Summary

The discovery of rapid eye movement (REM) sleep revolutionized the field of sleep research. REM sleep is that state in which most of our dreams occur. During REM sleep, the brain is active, while the body is asleep. These characteristics make REM sleep a unique and a paradoxical state. While we are struggling to understand the function of REM sleep, major advances have been made in understanding the cellular mechanisms responsible for REM-sleep control. In this chapter, we have described two neurochemical substrates involved in REM-sleep regulation. One of them is adenosine and the other is glycine.

Adenosine is implicated to be the homeostatic regulator of sleep. It has been suggested that adenosine acts via A1 receptors to inhibit wake-promoting neurons and promote the transition from wakefulness to sleep. Adenosine acts on multiple wake-promoting systems including the basal forebrain cholinergic and the non-cholinergic systems, namely the orexinergic, and the histaminergic systems. There are reports suggesting that adenosine may act via A2A receptors and activate sleep-promoting neurons of the preoptic region. In addition, studies suggest a direct role of adenosine in the modulation of REM sleep.

During REM sleep, there is a tonic muscle atonia coupled with phasic muscle twitches. This phenomenon is regulated by the dorsolateral pons and ventromedial medulla along with local neurons within the spinal cord. Glycinergic mechanisms are responsible for the control of muscle tone during REM sleep. However, the exact role is under debate.

Summary

Sleep is implicated in the consolidation of many types of learning and memory tasks. Place cells (hippocampal neurons responding to spatial location of the subject) associated with novel environments on a spatial task reactivate during subsequent sleep (Poe et al., 2000). Such neuronal firing is thought to strengthen memories formed during waking exploration (Huerta and Lisman, 1995). Once the initially novel environment becomes familiar to the animal, place cells reverse phase at which they fire with respect to local theta oscillations during REM sleep. Such phase-reversed firing during theta is consistent with patterns that induce the depotentiation of previously potentiated synapses. Depotentiation is important to prevent the saturation of synaptic weights in the hippocampus, keeping the differential weighting structure necessary for memory preservation. These results indicate that sleep in general seems to serve neither an overall synaptic erasing (Tononi and Cirelli, 2001) nor a general synaptic amplification effect. Rather, in a network-by-network manner (Ribeiro and Nicolelis, 2004) and, according to the requirements of the learning phase, REM-sleep reactivation serves to amplify as-yet-unconsolidated memories and erase already transferred networks from the temporary stores of the hippocampus (Best et al., 2007; Booth and Poe, 2006).

Summary

Research on the REM sleep-generating mechanism has been led by the research of the neuronal discharge (unit) recording and the most remarkable example was the discovery of REM-on neurons. At the current state, because of a technical difficulty, the information obtained from neurotransmitters’ changes cannot completely replace the information from unit activity. However, as the changes across sleep–wakefulness are much slower than unit discharges and have more general effects on the entire brain, the contributions of relatively slow-changing factors from neurotransmitters, such as receptor changes, second messenger contribution, or sleep-inducing factors need to be considered when researchers attempt to explain sleep–wake transition mechanisms. The input signal is converted into the neurotransmitter in the synaptic terminal, transmitted, and observed as unit activities. In pharmacological study, the sleep-generating mechanism is verified by investigating the changes of the unit activities (or sleep behavior), induced by external drug administration, instead of an internal neurotransmitter. For instance, it is considered that REM sleep is regulated by an inhibitory mechanism if it is modulated by a GABA agonist. However, the physiological mechanism is not necessarily simple; the neurotransmitters act synergistically as regulating factors, which modulate, buffer, and gate the input signals to regulate REM sleep. Therefore, although changes in the level of individual neurotransmitters are of course crucial, it is even more important to investigate the changes of neurotransmitters simultaneously during sleep–wake cycles. This chapter summarizes some of the recent findings showing sleep-related changes in the levels of neurotransmitters that regulate REM sleep. In addition, the role of neurotransmitters that exist as the background of the REM sleep-generating mechanism are discussed along with two reciprocal models, the flop-flip model and Sakai’s mutual-interaction model.

Summary

Research into the influence of monoamines on REM sleep-generating processes began as early as 1964, 11 years after the discovery of REM sleep. Various studies have now established that noradrenergic neurons of the locus coeruleus must be silent for REM sleep to occur. However, the maintenance of a low level of noradrenaline is still necessary. This phenomenon is linked to the persistence of noradrenaline in the brain resulting from its diffuse release at the varicosity level and the absence of rapid noradrenaline elimination by reuptake and enzymatic destruction. The role of dopamine in the regulation of REM sleep was discovered more recently. The infusion of dopamine agonists into the REM sleep-inducing structure called the peri-locus coeruleus-α inhibits REM sleep. However, this effect can be blocked by the concurrent administration of dopamine antagonists, indicating a basic noradrenergic function. In the same way, lesions of the dopaminergic ventral periaqueductal gray matter increase REM sleep. Serotonergic neurons become silent during REM sleep, and serotonin, which is involved in processes that support waking, also has REM sleep-off influences. Finally, histamine appears to have indirect influences on REM sleep, as histaminergic neurons become silent as soon as sleep onset occurs. This monoamine acts in connection with orexin, a deficit of which favors REM sleep and narcolepsy. The narcoleptic attacks seen in knock-out mice lacking orexin can be prevented by antagonists of the H3 histamine autoreceptor.

Summary

In the first half of the twentieth century, research by von Economo and Walle Nauta implicated the hypothalamus in sleep and waking. In the subsequent 50 years the hypothalamus was abandoned and instead the pons was considered to house the neurons regulating states of consciousness. In 1999, the linkage of a hypothalamic peptide, hypocretin, with narcolepsy shifted the emphasis back to the hypothalamus. However, since REM sleep originates from the pons, we sought to identify how the hypothalamus links with the pons, which would elucidate a network map of regions responsible for all three states. In this review we summarize our hypothesis that hypothalamic wake and non-REM sleep active neurons link with a group of i nhibitory pontine neurons to gate the transition to REM sleep. This hypothesis was first publically presented by us at the Society for Neuroscience meeting in 2004. We suggest that the pontine areas inhibiting REM sleep (PAIRS) represent GABA neurons; that these neurons are activated by glucosensing neurons, and neurons involved in emotion and arousal, and that their purpose is to keep the animal upright, mobile, and vigilant as it forages for food.

Summary

Rapid eye movement sleep (REMS), first described by Aserinsky and Kleitman (1953), is a distinct state during sleep when the electroencephalographic (EEG) recordings appear similar to those observed during wake with low-voltage, high-frequency asynchronous activity, whereas the electromyographic (EMG) recordings, unlike wake, show lowest levels of muscle tone (muscle atonia), accompanied by rapid eye movements detectable by electro-oculographic (EOG) recordings. This paradoxical vigilant state combining wake-like cortical activation and inactive state-like muscle atonia with rapid eye movements has been extensively studied using animal model systems since the 1950s. Today much is known about the brain regions, neuronal networks, and neurotransmitters involved in REMS regulation (Fort et al., 2009; Jones, 2004; Luppi et al., 2006; McCarley, 2007). However, promising discoveries about the mechanisms depend on the identification of molecular processes that are involved in the transition and maintenance of different vigilant states, especially REMS, which is recognized for its brevity. The recent advances in molecular biology, instrumentation, and bioinformatics further extend novel opportunities to understand the mechanisms involved in REMS regulation and its function. Currently, no study has identified a single specific protein needed for REM generation or maintenance, but several proteins have been identified as changing either during REMS or following REMS deprivation, indicating their involvement in REMS. This chapter will begin with a brief review of the genomic and proteomic studies on sleep followed by a review of reports on REMS describing these different proteins, which include transcription factors, receptors, enzymes, and small peptides, and how they have contributed significantly towards the anatomical localization of REMS-associated brain regions and neurotransmitter phenotype of neurons, and toward a better understanding of REMS regulation and function.

Summary

Withdrawal from the influence of the outside world seemed a reasonable explanation for the onset of sleep for many years. This view, the passive theory of sleep, held sway despite some evidence to the contrary from lesion and stimulation studies as well as the effects of natural disease of the hypothalamus. Discovery of the ascending reticular activating system did not demolish this idea; for this system was considered merely to transmit the effects of sensory withdrawal, a role previously assigned to long ascending pathways. Even the 1953 discovery of REM sleep, which presented features different from “classical” sleep, could not convince some to abandon the passive theory. By the end of the decade, though, so much evidence for complexity in the organization of sleep and wakefulness had accumulated, including the demonstration of REM sleep in decerebrate cats, that the active theory of sleep finally prevailed.

Summary

REM sleep has the dream experience as a frequent if not inevitable concomitant. Questions arise about the construction, function, and meaning of this peculiar and puzzling experience. How are the dreams of the night organized? How do they relate to REM sleep and to each other across the night? How do they relate to waking consciousness? And, do they serve an adaptive function? I will describe the selective mood-regulatory theory of dreaming as an experimentally based attempt to answer these questions.

The beginning of our exploration of a function for dreaming is at the observation that dreaming and sleep disturbances may be related.

Summary

Among sleep stages, awakenings from rapid eye movement (REM) sleep produce the greatest number and reported intensity of dream reports. Dreaming is a conscious state that lacks the insight and cognitive control typical of healthy waking but allows the remarkable emergence of coherent narrative, vivid visual imagery, strong emotion, and sometimes never-before-experienced elements. Similar to waking, ascending activation from the brain stem, basal forebrain, and diencephalon produces the brain-activated state of REM and its associated dream consciousness. However, in REM, the neuromodulatory influences producing this arousal are largely cholinergic and lack the aminergic activation accompanying cholinergic modulation in waking. Positron emission tomography (PET) studies have shown that in REM vs. waking, lateral cortical areas subserving cognitive control and higher order cognition are relatively less activated whereas midline anterior limbic cortical and subcortical structures are equally or more active. Such differences in neuromodulation and regional brain activity help shed light on the neural processes producing phenomenological differences between dream and waking consciousness. Advances in neuroimaging techniques including functional magnetic resonance imaging (fMRI) and electromagnetic source localization are providing new details on the tonic conditions and phasic neural events during REM that may contribute to dream experience.

Summary

Dream study is an ancient science dating to at least 6,000 years ago when dreams perceived as messages from gods were written on the clay codas of Mesopotamia. For the Ancient Greeks and Egyptians it was necessary to distinguish between the “true dreams” of kings and priests (potential messages from god) and other “false dreams” reported even by women and children. Several thousand years later, Rene Descartes, focusing on methods of elucidating such “truths,” developed his scientific method while attempting to differentiate dreaming from external reality. At the turn of the twentieth century, Freud developed his psychoanalytic theories of mental functioning from his approach to dream interpretation. In the 1960s, the apparent realization that REM sleep (REMS) was dreaming destroyed 500 years of belief in Cartesian Dualism and led us into this modern age of unitary activation–synthesis theory. If REMS is dreaming, in neuro-scientific actuality, mind equals brain. The literature is replete with such grand theories purporting to explain the dream state, and it is only recently that experimentally testable scientific approaches have been applied to the study of dreaming. Now, most scientists and philosophers accept that research overwhelmingly demonstrates that REMS occurs without dreaming and dreaming without REMS. It is currently unclear as to how much of the highly developed REMS neurocognitive model presented in this book is applicable to the cognitive state of dreaming.

Summary

The theta rhythm of the hippocampus is a large- amplitude (1–2 mV), nearly sinusoidal oscillation of 5 to 12 Hz. Theta is present in the hippocampus of the rat during the exploratory movements of waking and continuously throughout REM sleep. In early reports, we identified neurons of the nucleus pontis oralis (RPO) of the pons that discharged in association with the theta of waking and REM sleep, and subsequently showed that electrical stimulation or carbachol injections into the RPO very effectively elicited theta. These findings indicated that RPO was the brain-stem source for the generation of theta. In related studies, we described an ascending RPO to septohippocampal system routed through the hypothalamic supramammillary nucleus controlling theta, and further demonstrated that the serotonin-containing median raphe (MR) nucleus desynchronized the hippocampal EEG – or blocked theta. The latter indicates that theta, like other events of REM sleep, is subject to aminergic modulation; that is, the suppression of MR activity during REM releases theta in that state. Theta serves a well recognized role in memory processing in waking. We suggest that theta does not serve the same function in REM sleep (memory processing), but rather theta (of REM) is a by-product of the intense forebrain activation of REM sleep, which serves the important function of maintaining the minimum requisite levels of activity periodically throughout sleep to ensure and promote recovery from sleep.

Summary

The amygdala has a long-recognized role in emotion, and a growing body of work demonstrates that it plays an important part in the regulation of arousal state. Primary findings are that the amygdala, especially its central nucleus, is a strong regulator of rapid eye movement sleep (REMS) and related phenomena, though a smaller body of research indicates a role for the amygdala in regulating non-REM (NREM). Considering its vital place in the limbic circuitry that controls emotion, it is likely that the amygdala mediates fear- and stress-induced alterations in sleep, and investigations in animals have begun to provide confirmatory evidence. In particular, GABAergic regulation of the central nucleus of the amygdala appears to play a significant role in stress-induced reductions in REM. In humans, neuroimaging studies suggest that the pathophysiological mechanisms of narcolepsy and post-traumatic stress disorder (PTSD), two central nervous system disorders with a prominent emotional component and a demonstrated abnormality of REM, involve an amygdalar-mediated reorganization of fundamental REM systems.

Summary

Sleep disturbances are frequently associated with, and can comprise core features of, anxiety disorders. Studies using objective sleep recordings have demonstrated impaired sleep initiation and maintenance in persons with generalized anxiety disorder or panic disorder, but a normal latency to REM sleep. Increased phasic motor activity and eye movement density during REM sleep have been reported in combat veterans with post-traumatic stress disorder: moreover, nightmares and other symptomatic awakenings disproportionately arise from REM sleep.

One of the most consistent behavioral manifestations of sleep loss is the worsening of mood state. With prolonged sleep deprivation it is possible to observe an increase in self-reported feelings of depressed mood, anger, frustration, and anxiety. Interestingly, there is little evidence that waking stress leads to increased REM, although there have been reports of small elevations in REM following severe emotional upset. REM sleep might have some sort of calming effect.

The relationship between somatic distress and dream disturbance has been recently investigated: individuals who reported more incidents of both bad dreams and nightmares did report higher levels of somatic distress. However, REM sleep behavior disorder (RBD), a parasomnia characterized by complex and often violent motor behaviors that emerge from REM sleep and that are associated with violent and unpleasant dreams, represents a particular condition. A discrepancy between the aggressiveness displayed in dreams and the placid and mild-mannered temperament has been observed in patients with RBD.

Summary

Dreams have been known to mankind from time immemorial, while rapid eye movement sleep (REMS) has been objectively defined by characteristic electrophysiological signals since the mid twentieth century only. In the absence of better objective criteria, modern experimental sleep neurobiologists have objectively identified the dream state of a subject with REMS; thus, the dream state and REMS have often been used synonymously. There are reasons to believe that those states are not exclusively correlated to each other, rather they are independent phenomena that are often expressed simultaneously; however, neurobiological explanations are still lacking. In an attempt to better understand the relationship between them, we combined findings from objective science such as non-locality in physics with that of subjective science such as the phenomenon of consciousness. We explored the wisdom in the Upanishads, especially those instances where these ancient writings refer to sleep, dream, and states of consciousness, and attempted to offer an explanation based on modern experimental science. Our search led us towards a conceptual novelty in proposing the existence of an all-inclusive basal ground state (T or Turiya), which possibly equates to very slow waves in the electroencephalogram (EEG), during which waking, dream, non-REMS (NREMS), and REMS express apparently as independent phenomena, though overlapping to various degrees on many occasions. The proposed hypothesis and model, unlike several other earlier ones, is based on known and rational physiological principles, and hence is amenable to experimental verification.

Summary

Cognitive neuroscience continues to build meaningful connections between affective behavior and human brain function. Within the biological sciences, a similar renaissance has taken place, focusing on the role of sleep in various neurocognitive processes and, most recently, the interaction between sleep and emotional regulation. In this chapter, I survey an array of diverse findings across basic and clinical research domains, resulting in a convergent view of sleep-dependent emotional brain processing. Based on the unique neurobiology of sleep, I outline a model describing the overnight modulation of affective neural systems and the (re)processing of recent emotional experiences, both of which appear to redress the appropriate next-day reactivity of limbic and associated autonomic networks. Furthermore, an REM sleep hypothesis of emotional-memory processing is proposed, the implications of which may provide brain-based insights into the association between sleep abnormalities and the initiation and maintenance of mood disturbances.

Summary

Neuroanatomical, neurochemical, genetic, and neuropharmacological evidence presently indicates a role for histamine (HA) in the control of behavioral states. The known neuroanatomical connections of the HA-ergic pathways resemble those of the ascending noradrenergic and serotonergic components of the reticular activating system. Also, the arousing effect of intracerebroventricular (icv) HA administration indicates an important role for HA in this system as a major determinant of the waking state. This is further supported by findings in which 2-(3-trifluoromethylphenyl)histamine, the selective H1 receptor agonist, and thioperamide, the H3 receptor antagonist, increase waking while the HA synthesis inhibitor α-FMH, the H1 receptor antagonists mepyramine, diphenhydramine, chlorpheniramine, and promethazine, and the H3 receptor agonist AMH produce the opposite effects.

It has been proposed that HA may act to modulate REM sleep, such that inhibition of HA functional activity would be followed by increased amounts of REM sleep (permissive role). Accordingly, during REM sleep HA-containing neurons become silent. Moreover, rats treated with α-FMH and HD-KO mice show a significant increase of REM sleep. However, stimulation or blockade of the H1 or H3 receptor suppresses REM sleep. These seemingly conflicting sets of data could be partly related to the lack of specificity of drugs that modify HA transmission. However, experimental manipulations involving direct interactions with receptors may not necessarily have the same consequences for REM sleep as would manipulations that result in reduced HA availability. In this respect, the suppression of REM sleep after stimulation of H1 receptors could be related to the activation of GABAergic interneurons located within and around the LDT/PPT that express these receptors. On the other hand, the reduction of REM sleep after activation of H3 heteroreceptors located in cholinergic and glutamatergic neurons of the LDT/PPT and the mPRF involved in the induction and maintenance of REM sleep could be related to the inhibition of the release of ACh and GLU.

Summary

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain. GABA receptors are ubiquitous and are highly expressed in many brain areas modulating states of sleep and wakefulness. The consistent finding that drugs that enhance GABAergic transmission also enhance sleep supports the conclusion that endogenous GABA promotes sleep. The effects of GABA on sleep, however, vary as a function of brain region. GABAergic transmission in the pontine reticular formation, the tuberomammillary region of the posterior hypothalamus, and the ventrolateral part of the periaqueductal gray has been shown to promote wakefulness, non-rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep, respectively. The finding that hypothalamic GABA-containing neurons project to the dorsal raphe nucleus, locus coeruleus, and pontine reticular formation encourages future studies aiming to determine the extent to which these GABAergic neurons play a causal role in the generation and maintenance of REM sleep. Functional neuroanatomical studies have identified neural pathways that contribute to REM-sleep generation. Simultaneous, in vivo single-cell recordings of identified GABAergic neurons combined with direct measures of endogenous GABA offer a productive approach for gaining future insights.