Summary

The hypocretins (HCRTs) are two hypothalamic peptides that have been implicated in a variety of functions including the regulation of behavioral arousal. In the brain, HCRT-expressing neurons are localized within the perifornical-lateral hypothalamic area, where they are intermingled with various other neuronal groups, including GABAergic, glutamatergic, and melanin-concentrating hormone containing neurons. Hypocretin neurons are active during behavioral arousal and are quiet during non-REM and REM sleep. Deficiency of HCRTergic signaling is linked to the symptoms of narcolepsy in humans, dogs, and rodents. Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, disrupted nighttime sleep, sleep-onset REM sleep, and sudden loss of muscle tone during waking (cataplexy). Hypocretin neurons project extensively to brain structures, especially to those that are involved in arousal and motor control as well as receive extensive inputs from areas regulating emotions, autonomic tone, appetite, circadian rhythms, and sleep–wake behavior. Therefore, HCRT neurons are well positioned to integrate a variety of interoceptive and homeostatic signals to increase behavioral arousal and suppress REM sleep and its atonia. This chapter provides a brief review of the HCRTergic system, its interactions with other neuronal systems involved in sleep–wake regulation, and the neuronal circuitry and the potential mechanism(s) by which the HCRTergic system promotes behavioral arousal and suppresses REM sleep and its muscle atonia.

Summary

Sleep-deprivation protocols are useful to examine the consequences of inadequate or insufficient sleep on health. By employing different paradigms of sleep deprivation or sleep restriction in humans and animals, numerous laboratories have come to the conclusion that insufficient sleep is stressful. Particularly, activation of stress response systems – the locus coeruleus/ adrenal medulla and the hypothalamic–pituitary–adrenal (HPA) axis – appears to be a caveat of instrumental methods to induce REM-sleep deprivation. However, not all effects of REM-sleep deprivation are mediated by increased secretion of glucocorticoids (the final outcome of HPA axis activation) nor are these effects common to other protracted stressors. Therefore, the present chapter presents an overview of the very peculiar form of stress represented by inadequate or insufficient sleep, by means of REM-sleep deprivation.

Summary

Recently, we proposed the model consists of a quartet of neuron groups: (1) sleep-active preoptic/anterior hypothalamic neurons (N-R group); (2) wake-active hypothalamic and brain-stem neurons exhibiting the highest rate of discharge during wakefulness and the lowest rate of discharge during paradoxical or REM sleep (WA group); (3) brain-stem neurons exhibiting the highest rate of discharge during REM sleep (REM group); and (4) basal forebrain, hypothalamic, and brain-stem neurons exhibiting a higher rate of discharge during both wakefulness and REM sleep than during NREM sleep (W-R group). In this chapter, we explain our revised model of sleep–wakefulness regulation in the rat, which includes a neural regulator quartet of NREM sleep, REM sleep, wakefulness, and a coregulator of REM sleep and wakefulness, whose parameters are tuned up so that the model reproduces some of the recent findings concerning the WA neurons. The physiological reality of the model structure is demonstrated by comparing the model neuron activities with the actual neuronal activities across state transition. Among the conceptual and mathematical models, one of the novel features of our model is involvement of the cholinergic W-R neuron group, which is assumed to contribute toward induction of wakefulness as well as REM sleep by selectively mediating autocatalytic activation with the WA or REM neurons. Through activity of this neuron group, the wakefulness–sleep flip-flop and the REM–NREM flip-flop interact with each other in our model. In fact pharmacological or physiological manipulations of REM sleep were shown to affect not only NREM sleep but wakefulness. Our successful modeling suggests that REM sleep is regulated cooperatively/competitively with NREM sleep and wakefulness by well orchestrated interactions among the aforementioned quartet of neural groups distributed in the hypothalamus and the brain stem with the aid of sleep-promoting substances. Finally, further possible updates in the model structure are described considering recent physiological findings.

Summary

The medial pontomedullary reticular formation has been implicated in the control of motor activity in REM sleep. Electrical stimulation of points within this area elicits global inhibition of skeletal motor activity in decerebrate animals. This area can be segregated into four distinct subregions based on the response to chemical stimulation. Injection of glutamate, acetylcholine, and corticotropin-releasing factor into the medial pons, the pontine inhibitory area, induces muscle atonia. In the medial medulla, the nucleus magnocellularis (NMC) of the rostroventral medulla responds to glutamate and corticotropin-releasing factor and the nucleus paramedianus of the caudomedial medulla responds to acetylcholine injection, with suppression of muscle tone being induced by these chemicals. In contrast, the transmitter involved in elicitation of atonia by electrical stimulation of the nucleus gigantocellularis of the dorsomedial medulla is unclear. Lesions in this area increase phasic and tonic muscle activity in REM sleep in the chronic animal. Our recent study found that an area rostral to the pons, located at the ventral portion of the junction of the midbrain and pons, the ventral mesopontine junction (VMPJ), is also involved in the control of muscle activity in sleep. Neurotoxic lesions of the VMPJ produce periodic leg movements in slow-wave sleep and increase phasic and tonic muscle activity in REM sleep in the cat, symptoms resembling the human REM sleep behavior disorder (RBD). The anatomical proximity of the VMPJ and the substantia nigra may thus provide a link between RBD and Parkinsonism.

Preface

Since the publication of the first edition of Rapid Eye Movement Sleep (Mallick and Inoue, 1999), the advances in the field of sleep research have been phenomenal; in particular, those concerning rapid eye movement (REM) sleep. The emphasis on REM sleep may be gauged by the fact that recently a conference exclusively devoted to this subject was organized in France to celebrate 50 years since the discovery of REM sleep as well as to honor Professor Michel Jouvet, a pioneer and one of the doyens in this field.

Summary

Sleep has been generally divided into rapid eye movement (REM) sleep and non-REM (NREM) sleep in higher order mammals, including humans. Several theories have proposed various functions of different stages of sleep. We hypothesized that REM sleep maintains brain excitability. In this chapter, we discuss the significance of REM sleep in the maintenance of neuronal electrochemical homeostasis, which governs brain excitability. Selective REM-sleep loss increases the activity of Na-K ATPase, a membrane-bound enzyme that maintains neuronal Na+ and K+ homeostasis and, thus, the neuronal resting membrane potential. Further, the REM sleep deprivation-induced increase in Na-K ATPase activity has been attributed to an increased level of norepinephrine in the brain.

Summary

Disinhibition of REM sleep is a characteristic finding in patients with major depression. REM disinhibition includes shortened REM latency, prolonged first REM periods, and increased REM density (measure of the frequency of rapid eye movements). REM latency, but not REM density, is influenced by age. REM-sleep changes appear to be closely related to the development and the course of depression. A relationship between REM-sleep changes before treatment and treatment outcome is suggested by several studies. REM density is elevated in healthy subjects who have a high genetic load for affective disorders. Most antidepressants suppress REM sleep in patients, normal controls, and laboratory animals. REM-sleep suppression appears to be a distinct hint for the antidepressive properties of a substance, whereas it is not absolutely required. REM-sleep variables during treatment with antidepressants appear to predict the course of the illness. The noradrenergic locus coeruleus and the serotonergic dorsal raphe nuclei, the cholinergic nuclei, and the nucleus of the solitary tract (NTS) are involved in sleep and mood regulation. Hyperaldosteronism has been demonstrated in major depression. Subchronic aldosterone administration can induce anxiety-like behavior. Because of the unusual presence within the brain of both mineralocorticoid receptors and 11-β hydroxysteroid dehydrogenase (11-β HSD), the NTS can act as the gate of the influence of peripheral aldosterone into the brain. Importantly, aldosterone secretion is closely related to the REM/non-REM cycle and is sensitive to sleep manipulations. Hypersecretion of corticotropin-releasing hormone (CRH), the key hormone of the hypothalamo–pituitary–adrenocortical system appears to participate in the pathophysiology of REM-sleep disinhibition. This is supported by increased time spent in REM sleep in mice overexpressing corticotropin-releasing hormone (CRH) in the brain. Furthermore CRH-receptor-type 1 antagonism seems to induce normalization of the REM-sleep changes related to the depression.

Summary

Since the discovery of rapid eye movement (REM) sleep (also known as paradoxical sleep, PS), it has been accepted that sleep is an active process. Paradoxical sleep is characterized by electroencephalogram (EEG) rhythmic activity resembling that of waking with a disappearance of muscle tone and the occurrence of REMs in contrast to slow-wave sleep (SWS, also known as non-REM sleep) identified by the presence of delta waves. Here, we review the most recent data indicating that glutamatergic neurons play a key role in the genesis of PS. We propose an updated integrated model of the mechanisms responsible for PS integrating these neurons. We hypothesize that the entrance from SWS to PS is due to the activation of PS-active glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD). We further propose that these neurons are tonically excited across all the sleep–waking cycle by glutamatergic neurons localized in the lateral periaqueductal gray. We finally hypothesize that the onset of activity of the SLD glutamatergic neurons is due to the removal of a GABAergic input from neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus.

Summary

Sleep is a process occurring in all living animals. Although it is still controversial whether insects and other animals sleep alike; there is no doubt that they rest, as many studies in Drosophila melanogaster have shown. In this context, several seminal studies have documented species-dependent variations in sleep patterns. These findings along with obvious non-learned characteristics of sleep in general, such as the total time of sleep, the alternating NREM–REM sleep pattern, among many others, suggest strong regulation by genes. Clearly, the way genes may influence sleep physiology is via proteins. Hence, the importance of proteins in the regulation of sleep is observed in every minute event occurring to trigger or to maintain sleep. In this chapter we discuss families of proteins that are grouped by their effect on food ingestion, immunological response, trophic activity, and intracellular signaling, all of them affecting the sleep–waking cycle. Although we do not fully discuss the mechanisms of action, we put our effort in highlighting their effects on sleep. Along with the proteins and their effects we have listed those genes encoding them. We also show examples of proteins and the way they affect sleep. Hence, we hope that the overall message that readers will gather from this chapter is the importance of several proteins in the regulation of sleep. Also, by observing the effects of each family of proteins we can infer at least some functions of sleep and, finally, that sleep is a multigenic trait.

Summary

The organization of regional brain function during human rapid eye movement sleep (REMS) can be characterized at the macroscopic systems level by functional neuroimaging techniques. Several aspects of REMS have been investigated. During REMS, forebrain activation pattern is characterized by a hyperactivity in posterior cortical areas and regions of the limbic and paralimbic system, contrasting with a relative quiescence of the polymodal associative cortices of the lateral frontal and parietal cortices. This activity pattern has been related to the main characteristic of dreams. The activity associated with rapid eye movements has been identified in the thalamus and primary visual cortex, suggesting the existence of ponto-geniculo-occipital (PGO) waves in humans. The variability of heart rate during REMS is associated with the activity in the extended amygdala, suggesting a specific organization of autonomic regulation during REMS. The distribution of regional brain activity during REMS was shown to depend on experience acquired during previous wakefulness. Training on a serial reaction time task induces an increase in activity in the brain stem, thalamus, occipital, and premotor areas during subsequent REMS. These data suggest that REMS is implicated in offline memory processing. With the advent of multimodal functional imaging (electroencephalography/functional magnetic resonance imaging (EEG/fMRI), transcranial magnetic stimulation/ electroencephalography (TMS/EEG), and multichannel electroencephalography (MEEG)), a finer grain characterization of human REMS will lead to a better understanding of this intriguing state of vigilance.

Summary

The first and most important active defense of homeothermy in non-rapid eye movement (NREM) sleep is both reactive, i.e., depending on actual ambient temperature, and predictive, in that it is set before sleep by behavioral temperature regulation. This behavior provides thermal conditions counteracting the static influence of ambient temperature on the thermal balance of the body. An important passive defense is the thermal inertia of the body, particularly with regard to negative thermal loads. Such inertia is sufficient to buffer temporarily transient thermal imbalances due to sleep processes. In addition, under the influence of thermal loads and in the presence of an important pressure for sleep, autonomic temperature regulation is fully operative during NREM sleep without eliciting immediate awakening from sleep. This defense is energetically expensive, but the advantage is that as a result of the maintenance of brain thermal homeostasis REM sleep onset may also be promoted and then sustained for a while by the thermal inertia of the body. The important tenet is that the more the behavioral temperature regulation and the thermal inertia of the body constrain the activation of autonomic temperature regulation, the more they protect sleep from terminating. Awakening is the extreme defense of body core homeothermy but at the expense of REM sleep initially and, secondarily, of NREM sleep.

More than 40 years have elapsed since it was experimentally shown in cats exposed to cold and warm ambient thermal loads that shivering and panting, respectively, are present in NREM sleep and absent during REM sleep (Parmeggiani and Rabini, 1967). Then, the interaction between sleep and temperature regulation was the object of study in several mammals, and particularly in cats, rabbits, rats, and humans, which will be dealt with in this chapter. Such experiments not only confirmed the original result but also extended and deepened our knowledge of the changes in temperature regulation that characterize the sleep states. Nevertheless, the physiologic reason why temperature regulation is suspended during REM sleep is still a mystery.

Summary

We have used the brain lesion method and chronically maintained cats to elucidate the contribution of key encephalic structures to the control of REM sleep. The results indicate that the physiological processes that participate in REM sleep generation and maintenance are all located in the pons, with the exception of those involved in REM sleep homeostasis. As we have shown, after a mesencephalic transection, REM sleep-deprived cats show a strong REM sleep pressure, but rebound does not occur. This finding indicates that the pontine mechanisms are modulated by a complex forebrain system, which, as we have shown, originates in the neocortex and has a powerful diencephalic stage. Part of this descending influence is a permissive mechanism for REM sleep rebound, which probably originates in the hypothalamus. Therefore the ultimate control of REM sleep rebound originates in the forebrain. This makes sense because it allows for a needed tight coupling with NREM sleep, which, as is well known, is also controlled by the forebrain. We have demonstrated that the electrocortical desynchronization induced by REM sleep is stronger that the one seen during waking (W), and this allows for REM sleep to accomplish what, we believe, is perhaps an REM sleep main function, i.e., to maintain the continuity of true sleep (S) given the limited duration of NREM sleep periods (by co-opting W at the end of NREM sleep periods).

Summary

In most mammals, sleep is composed of two distinct states, rapid eye movement (REM) sleep and slow-wave sleep (SWS). The differentiated nature of mammalian sleep suggests that each state performs a different function, or perhaps different, but complementary components of a unified function. Despite extensive research, the function(s) provided by sleep and its respective sub-states remains the subject of debate (Cirelli and Tononi, 2008; Mignot, 2008; Siegel, 2009; Stickgold and Walker, 2007). One approach to unraveling the function of each sleep state is to trace its evolution. Through identifying the type(s) of animals in which each state evolved, we may reveal biological traits that coevolved with a particular sleep state. Cases of convergent evolution may be particularly informative because they provide the opportunity to isolate traits shared by only those animals that evolved a particular sleep state. The independent coevolution of certain sleep states and traits may be functionally linked. Conversely, the subsequent coevolutionary loss of a particular sleep state and certain traits may also reveal traits that benefit from a particular sleep state. Moreover, assuming that sleep serves an important function, determining how such animals compensate for the loss of a particular sleep state may yield clues to its purpose. Finally, another approach is to identify biological traits that account for the variation in time spent in, and presumably need for, each state. Traits that influence the allocation of time to a particular state may suggest a function for that state. The following chapter summarizes insights into the function of REM sleep gleaned from these comparative approaches.

Summary

The data outlined in this chapter provides evidence to support a concept that the activation of pontine-wave (P-wave) generating neurons plays a critical role in long-term memory formation. The P-wave, generated by the phasic activation of glutamatergic neurons in the pons, is one of the most prominent phasic events of REM sleep. These P-wave generating neurons project to the hippocampus, amygdala, entorhinal cortex and many other regions of the brain known to be involved in cognitive processing. These P-wave generating glutamatergic neurons remain silent during wakefulness and slow-wave sleep (SWS), but during the transition from SWS to REM sleep and throughout REM sleep these neurons discharge high-frequency spike bursts in the background of tonically increased firing rates. Activation of these P-wave generating neurons increases glutamate release and activates postsynaptic N-methyl-D-aspartic acid (NMDA) receptors in the dorsal hippocampus. Activation of P-wave generating neurons increases phosphorylation of transcription factor cAMP response element binding protein (CREB) in the dorsal hippocampus and amygdala by activating intracellular protein kinase A (PKA). The P-wave generating neurons activation-dependent PKA-CREB phosphorylation increases the expression of activity-regulated cytoskeletal-associated protein (Arc), brain-derived neurotrophic factor (BDNF), and early growth response-1 (Egr-1) genes in the dorsal hippocampus and amygdala. The P-wave generator activation-induced increased activation of PKA and expression of pCREB, Arc, BDNF, and Egr-1 in the dorsal hippocampus is shown to be necessary for REM sleep-dependent memory processing. Continued research on P-wave generation and its functions may provide new advances in understanding memory and treating its disorders.

Summary

The last decade has seen a dramatic increase in our understanding of the role of sleep in off-line memory reprocessing, with published articles on sleep and memory increasing more than five-fold from the 1990s to 2008. While there is now clear evidence that sleep can enhance performance on previously learned tasks, several key questions remain unanswered. Chief among these are (1) the types of learning and memory that are enhanced; (2) the nature of the enhancement; (3) the differential roles of the various sleep stages; and (4) the cellular, molecular, and neurophysiological processes that mediate this enhancement. In this chapter, we review our current state of knowledge in regard to each of these questions, and then focus on the specific role of REM sleep.