Clifford B. Saper

Harvard University, Cambridge, Massachusetts, United States

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Publications (333)2190.84 Total impact

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    ABSTRACT: Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type-specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor-expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation.
    Full-text · Article · Dec 2015 · The Journal of clinical investigation
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    Satvinder Kaur · Daniel Kroeger · Patrick M Fuller · Clifford B Saper

    Full-text · Dataset · Nov 2015
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    ABSTRACT: The mesencephalic (or midbrain) locomotor region (MLR) was first described in 1966 by Shik and colleagues, who demonstrated that electrical stimulation of this region induced locomotion in decerebrate (intercollicular transection) cats. The pedunculopontine tegmental nucleus (PPT) cholinergic neurons and midbrain extrapyramidal area (MEA) have been suggested to form the neuroanatomical basis for the MLR, but direct evidence for the role of these structures in locomotor behavior has been lacking. Here, we tested the hypothesis that the MLR is composed of non-cholinergic spinally projecting cells in the lateral pontine tegmentum. Our results showed that putative MLR neurons medial to the PPT and MEA in rats were non-cholinergic, glutamatergic, and express the orexin (hypocretin) type 2 receptors. Fos mapping correlated with motor behaviors revealed that the dorsal and ventral MLR are activated, respectively, in association with locomotion and an erect posture. Consistent with these findings, chemical stimulation of the dorsal MLR produced locomotion, whereas stimulation of the ventral MLR caused standing. Lesions of the MLR (dorsal and ventral regions together) resulted in cataplexy and episodic immobility of gait. Finally, trans-neuronal tracing with pseudorabies virus demonstrated disynaptic input to the MLR from the substantia nigra via the MEA. These findings offer a new perspective on the neuroanatomic basis of the MLR, and suggest that MLR dysfunction may contribute to the postural and gait abnormalities in Parkinsonism.
    Full-text · Article · Jun 2015 · Frontiers in Neurology
  • Clifford B Saper

    No preview · Article · Jun 2015 · Annals of Neurology
  • Satvinder Kaur · Daniel Kroeger · Patrick M Fuller · Clifford B Saper
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    ABSTRACT: We have reported that glutamatergic signaling in the lateral parabrachial area that includes both the lateral crescent and external lateral PB (PBel) regulates cortical arousals to hypercapnia1. The majority of the PBel neurons express calcitonin gene-related peptide (CGRP), and are possibly a necessary relay for the hypercapnic signal to cause arousal. Methods: We conducted optogenetic inhibition of CGRP PBel neurons selectively in CGRP-CreER mice (n=5) and tested their arousal responses to 10% CO2. On one side of the brain, we injected an adeno-associated virus containing the gene for Archaerhodopsin TP009 T in a Cre-inducible FLEX cassette (AAV-FLEX-ArchT-GFP), that expressed ArchT in CGRP+ PBel cells. On the other side we deleted the CGRP neurons by injecting a Cre dependent virus expressing the diphtheria toxin subunit A (AAV-FLEX-DTA). Mice were also instrumented for sleep recording and optogenetics. To model cyclic hypercapnia as seen during sleep apnea, we investigated EEG arousals to 10% CO2 given for 30s every 300s. We compared the cortical arousals to 10% CO2 in these mice, with and without the 593nm laser light that hyperpolarizes the CGRP-PBel neurons. Results: Without the laser, mice showed normal responses to CO2 (arousal latency- 16.8 ± 0.6sec), and woke-up on every CO2 trial (0% failure to arouse). With 593nm laser-ON, the arousal latency increased five- fold (74.4 ± 6.9sec) and in 43.7 ± 5.2% of the trials the mice did not wake up to CO2 stimulus. ArchT-induced inhibition of CGRP-PBel had no effect on sleep and wake percentages, and on their responses to acoustic stimuli. Conclusions: These results suggest that CGRP-PBel neurons mediate cortical EEG arousals to hypercapnia, by projecting to the lateral hypothalamus, basal forebrain, and central nucleus of amygdala. Current studies are underway to dissect the role of these targets of the CGRP-PBel neurons in CO2 arousal. 1. Kaur S et al., J.Neurosci. 2013, 33:7627-7640.
    No preview · Conference Paper · Jun 2015
  • Clifford B. Saper

    No preview · Article · Jun 2015 · Annals of Neurology
  • Nina Vujovic · Joshua J. Gooley · Thomas C. Jhou · Clifford B. Saper
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    ABSTRACT: The subparaventricular zone of the hypothalamus (SPZ) is the main efferent target of neural projections from the suprachiasmatic nucleus (SCN) and an important relay for the circadian timing system. Although the SPZ is fairly homogeneous cytoarchitecturally and neurochemically, it has been divided into distinct functional and connectional subdivisions. The dorsal subdivision of the SPZ (dSPZ) plays an important role in relaying signals from the SCN controlling body temperature rhythms while the ventral subdivision (vSPZ) is critical for rhythms of sleep and locomotor activity (Lu et al., 2001). On the other hand, the medial part of the SPZ receives input mainly from the dorsomedial SCN, whereas the lateral SPZ receives input from the ventrolateral SCN and the retinohypothalamic tract (Leak and Moore, 2001). We have therefore investigated whether there are corresponding differences in efferent outputs from these four quadrants of the SPZ (dorsolateral, ventrolateral, dorsomedial and ventromedial) by a combination of anterograde and retrograde tracing. We found that while all four subdivisions of the SPZ share a similar backbone of major projection pathways to the septal region, thalamus, hypothalamus, and brainstem, each segment of the SPZ has a specific set of targets where its projections dominate. Furthermore, we observed intra-SPZ projections of varying densities between the four subdivisions. Taken together, this pattern of organization suggests that the circadian timing system may have several parallel neural outflow pathways that provide a road map for understanding how they subserve different functions. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · The Journal of Comparative Neurology
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    ABSTRACT: The suprachiasmatic nucleus (SCN) of the hypothalamus, the master mammalian circadian pacemaker, synchronizes endogenous rhythms with the external day-night cycle. Older humans, particularly those with Alzheimer's disease (AD), often have difficulty maintaining normal circadian rhythms compared to younger adults, but the basis of this change is unknown. We report that the circadian rhythm amplitude of motor activity in both AD subjects and age-matched controls is correlated with the number of vasoactive intestinal peptide-expressing SCN neurons. AD was additionally associated with delayed circadian phase compared to cognitively healthy subjects, suggesting distinct pathologies and strategies for treating aging- and AD-related circadian disturbances. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    No preview · Article · Apr 2015 · Annals of Neurology
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    ABSTRACT: Urinary urgency and frequency are common in α-synucleinopathies such as Parkinson's Disease, Lewy Body Dementia and Multiple System Atrophy. These symptoms cannot be managed with dopamine therapy, and their underlying pathophysiology is unclear. We show that in individuals with Parkinson's Disease, Lewy Body Dementia or Multiple System Atrophy α-synuclein pathology accumulates in the lateral collateral pathway, a region of the sacral spinal dorsal horn important for the relay of pelvic visceral afferents. Deposition of α-synuclein in this region may contribute to impaired micturition and/or constipation in Parkinson's Disease and other α-synucleinopathies. This article is protected by copyright. All rights reserved. © 2015 American Neurological Association.
    No preview · Article · Apr 2015 · Annals of Neurology
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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.
    Full-text · Article · Apr 2015 · The Journal of Comparative Neurology
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    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.
    Full-text · Article · Dec 2014 · Brain Behavior and Immunity
  • Heinrich S Gompf · Patrick M Fuller · Samer Hattar · Clifford B Saper · Jun Lu
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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).
    No preview · Article · Dec 2014 · Journal of Biological Rhythms
  • 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.
    No preview · Article · Dec 2014 · Current Opinion in Neurobiology
  • 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.
    No preview · Article · Dec 2014 · Current Biology
  • 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.
    No preview · Article · Nov 2014 · Annals of Neurology
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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. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected] /* */
    No preview · Article · Aug 2014 · Brain
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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.
    Full-text · Article · Aug 2014 · Nature Neuroscience
  • Clifford B. Saper

    No preview · Article · Jul 2014 · Annals of Neurology
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    Ramalingam Vetrivelan · Clifford B Saper · Patrick M Fuller
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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.
    Preview · Article · May 2014 · Nature and Science of Sleep
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    ABSTRACT: This report describes gelastic seizures in patients with optic nerve hypoplasia and hypothalamic dysfunction without hypothalamic hamartoma. All participants (n = 4) from the optic nerve hypoplasia registry study at Children's Hospital Los Angeles presenting with gelastic seizures were included. The clinical and pathology characteristics include hypothalamic dysgenesis and dysfunction, but no hamartomas. Optic nerve hypoplasia is the only reported condition with gelastic seizures without hypothalamic hamartomas, suggesting that hypothalamic disorganization alone can cause gelastic seizures.
    No preview · Article · Apr 2014 · Journal of child neurology

Publication Stats

46k Citations
2,190.84 Total Impact Points


  • 2000-2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1993-2015
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, Massachusetts, United States
    • Emory University
      • Department of Neurology
      Atlanta, GA, United States
  • 1985-2010
    • University of Chicago
      • • Department of Pharmacological and Physiological Sciences
      • • Committee on Neurobiology
      • • Department of Neurology
      Chicago, Illinois, United States
  • 1992-2005
    • Harvard Medical School
      • Department of Neurology
      Boston, MA, United States
    • Howard Hughes Medical Institute
      • Molecular Biology Facility
      Ашбърн, Virginia, United States
  • 1999
    • University of Texas Southwestern Medical Center
      • Department of Psychiatry
      Dallas, Texas, United States
  • 1996
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1991
    • Mie University
      • School of Medicine
      Tu, Mie, Japan
  • 1976-1988
    • Washington University in St. Louis
      • • Department of Anatomy and Neurobiology
      • • Division of Urologic Surgery
      San Luis, Missouri, United States
  • 1987
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1986
    • University of Illinois at Chicago
      • Institute for Juvenile Research
      Chicago, Illinois, United States