefulness to quiet sleep. It was slightly but consistently higher during active sleep compared with quiet sleep.     

Somesthetic cortex reactivity during sleeping and waking in the rat

Summary The cortical S1 responsiveness was studied by unique and coupled stimuli of non-maximal intensity applied to somesthetic radiations. The reactivity is highest during sleep with slow waves, lowest during active waking, intermediate during non-active waking and rapid sleep. The recovery of responsiveness presents an exactly opposite form and begins at a long interstimulus delay (>150 msec).     

Human slow wave sleep: a review and appraisal of recent findings, with implications for sleep functions, and psychiatric illness.

Recent findings concerning human slow wave sleep (hSWS-stages 3 + 4; delta EEG activity) are critically reviewed. Areas covered include the significance of the first hSWS cycle; hSWS in extended sleep; relationship between hSWS, prior wakefulness and sleep loss; hSWS influence on sleep length; problems with hSWS deprivation; influence of the circadian rhythm; individual differences in hSWS, especially, age, gender and constitutional variables such as physical fitness and body composition. Transient increases in hSWS can be produced by increasing both the quality and quantity of prior wakefulness, with an underlying mechanism perhaps relating to the waking level of brain metabolism. Whilst there may also be thermoregulatory influences on hSWS, hypotheses that energy conservation and brain cooling are major roles for hSWS are debatable. hSWS seems to offer some form of cerebral recovery, with the prefrontal cortex being particularly implicated. The hSWS characteristics of certain forms of major psychiatric disorders may well endorse this prefrontal link.     

Human slow wave sleep: A review and appraisal of recent findings,with implications for sleep functions,and psychiatric illness

Recent findings concerning human slow wave sleep (hSWS-stages 3+4; delta EEG activity) are critically reviewed. Areas covered include the significance of the first hSWS cycle; hSWS in extended sleep; relationship between hSWS, prior wakefulness and sleep loss; hSWS influence on sleep length; problems with hSWS deprivation; influence of the circadian rhythm; individual differences in hSWS, especially, age, gender and constitutional variables such as physical fitness and body composition. Transient increases in hSWS can be produced by increasing both the quality and quantity of prior wakefulness, with an underlying mechanism perhaps relating to the waking level of brain metabolism. Whilst there may also be thermoregulatory influences on hSWS, hypotheses that energy conservation and brain cooling are major roles for hSWS are debatable. hSWS seems to offer some form of cerebral recovery, with the prefrontal cortex being particularly implicated. The hSWS characteristics of certain forms of major psychiatric disorders may well endorse this prefrontal link.     

Memory processes during sleep: beyond the standard consolidation theory

Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and challenging these two views and suggest an integrative model of memory consolidation.     

Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation

Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.     

Effects of bilateral dorsolateral pontine tegmentum lesions on hippocampus theta rhythm during paradoxical sleep in the rat]

Electrolytic lesions of the dorsolateral pontine tegmentum aimed at the locus coeruleus (LC) were performed bilaterally in 13 chronically implanted Rats. Following lesions, transient alterations of characteristic components of theta rhythm appeared. No shortening of duration of paradoxical sleep (PS) was observed. These results do not support the hypothesis that neurons of LC are directly involved in the production of theta rhythm during PS; moreover they seem not to be necessary to the normal appearance of this state of sleep.     

The effects of intraventricular injection of 6-hydroxydopamine on the sleep of kittens during development]

Intraventricular injection of 6-hydroxydopamine does not modify the states of alertness in the Kitten, if it is performed in the first week of postnatal life. At three weeks of age, it induces the same sleep impairments as those observed in the adult Cat. Therefore, in the immediate postnatal period, sleep control is not achieved through the monoaminergic systems.     

Intrathalamic sensory connections mediated by the thalamic reticular nucleus

The thalamus and cerebral cortex are linked together to form a vast network of interconnections. Different modes of interactions among the cells in this network underlie different states of consciousness, such as wakefulness and sleep. Interposed between the dorsal thalamus and cortex are the GABAergic neurons of the thalamic reticular nucleus (TRN), which play a pivotal role not only in switching between the awake and sleep states but also in sensory processing during the awake state. The visual, somatosensory, and auditory sectors of TRN share many of the same organizational features. Each of these sectors contains maps, which are related to its inputs and outputs, and organizational components called ‘slabs.’ It is proposed that, during wakefulness, TRN is crucially involved in resetting the activity levels in sensory nuclei of the dorsal thalamus, which allows the cortex to actively and periodically compare its on-going sensory processing with the available sensory information. Received 11 May 1999; received after revision 15 July 1999; accepted 21 July 1999     

Sleep in an Amazonian manatee, Trichechus inunguis.

For the first time, sleep was studied in a representative of the order of Sirenia. Slow wave sleep occupied 27%, and paradoxical sleep 1% of the total recording time in the Amazonian manatee. Trichechus inunguis. The circadian rhythmicity of sleep was pronounced. During the sleep period, the manatee woke up for a short time for each respiratory act. Interhemispheric asynchrony of the electrocortical slow wave activity was found.     

Genetics of sleep and sleep disorders

Genetic factors affect sleep. Studies in twin pairs demonstrate that the strong hereditary influences on sleep architecture and some sleep disorders are transmitted through families. Evidence like this strongly suggests that sleep regulation receives significant influence from genetic factors. Although recent molecular technologies have revealed evidence that genetic traits or gene products trigger particular changes in sleep electroencephalogram activity, we are still far from finding candidate genes or multiple mutations responsible for individual sleep disorders. Sleep is a very complex phenotype. Genetic susceptibility and environmental factors should be also considered as contributors to sleep phenotype. The aim of this review is to present a current summary and future prospects for genetic studies on sleep and selected sleep-associated disorders. An erratum to this article is available at .     

Sleep and sleep disturbances: biological basis and clinical implications

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.     

Sleep and body restitution

Summary Although human non-REM sleep is usually associated with body restitution, such an hypothesis is debatable. This sleep, like REM sleep, may have a beneficial role for the brain. Because man demonstrates relaxed wakefulness, body restitution may not be confined to human sleep. However, for active mammals, sleep may be an enforced immobiliser facilitating this restitution.     

Sleep in an Amazonian manatee,Trichechus inunguis

For the first time, sleep was studied in a representative of the order of Sirenia. Slow wave sleep occupied 27%, and paradoxical sleep 1% of the total recording time in the Amazonian manatee,Trichechus inunguis. The circadian rhythmicity of sleep was pronounced. During the sleep period, the manatee woke up for a short time for each respiratory act. Interhemispheric asynchrony of the electrocortical slow wave activity was found.     

Indoleamines and the UV-light-sensitive photoperiodic responses of the melanocyte network: a biological calendar?

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the dark phase. The neural network that responds to seasonal variations in day/night length has not been identified. The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin. Higher melatonin levels correspond to long nights and long days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This response recapitulates the sleep/arousal patterns in animals exposed to large variations in day/night cycle that cause changes in coat colour from pure white in winter to complete repigmentation in summer.     

Physiological arousal: a role for hypothalamic systems

The lateral hypothalamus (LH) has long been known as a homeostasis center of the brain that modulates feeding behavior, arousal and reward. The hypocretins (Hcrts, also called orexins) and melanin-concentrating hormone (MCH) are neuropeptides produced in two intermingled populations of a few thousand neurons in the LH. The Hcrts have a prominent role in regulating the stability of arousal, since Hcrt system deficiency leads to narcolepsy. MCH is an important modulator of energy balance, as MCH system deficiency in mice leads to leanness and increased metabolism. Recently, MCH has been proposed to modulate rapid eye movement sleep in rodents. In this review, we propose a working model of the cross-talk between Hcrt and MCH circuits that may provide an arousal balance system to regulate complex goal-oriented behaviors.     

Immunocytochemical characterization of vasotocin and mesotocin secretory systems in duck brain

The neural systems secreting vasotocin and mesotocin has been characterized in the Duck brain with indirect immunofluorescent techniques, using specific antisera. In the anterior preoptic region and in supraoptic and paraventricular nuclei, neurons producing vasotocine and neurons producing mesotocine have been identified separately. Only vasotocinergic neurons were localized in ectomammillary tract. Vasotocin--and mesotocin--containing axons together enter the median eminence, some of them crossed the internal zone of the median eminence before ending in the posterior lobe of the pituitary, whereas other axons of both classes entered the external layer of the rostral median eminence, in close contact with the capillaries of the hypophysial portal system.     

Technologies of sleep research

Sleep is investigated in many different ways, many different species and under many different circumstances. Modern sleep research is a multidisciplinary venture. Therefore, this review cannot give a complete overview of all techniques used in sleep research and sleep medicine. What it will try to do is to give an overview of widely applied techniques and exciting new developments. Electroencephalography has been the backbone of sleep research and sleep medicine since its first application in the 1930s. The electroencephalogram is still used but now combined with many different techniques monitoring body and brain temperature, changes in brain and blood chemistry, or changes in brain functioning. Animal research has been very important for progress in sleep research and sleep medicine. It provides opportunities to investigate the sleeping brain in ways not possible in healthy volunteers. Progress in genomics has brought new insights in sleep regulation, the best example being the discovery of hypocretin/orexin deficiency as the cause of narcolepsy. Gene manipulation holds great promise for the future since it is possible not only to investigate the functions of different genes under normal conditions, but also to mimic human pathology in much greater detail.     

Demonstration of a 2d LH-RH neurosecretory system in the duck hypothalamus]

Using immunocytochemical techniques with an anti-LH-RH immuneserum, evidence of two neuronal systems secreting LH-RH has been shown in the Duck hypothalamus. In addition to the previously described system, located in the preoptic nucleus, a second system could be demonstrated in the infundibular nucleus. The perikarya of the infundibular LH-RH producing neurons were significantly smaller than those of the preoptic neurons. On the other hand, under the experimental conditions used, the infundibular system had approximately five times less LH-RH secreting neurons than the preoptic system, and its perikarya appeared less heavily loaded in IR LH-RH. The LH-RH containing axons from both neuronal populations ran down to the external layer of the median eminence, where they ended in close contact with the capillaries of the hypophysial portal system.