Clifford B Saper

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

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Publications (285)2032.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). Prostaglandin E2 (PGE2) is the principal mediator of fever, and both PGE2 and PGD2 regulate sleep-wake behavior. The extent to which PGE2 and PGD2 are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE2 receptors, EP3 or EP4; in mice with total body KO of microsomal PGE synthase-1, or the PGD2 receptor DP; and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP4 receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP3 receptors or in the presence of a COX inhibitor. Copyright © 2014. Published by Elsevier Inc.
    Brain Behavior and Immunity 12/2014; · 5.61 Impact Factor
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    ABSTRACT: Intrinsically photoreceptive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin and convey retinal light inputs to the circadian system via the retinohypothalamic tract (RHT) projection to the suprachiasmatic nucleus (SCN). The principal neurotransmitter of this projection is glutamate, and ipRGCs use the vesicular glutamate transporter 2 (VGLUT2) to package glutamate into synaptic vesicles. However, these neurons contain other potential neurotransmitters, such as pituitary adenylate cyclase activating polypeptide (PACAP). To test the role of glutamate in mediating ipRGC light inputs into the SCN, we crossed mice in which Cre-recombinase expression is driven by the melanopsin promotor (Opn4(Cre/+)) with mice in which the second exon of VGLUT2 is flanked by loxP sites (VGLUT2(fl/fl)), producing ipRGCs that are unable to package glutamate into synaptic vesicles. Such mice had free-running circadian rhythms that did not entrain to a 12:12 light-dark (12:12 LD) cycle, nor did they show a phase delay after a 45-min light pulse administered at circadian time (CT) 14. A small subset of the mice did appear to entrain to the 12:12 LD cycle with a positive phase angle to lights-off; a similar entrainment pattern could be achieved in free-running mice if they were exposed to a 12:12 LD cycle with light of a greater intensity. Glutamate transmission from the ipRGCs is necessary for normal light entrainment of the SCN at moderate (0.35 W/m(2)) light levels, but residual transmission (possibly by PACAP in ipRGCs or by other RGCs) can weakly entrain animals, particularly at very high (6.53 W/m(2)) light levels, although it may be less effective at suppressing locomotor activity (light masking). © 2014 The Author(s).
    Journal of Biological Rhythms 12/2014; · 3.32 Impact Factor
  • Clifford B Saper, Bradford B Lowell
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    ABSTRACT: The hypothalamus is one of the oldest and smallest parts of the brain, constituting just 4 gm of the 1400 gm of adult human brain weight. And yet this tiny area contains highly conserved neural circuitry that controls basic life functions: these include energy metabolism, from feeding through digestion, metabolic control, and energy expenditure; fluid and electrolyte balance, from drinking through fluid absorption and excretion; thermoregulation, from choice of environment through heat production and conservation, and fever responses; wake-sleep cycles and emergency responses to stressors in the environment; and reproduction, from reproductive hormone control through mating, pregnancy, birth, and suckling. In this Primer, we will give an overview of the structure of the hypothalamus, and outline what we know about how that relates to its functional circuitry. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Current Biology 12/2014; 24(23):R1111-6. · 9.92 Impact Factor
  • Elda Arrigoni, Clifford B Saper
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    ABSTRACT: In the last eight years optogenetic tools have been widely used to identify functional synaptic connectivity between specific neuronal populations. Most of our knowledge comes from the photo-activation of channelrhodopsin-2 (ChR2) expressing inputs that release glutamate and GABA. More recent studies have been reporting releases of acetylcholine and biogenic amines but direct evidence for photo-evoked released of neuropeptides is still limited particularly in brain slice studies. The high fidelity in the responses with photo-evoked amino-acid transmission is ideal for ChR2-assisted circuit mapping and this approach has been successfully used in different fields of neuroscience. Conversely, neuropeptides employ a slow mode of communication and might require higher frequency and prolonged stimulations to be released. These factors may have contributed to the apparent lack of success for optogenetic release of neuropeptides. In addition, once released, neuropeptides often act on multiple sites and at various distances from the site of release resulting in a greater complexity of postsynaptic responses. Here, we focus on what optogenetics is telling us — and failing to tell us — about fast neurotransmitters and neuropeptides.
    Current Opinion in Neurobiology 12/2014; 29:165–171. · 6.77 Impact Factor
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    ABSTRACT: In patients with obstructive sleep apnea, airway obstruction during sleep produces hypercapnia which in turn activates respiratory muscles that pump air into the lungs (e.g. the diaphragm) and that dilate and stabilize the upper airway (e.g., the genioglossus). We hypothesized that these responses are facilitated by glutamatergic neurons in the parabrachial complex (PB) that respond to hypercapnia and project to premotor and motor neurons that innervate the diaphragm and genioglossus muscles. To test this hypothesis we combined c-Fos immunohistochemistry with in situ hybridization for vGluT2 or GAD67 or with retrograde tracing from the ventrolateral medullary region that contains phrenic premotor neurons, the phrenic motor nucleus in the C3-C5 spinal ventral horn, or the hypoglossal motor nucleus. We found that hypercapnia (10% CO2 for 2 hours) activated c-Fos expression in neurons in the external lateral, lateral crescent (PBcr), and Kölliker-Fuse (KF) PB subnuclei and that most of these neurons were glutamatergic and virtually none GABAergic. Numerous CO2 -responsive neurons in the KF and PBcr were labeled after retrograde tracer injection into the ventrolateral medulla or hypoglossal motor nuclei, and in the KF after injections into the spinal cord, making them candidates for mediating respiratory-facilitatory and upper airway stabilizing effects of hypercapnia. This article is protected by copyright. All rights reserved. Copyright © 2014 Wiley Periodicals, Inc., A Wiley Company.
    The Journal of Comparative Neurology 11/2014; · 3.51 Impact Factor
  • Clifford B. Saper
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    ABSTRACT: Since I began reading the scientific literature when I was a student, I have had a bucket list of journals that published work I admired, and in which I eventually wanted to see some of my own work published. Getting papers into some of those journals (no, I have not yet completed the list…) has been a very satisfying part of my career. Along the way, as an author, reviewer, and editor, I have learned a great deal about how to prepare a paper so that it has the best chance of making it into my journal of choice. In the first two segments of this series, we explored the peer-review process and how to choose a journal in which to publish your work. In this article, we will discuss the process of writing a research paper to maximize the chance of its being accepted in your first-choice journal. This article is protected by copyright. All rights reserved.
    Annals of Neurology 11/2014; · 11.91 Impact Factor
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    ABSTRACT: Fragmented sleep is a common and troubling symptom in ageing and Alzheimer's disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer's disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer's disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer's disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer's disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer's disease.
    Brain 08/2014; · 10.23 Impact Factor
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    ABSTRACT: Work in animals and humans has suggested the existence of a slow wave sleep (SWS)-promoting/electroencephalogram (EEG)-synchronizing center in the mammalian lower brainstem. Although sleep-active GABAergic neurons in the medullary parafacial zone (PZ) are needed for normal SWS, it remains unclear whether these neurons can initiate and maintain SWS or EEG slow-wave activity (SWA) in behaving mice. We used genetically targeted activation and optogenetically based mapping to examine the downstream circuitry engaged by SWS-promoting PZ neurons, and we found that this circuit uniquely and potently initiated SWS and EEG SWA, regardless of the time of day. PZ neurons monosynaptically innervated and released synaptic GABA onto parabrachial neurons, which in turn projected to and released synaptic glutamate onto cortically projecting neurons of the magnocellular basal forebrain; thus, there is a circuit substrate through which GABAergic PZ neurons can potently trigger SWS and modulate the cortical EEG.
    Nature Neuroscience 08/2014; · 14.98 Impact Factor
  • Clifford B. Saper
    Annals of Neurology 07/2014; 76(1). · 11.91 Impact Factor
  • Clifford B Saper
    Annals of Neurology 01/2014; · 11.91 Impact Factor
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    ABSTRACT: Armodafinil is the pharmacologically active R-enantiomer of modafinil, a widely prescribed wake-promoting agent used to treat several sleep-related disorders including excessive daytime sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome. Remarkably, however, the neuronal circuitry through which modafinil exerts its wake-promoting effects remains unresolved. In the present study, we sought to determine if the wake-promoting effects of armodafinil are mediated, at least in part, by inhibiting the sleep-promoting neurons of the ventrolateral preoptic (VLPO) nucleus. To do so, we measured changes in waking following intraperitoneal administration of armodafinil (200 mg/kg) or the psychostimulant methamphetamine (1 mg/kg) in rats with cell-body specific lesion of the VLPO. Rats with histologically confirmed lesions of the VLPO demonstrated a sustained increase in wakefulness at baseline, but the increase in wakefulness following administration of both armodafinil and methamphetamine was similar to that of intact animals. These data suggest that armodafinil increases wakefulness by mechanisms that extend beyond inhibition of VLPO neurons.
    Nature and Science of Sleep 01/2014; 6:57-63.
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    ABSTRACT: Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of REM sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces a REM sleep-like state with muscle atonia and cortical activation, both of which are cardinal features of REM sleep. Located within this region of the pons is the sublaterodorsal nucleus (SLD), a structure thought to be both necessary and sufficient for generating REM sleep muscle atonia. Subsets of glutamatergic SLD neurons potently contribute to motor inhibition during REM sleep through descending projections to motor-related glycinergic/GABAergic neurons in the spinal cord and ventromedial medulla. Prior electrophysiologic and pharmacologic studies examining the effects of acetylcholine on SLD neurons have however produced conflicting results. In the present study, we sought to clarify how acetylcholine influences the activity of spinally-projecting SLD (SLDsp) neurons. We used retrograde tracing in combination with patch clamp recordings and recorded pre- and post-synaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs). We also found that carbachol directly excited SLDsp neurons by activating a Na(+)/Ca(2+) exchanger. Both pre- and postsynaptic effects were mediated by co-activation of M1 and M3 muscarinic receptors. These observations suggest that acetylcholine produces synergistic, excitatory pre- and post-synaptic responses on SLDsp neurons that in turn likely serve to promote muscle atonia during REM sleep.
    The Journal of Physiology 12/2013; · 4.38 Impact Factor
  • Annals of Neurology 11/2013; 75(1). · 11.91 Impact Factor
  • Clifford B Saper
    Annals of Neurology 10/2013; 74(6). · 11.91 Impact Factor
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    ABSTRACT: A solitary cluster of parvalbumin-positive neurons - the PV1 nucleus - has been observed in the lateral hypothalamus of rodents. In the present study, we mapped the efferent connections of the PV1 nucleus using nonspecific antero- and retrograde tracers in rats, and chemoselective, Cre-dependent viral constructs in parvalbumin-Cre mice. In both species, the PV1 nucleus was found to project mainly to the periaqueductal grey matter (PAG), predominantly ipsilaterally. Indirectly in rats and directly in mice, a discrete, longitudinally oriented cylindrical column of terminal fields (PV1-CTF) was identified ventrolateral to the aqueduct on the edge of the PAG. The PV1-CTF is particularly dense in the rostral portion, which is located in the supraoculomotor nucleus (Su3). It is spatially interrupted over a short stretch at the level of the trochlear nucleus and abuts caudally on a second parvalbumin-positive (PV2) nucleus. The rostral and the caudal portions of the PV1-CTF consist of axonal endings, which stem from neurons scattered throughout the PV1 nucleus. Topographically, the longitudinal orientation of the PV1-CTF accords with that of the likewise longitudinally oriented functional modules of the PAG, but overlaps none of them. Minor terminal fields were identified in a crescentic column of the lateral PAG, as well as in the Edinger-Westphal, the lateral habenular, and the laterodorsal tegmental nuclei. So far, no obvious functions have been attributed to this small, circumscribed column ventrolateral to the aqueduct, the prime target of the PV1 nucleus. J. Comp. Neurol. 521:3133-3153, 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 10/2013; 521(14):Spc1. · 3.51 Impact Factor
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    Annals of Neurology 09/2013; 74(3):A9-A10. · 11.91 Impact Factor
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    Clifford B Saper, Thomas E Scammell
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    ABSTRACT: The development of new therapeutics for sleep disorders is increasingly dependent upon understanding the basic brain circuitry that underlies sleep-wake regulation, and how it may be pharmacologically manipulated. In this review, we consider the pathophysiological basis of major sleep disorders that often are seen by neurologists, including excessive daytime sleepiness, insomnia, narcolepsy, REM sleep behavior disorder and restless legs syndrome, as well as circadian disorders, and we review the current and potential future therapeutic approaches. ANN NEUROL 2013. © 2013 American Neurological Association.
    Annals of Neurology 08/2013; · 11.91 Impact Factor
  • Clifford B Saper, Amita Sehgal
    Current opinion in neurobiology 07/2013; · 7.21 Impact Factor
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    ABSTRACT: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.
    Sleep Medicine 07/2013; · 3.10 Impact Factor
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    ABSTRACT: Rapid eye movement (REM) sleep in mammals is associated with wakelike cortical and hippocampal activation and concurrent postural muscle atonia. Research during the past 5 decades has revealed the details of the neural circuitry regulating REM sleep and muscle atonia during this state. REM-active glutamatergic neurons in the sublaterodorsal nucleus (SLD) of the dorsal pons are critical for generation for REM sleep atonia. Descending projections from SLD glutamatergic neurons activate inhibitory premotor neurons in the ventromedial medulla (VMM) and in the spinal cord to antagonize the glutamatergic supraspinal inputs on the motor neurons during REM sleep. REM sleep behavior disorder (RBD) consists of simple behaviors (i.e., twitching, jerking) and complex behaviors (i.e., defensive behavior, talking). Animal research has lead to the hypothesis that complex behaviors in RBD are due to SLD pathology, while simple behaviors of RBD may be due to less severe SLD pathology or dysfunction of the VMM, ventral pons, or spinal cord.
    Sleep Medicine 06/2013; · 3.10 Impact Factor

Publication Stats

35k Citations
2,032.58 Total Impact Points


  • 1993–2014
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, Massachusetts, United States
    • Harvard Medical School
      • • Department of Neurology
      • • Division of Sleep Medicine
      Boston, Massachusetts, United States
    • Emory University
      • Department of Neurology
      Atlanta, GA, United States
  • 2010
    • University of Texas Southwestern Medical Center
      • Department of Internal Medicine
      Dallas, TX, United States
  • 2009
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Oslo
      Kristiania (historical), Oslo County, Norway
  • 2001
    • University of São Paulo
      • Departamento de Anatomia (FM)
      Ribeirão Preto, Estado de Sao Paulo, Brazil
  • 2000
    • University of Pennsylvania
      • Department of Medicine
      Filadelfia, Pennsylvania, United States
  • 1988–1997
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • University of Washington Seattle
      • Department of Pharmacology
      Seattle, WA, United States
  • 1996
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1985–1996
    • University of Chicago
      • • Department of Pharmacological and Physiological Sciences
      • • Committee on Neurobiology
      Chicago, IL, United States
  • 1994
    • University of Pittsburgh
      • Department of Psychiatry
      Pittsburgh, PA, United States
  • 1992
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1991
    • Robarts Research Institute
      London, Ontario, Canada
  • 1976–1987
    • Washington University in St. Louis
      • • Department of Neurology
      • • Department of Anatomy and Neurobiology
      • • Division of Urologic Surgery
      San Luis, Missouri, United States
  • 1980
    • Cornell University
      Ithaca, New York, United States