JEROME M SIEGEL - Academia.edu (original) (raw)

Papers by JEROME M SIEGEL

Sleep Medicine Reviews, Jun 1, 2011

Sleep and rest can be satisfactorily explained as adaptive states 1, 2 whose core function is ene... more Sleep and rest can be satisfactorily explained as adaptive states 1, 2 whose core function is energy conservation and behavioral regulation. In addition to these functions, certain recuperative processes may be accomplished within sleep. However, the adaptive role of REM sleep remains a complete mystery. The high levels of brain metabolic demand and attenuation of homeostatic regulation make it difficult to understand how animals benefit from this state. Adding to the mystery, it is well known that drug induced suppression of REM sleep is without any striking effect on behavior. Humans taking selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and antidepressants have a massive suppression of REM sleep 3 yet they do not go insane and do not have any apparent impairment of memory-indeed may have some small improvements of memory 4. Even longterm usage of these drugs, with concomitant reduction or elimination of REM sleep does not generally have deleterious effects on health. Indeed they are often given to regulate blood pressure or improve mood. Similarly, no cognitive or health impairment has been identified in the few humans who have lost REM sleep because of brain injury 5. So, REM sleep truly has earned the name "paradoxical sleep," first given to it by the French researcher Michel Jouvet because of its waking EEG during behavioral sleep. It should be noted that in contrast to the findings in humans, deprivation of rats of REM or nonREM sleep by the disk over water method can be lethal 6. However, this may well be due to stress involved in repeated arousals rather than sleep loss itself. Lethal effects of sleep loss have not been reported in mice, cats or other animal sleep subjects. So we are left with a profound question; why do all land mammals (but not necessarily marine mammals 1, 7) and many, perhaps all birds have REM sleep 8 if it uses so much energy and can apparently be dispensed with without obvious negative consequences?

The Journal of Neuroscience, Sep 15, 2001

A complete suppression of muscle tone in the postural muscles and a reduction of muscle tone in t... more A complete suppression of muscle tone in the postural muscles and a reduction of muscle tone in the respiratory related musculature occur in rapid eye movement (REM) sleep. Previous studies have emphasized the role of glycine in generating these changes. Because the activity of norepinephrine-and serotonin-containing neurons is known to decrease in REM sleep, we hypothesized that a decrease in release in one or both of these transmitters might be detected at the motoneuronal level during muscle tone suppression elicited by brainstem stimulation in the decerebrate animal. We compared release in the ventral horn with that in the hypoglossal nucleus to determine whether the mechanism of muscle tone suppression differs in these nuclei as has been hypothesized. Electrical stimulation and cholinergic agonist injection into the mesopontine reticular formation produced a suppression of tone in the postural and respiratory muscles and simultaneously caused a significant reduction of norepinephrine and serotonin release of similar magnitude in both hypoglossal nucleus and spinal cord. Norepinephrine and serotonin release in the motoneuron pools was unchanged when the stimulation was applied to brainstem areas that did not generate bilateral suppression. No change in dopamine release in the motoneuron pools was seen during mesopontine stimulation-induced atonia. We hypothesize that the reduction of monoamine release that we observe exerts a disfacilitatory effect on both ventral horn and hypoglossal motoneurons and that this disfacilitatory mechanism contributes to the muscle atonia elicited in the decerebrate animal and in the intact animal during REM sleep.

Sleep, Apr 1, 2020

Introduction: It was reported that adult ostriches displayed the longest REM sleep episodes (up t... more Introduction: It was reported that adult ostriches displayed the longest REM sleep episodes (up to 5 min) and more REM sleep (24% of the nighttime) than any other avian species. In all mammals studied so far REM sleep predominates at early age suggesting it promotes development of the brain. The aim of this study was to examine REM sleep in ostrich chicks. Methods: EEG, electrooculogram and electromyogram of the neck muscles were recorded in 4 chronically implanted 2-3 month old ostrich chicks over 3 nights. The last night was scored in 4-sec epochs for waking, nonREM and REM sleep. Results: NonREM sleep and REM sleep in the ostrich chicks occurred when they were sitting or lying with the head held above the ground or rested on the ground. REM sleep was characterized by distinct rapid eye movements, head drops and eye closure. The amplitude of the EEG during episodes of REM sleep ranged between low voltage EEG, as recorded during quiet waking and high voltage slow waves, as recorded during nonREM sleep EEG. The ostrich chicks spent on average 70.7 + 2.2% of the nighttime in nonREM sleep and 12.3 + 3.9% in REM sleep. The episodes of REM sleep lasted on average 9 + 1 sec and ranged between 4 and 36 sec. Conclusion: Similar to adult birds, 2-3 mo old ostrich chicks displayed a "mixed" sleep state which has features of both slow wave sleep / nonREM and REM sleep, as we have described in the platypus and echidna. An unexpected result of this study is the total amount and duration of episodes of REM were considerably smaller than has been reported in adult ostriches. More studies need to be done on the developmental and environmental determinants of REM sleep in the ostrich.

Cell, Aug 1, 1999

a single-gene autosomal recessive trait with full penetrance. The sleepiness of narcolepsy can be... more a single-gene autosomal recessive trait with full penetrance. The sleepiness of narcolepsy can be treated by a Jerome M. Siegel Neurobiology Research Veterans Administration Medical Center number of agents, such as amphetamine-like drugs and North Hills, California 91343 Modafinil, which increase arousal. Cataplexy is com-Department of Psychiatry and monly treated with tricyclic antidepressants and by se-Brain Research Institute lective serotonin reuptake inhibitors. Nishino and col-University of California at Los Angeles leagues have shown that the selective serotonin reuptake Los Angeles, California 90024 inhibitors and the antidepressants inhibit cataplexy in proportion to their activation of norepinephrine receptors. In contrast, prazosin, which blocks ␣1 noradrener-Two recent papers have linked narcolepsy to dysfuncgic receptors, greatly exacerbates cataplexy in both tion of the newly discovered hypocretin (Hcrt) (orexin) dogs and humans. Cholinergic agonists and the cholinpeptide system. The paper by Lin et al. (1999 [previous esterase blocker physostigmine also exacerbate cataissue of Cell]) examined the genetic correlate of canine plexy, consistent with a role of cholinoceptive neurons narcolepsy, using the well-characterized Doberman in triggering muscle tone suppression. Thus, the balance pinscher and Labrador retriever models. They found a between the noradrenergic and cholinergic systems is deletion in the transcripts of the hypocretin receptor 2 a major factor in the control of cataplexy. (Hcrtr2) gene in the narcoleptic Doberman and a differ-In normal individuals, postural muscles maintain some ent deletion in transcripts of the same receptor gene in level of tone throughout waking and non-REM sleep. the narcoleptic Labrador. Lin et al. speculate that these Only in REM sleep is muscle tone completely abolished. changes disrupt the proper membrane localization or This suppression of tone prevents the motor programs transduction functions of this receptor. The paper by generated in REM sleep from causing dangerous and Chemelli et al. (1999 [this issue of Cell]) used a different sleep-disrupting movements. The similarity between the approach to arrive at a similar conclusion. They created atonia in REM sleep and the atonia in cataplexy, and a knockout of the Hcrt gene in mice. Mice lacking Hcrt the abnormally short latency to REM sleep onset shown had abnormalities of sleep control resembling aspects by narcoleptics, have led to the hypothesis that cataof narcolepsy. Together these two studies implicate dysplexy may represent a triggering, in waking, of the mechfunction of the Hcrt system or systems closely linked anism that normally functions to suppress muscle tone to it in the pathophysiology of narcolepsy. The implicain REM sleep. Studies in the narcoleptic dog have suptions of these findings can best be understood by reported this hypothesis and provided insights into the viewing the nature of narcolepsy and of the Hcrt system. nature of the mechanisms controlling posture in waking. What Is Narcolepsy? Recordings of brainstem neuronal activity in narcoleptic Narcolepsy is a disease affecting approximately 1 in dogs have shown that cataplexy is linked to the activa-2,000 individuals (about 125,000 in the U.S.) and usually tion of a population of cells in the medulla and pons develops in the second or third decade of life with sympthat in normal animals is active only during REM sleep toms progressing over a period of 1 or more years and (Siegel et al., 1991; Siegel, 1994). During REM sleep then stabilizing. Narcolepsy is characterized by sleepiand presumably during cataplexy, this pontomedullary ness and cataplexy, which is a loss of muscle tone trigsystem causes the release of glycine onto motoneurons, gered by sudden strong emotions such as laughter and producing hyperpolarization (Figure 1). anger. Attacks of cataplexy are usually over within sec-At cataplexy onset, at the same time as glycine begins onds but in some narcoleptic patients can last for minto be released, the norepinephrine-containing neurons utes and be disabling. In contrast to sleep attacks, conof the locus coeruleus, which are normally continuously sciousness is maintained during cataplexy. In most active in waking, abruptly and completely cease disnarcoleptic patients, sleepiness rather than cataplexy charge (Wu et al., 1999). They also cease discharge in is the more troublesome symptom. Narcoleptics go REM sleep. Norepinephrine released from these neuthrough life feeling the way most of us would feel if we rons is known to facilitate motoneurons (Figure 1). Thus, had been awake for 24 hr. They awake refreshed from a combination of active inhibition and disfacilitation (renaps, but soon are sleepy again. Their nighttime sleep duced excitatory input) appears to underlie both catais fragmented with less of the deeper stages of sleep. plexy and the muscle atonia of REM sleep. Narcolepsy also has been reported in horses, cattle, What Are the Hypocretins (Orexins)? and dogs. Some cases of canine narcolepsy are spo-In 1998, de Lecea et al., using directional tag PCR subradic and these dogs cannot be bred to produce narcotraction, described a hypothalamus-specific mRNA that leptic offspring. Occasionally, entire litters are born that encoded "preprohypocretin," which was thought to be develop the symptoms of narcolepsy at 1-4 months of the precursor of two peptides, Hcrt1 and-2. They named age and show both sleepiness and cataplexy. In the these peptides hypocretins (Hcrts) to indicate their hyearly 1970s, Dement, Mitler, and their colleagues found pothalamic localization and similarity to the gut hormone that it was possible to breed these familial narcoleptic secretin. At about the same time, Sakurai et al. (1998) Doberman pinschers or Labrador retrievers. The disorwere searching for ligands for certain cDNA sequences that resembled G protein-coupled receptors but had no der is transmitted in the Dobermans and Labradors as

The neural control of sleep and waking / Jerome Siegel. p. cm. Includes bibliographical reference... more The neural control of sleep and waking / Jerome Siegel. p. cm. Includes bibliographical references and index.

Science, 1978

tonic hyperpolarization of the jaw-closer masseteric motoneuron in the decerebrate cat, associate... more tonic hyperpolarization of the jaw-closer masseteric motoneuron in the decerebrate cat, associated with asynchronous activation of cutaneous trigeminal afferents, is accompanied by an increase in synaptic activity (12). Hyperpolarization of jaw-closer motoneurons induced by this pattern of stimulation of mucosal afferents is accomplished by a postsynaptic inhib-*itory mechanism, in which the synapses that mediate the inhibitory postsynaptic potential are located in the region of the soma (4, 12).

PLoS Biology, 2005

Primers provide a concise introduction into an important aspect of biology highlighted by a curre... more Primers provide a concise introduction into an important aspect of biology highlighted by a current PLoS Biology research article.

Neuroscience, 2008

There is no adequate animal model of restless legs syndrome (RLS) and periodic leg movements diso... more There is no adequate animal model of restless legs syndrome (RLS) and periodic leg movements disorder (PLMD), disorders affecting 10% of the population. Similarly, there is no model of rapid eye movement (REM) sleep behavior disorder (RBD) that explains its symptoms and its link to Parkinsonism. We previously reported that the motor inhibitory system in the brainstem extends from the medulla to the ventral mesopontine junction (VMPJ). We now examine the effects of damage to the VMPJ in the cat. Based on the lesion sites and the changes in sleep pattern and behavior, we saw three distinct syndromes resulting from such lesions; the rostrolateral, rostromedial and caudal VMPJ syndromes. The change in sleep pattern was dependent on the lesion site, but was not significantly correlated with the number of dopaminergic neurons lost. An increase in wakefulness and a decrease in slow wave sleep (SWS) and REM sleep were seen in the rostrolateral VMPJ-lesioned animals. In contrast, the sleep pattern was not significantly changed in the rostromedial and caudal VMPJ-lesioned animals. All three groups of animals showed a significant increase in periodic and isolated leg movements in SWS and increased tonic muscle activity in REM sleep. Beyond these common symptoms, an increase in phasic motor activity in REM sleep, resembling that seen in human RBD, was found in the caudal VMPJlesioned animals. In contrast, the increase in motor activity in SWS in rostral VMPJ-lesioned animals is similar to that seen in human RLS/PLMD patients. The proximity of the VMPJ region to the substantia nigra suggests that the link between RLS/PLMD and Parkinsonism, as well as the progression from RBD to Parkinsonism may be mediated by the spread of damage from the regions identified here into the substantia nigra.

Behavioural Brain Research, 2002

We recorded electroencephalogram (EEG) and simultaneously documented the state of both eyelids du... more We recorded electroencephalogram (EEG) and simultaneously documented the state of both eyelids during sleep and wakefulness in a sub-adult male white whale over a 4-day-period. We showed that the white whale was the fifth species of Cetaceans, which exhibits unihemispheric slow wave sleep. We found that the eye contralateral to the sleeping hemisphere in this whale was usually closed (right eye, 52% of the total sleep time in the contralateral hemisphere; left eye, 40%) or in an intermediate state (31 and 46%, respectively) while the ipsilateral eye was typically open (89 and 80%). Episodes of bilateral eye closure in this whale occupied less than 2% of the observation time and were usually recorded during waking (49% of the bilateral eye closure time) or low amplitude sleep (48%) and rarely in high amplitude sleep (3%). In spite of the evident overall relationship between the sleeping hemisphere and eye state, EEG and eye position in this whale could be independent over short time periods (less than 1 min). Therefore, eye state alone may not accurately reflect sleep state in Cetaceans. Our data support the idea that unihemispheric sleep allows Cetaceans to monitor the environment.

SLEEP

Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the c... more Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt...

Disease Models & Mechanisms

Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete.... more Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most ap...

The Journal of Neuroscience, 2021

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a ... more We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal.SIGNIFICANCE STATEMENTPreviously, we have sh...

Sleep, 2018

found in young individuals exposed to a dawn simulation light, an increase in both heart rate and... more found in young individuals exposed to a dawn simulation light, an increase in both heart rate and sympathovagal tone prior to awakening and a decrease in sleepiness. In this study we will determine whether a dawn simulation light is able to decrease sleepiness in older adults and increase their cardiovascular tone such that they would have reduced or absent postural hypotension when they get out of bed in the morning. Methods: In this preliminary study, seven older patients (69.71 ± 10.26 y) who experienced morning dizziness underwent two overnight stays in the laboratory. During both nights, they slept in complete darkness, except for the last 30 minutes of one night, where a dawn simulation light was on. Sleepiness and balance were tested before and after the night of sleep; heart rate, EEG and blood pressure were continuously recorded. Results: We found no significant effects of "light" or "time" on sleepiness upon awakening, nor were there changes in measures of standing or ambulatory balance or heart rate. Blood pressure data are still under analysis. Conclusion: Unlike younger adults, we found no significant effect on sleepiness or heart rate after a dawn simulation light exposure in older adults. We also did not see an impact on measures of balance. Further analyses and an increased number of participants are planned. Support (If Any): none.

Journal of Comparative Neurology, 2020

The presence of dreams in human sleep, especially in REM sleep, and the detection of physiologica... more The presence of dreams in human sleep, especially in REM sleep, and the detection of physiologically similar states in mammals has led many to ponder whether animals experience similar sleep mentation. Recent advances in our understanding of the anatomical and physiological correlates of sleep stages, and thus dreaming, allow a better understanding of the possibility of dream mentation in nonhuman mammals. Here, we explore the potential for dream mentation, in both non‐REM and REM sleep across mammals. If we take a hard‐stance, that dream mentation only occurs during REM sleep, we conclude that it is unlikely that monotremes, cetaceans, and otariid seals while at sea, have the potential to experience dream mentation. Atypical REM sleep in other species, such as African elephants and Arabian oryx, may alter their potential to experience REM dream mentation. Alternatively, evidence that dream mentation occurs during both non‐REM and REM sleep, indicates that all mammals have the poten...

Scientific Reports, 2019

It has been hypothesized that sleep in the industrialized world is in chronic deficit, due in par... more It has been hypothesized that sleep in the industrialized world is in chronic deficit, due in part to evening light exposure, which delays sleep onset and truncates sleep depending on morning work or school schedules. If so, societies without electricity may sleep longer. However, recent studies of hunter-gatherers and pastoralists living traditional lifestyles without electricity report short sleep compared to industrialized population norms. To further explore the impact of lifestyles and electrification on sleep, we measured sleep by actigraphy in indigenous Melanesians on Tanna Island, Vanuatu, who live traditional subsistence horticultural lifestyles, in villages either with or without access to electricity. Sleep duration was long and efficiency low in both groups, compared to averages from actigraphy studies of industrialized populations. In villages with electricity, light exposure after sunset was increased, sleep onset was delayed, and nocturnal sleep duration was reduced....

IUPHAR/BPS Guide to Pharmacology CITE, 2019

Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [39]) ... more Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [39]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [102]. Currently the only orexin receptor ligand in clinical use is suvorexant, which is used as a hypnotic. Orexin receptor crystal structures have been solved [124, 123].

Journal of Neurophysiology, 1983