Faculty Profile

Clifford B. Saper, MD, PhD

Clifford B. Saper, MD, PhD
James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School
Professor, Department of Neurology, Beth Israel Deaconess Medical Center

Administrative Title(s)

Head of the Department of Neurology, Beth Israel Deaconess Medical Center

See publications

Inter-office Mail Address

77 Louis-Pasteur/HMI
8th floor
Saper lab

Society Memberships

Sleep Research Society
Society for Neuroscience
American Physiological Society
American Neurological Association
American Academy of Neurology

Research Unit(s)

Systems Neurobiology Group (Saper), Beth Israel Deaconess Medical Center
Sleep and Sleep Apnea PPG Group, Harvard Medical School

Research Interests

The focus of the Saper laboratory is on the integrated functions maintained by they hypothalamus. These include regulation of wake-sleep cycles, body temperature, and feeding. These functions interact with one another extensively, and all three are driven by homeostatic mechanisms as well as by circadian influences. In addition, all three must be adjusted in response to external stressors, ranging from immune stimuli, to food or sleep deprivation, to behavioral stress.

The goal of our laboratory is to identify the neuronal circuitry that is involved in regulating these responses. To do this, we use a wide range of methodologies. To establish specific circuitry, we often use morphological methods, particularly combininb axonal tracer methods with in situ hybridization and immunohistochemistry to determine the chemical phenotypes of neurons. We also examine the changes in gene expression in these neurons under different physiological conditions, such as changes in feeding, wake-sleep, and after applying immune stressors. At the same time, we also employ a wide range of physiological chronic recording methods, including wake-sleep, body temperature, activity, feeding, hormone levels, etc. to correlate the changes in gene expression in the brain with the changes in behavior. We then use both cell-specific lesion methods, as well as genetic knockouts, and intracerebral application of drugs to manipulate these systems, and identify the roles played by specific neurotransmitter systems. This work is augmented by our use of intracellular recordings in slice preparations, to determine the effects of specific neurotransmitters on identified cell populations in the hypothalamus.

Most recently, we have been developing conditional knockin and knockout models for specific neurotransmitter receptors involved in these responses. We combine this with either animals that express recombinases regionally under specific promoters, or with injection of a viral vector containing the recombinase genes. This allows us to turn the expression of specific receptors on or off in specific cell populations, and to test the roles played by those neurotransmitters at those site.

Finally, in addition to identifying this circuitry in experimental animals, we also are interested in determining the homologous circuitry in human brains, and in determining how it may be disrupted in specific neurological and psychiatric disorders. We study these neurotransmitter systems in tissue from humans with Parkinson's disease, Alzheimer's disease, Tourette syndrome, schizophrenia, Prader-Willi syndrome, and other conditions.


Students/Thesis advisor:
Christopher D. Breder, MD, PhD, 1986-1992
Karen M. Hurley, PhD, 1987-1993
Peter T. Nelson, MD, PhD, 1990-1995
Chun Lim, MD,PhD student, 1991-1996
Jon Sherin, MD,PhD student, 1991-1996
Daphne Holt, MD,PhD student, 1991-1996
Stephanie Gaus, PhD student, 1997-2002
Thomas Chou, PhD student, 1998-2004
Joshua Gooley, PhD student, 2001-2006
Nina Vujovic, PhD student, 2007-present

Post-doctoral fellows:
Margaret Moga, PhD, 1989-1992
Nancy L. Chamberlin, PhD, 1989-1996
Sonsoles de Lacalle, MD, PhD, 1990-1996
James Leverenz, MD, 1990- 1992
Thomas E. Scammell, MD, 1993-1997
John D. Griffin, PhD, 1993-1996
Joel K. Elmquist, PhD, 1994-1996
David Wilson, PhD, 1996-1999
Jun Lu, PhD, 1996-1999
Carol Elias, PhD, 1997-1999
Yi-Hong Zhang, PhD, 1997-1999
Takakazu Oka, MD, 1999-2002
Matthew Beaudet, PhD, 1999-2000
Elda Arrigoni, PhD, 2001-2003
Michael Lazarus, PhD, 2002-2005
Xiaodong Li, PhD, 2002-2003
Georgina Cano, PhD, 2003-2006
Patrick Fuller, PhD, 2005-2007
Kyoko Yoshida, PhD, 2005-present
Heinrich Gompf, PhD, 2006-present
David Wood, PhD, 2006-present
Elizabeth Hur, PhD, 2007-present
Vetrivelan Ramilangan, PhD, 2007-present
Nigel P. Pedersen, MBBS, 2008-present
William Todd, 2010-present

Research Funding

NHLBI, PI, PPG on Sleep and Sleep Apnea, Project 1 Leader, Mechanisms of cardiovascular and EEG arousal in OSA
NINDS, PI, Mechanisms of fever
NIA, Project Leader, Effect of sleep restriction on cognitive and metabolic function with aging


Human Nervous System and Behavior (HMS)
Weekly seminar for HMS medical students and residents in Neurology at BIDMC

Selected Publications

Original Articles

Vetrivelan R, Fuller PM, Yokota S, Lu J, Saper CB. Metabolic effects of chronic sleep restriction in rats.
Sleep. 2012 Nov 1;35(11):1511-20. [ PMID: 23115400]

Lim AS, Chang AM, Shulman JM, Raj T, Chibnik LB, Cain SW, Rothamel K, Benoist  C, Myers AJ, Czeisler CA, Buchman AS, Bennett DA, Duffy JF, Saper CB, De Jager PL. A common polymorphism near PER1 and the timing of human behavioral rhythms.
Ann Neurol. 2012 Sep;72(3):324-34. [ PMID: 23034908]

Bruinstroop E, Cano G, Vanderhorst VG, Cavalcante JC, Wirth J, Sena-Esteves M, Saper CB. Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats.
J Comp Neurol. 2012 Jun 15;520(9):1985-2001. [PMID: 22173709]

Lim AS, Yu L, Costa MD, Leurgans SE, Buchman AS, Bennett DA, Saper CB. Increased fragmentation of rest-activity patterns is associated with a characteristic pattern of cognitive impairment in older individuals.
Sleep. 2012 May 1;35(5):633-40B. [ PMID: 22547889]

Mészár Z, Girard F, Saper CB, Celio MR. The lateral hypothalamic parvalbumin-immunoreactive (PV1) nucleus in rodents.
J Comp Neurol. 2012 Mar 1;520(4):798-815. [PMID: 22020694]

Hof PR, Saper CB. Passages 2012.
J Comp Neurol. 2012 Jan 1;520(1):1-5. [PMID: 22081453]

Eikermann M, Vetrivelan R, Grosse-Sundrup M, Henry ME, Hoffmann U, Yokota S, Saper CB, Chamberlin NL. The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia.
Brain Res. 2011 Dec 2;1426:30-7. [ PMID: 22041226]

Lim AS, Saper CB. Sleep, circadian rhythms, and dementia.
Ann Neurol. 2011 Nov;70(5):677-9. [ PMID: 22162052]

Lim AS, Yu L, Costa MD, Buchman AS, Bennett DA, Leurgans SE, Saper CB. Quantification of the fragmentation of rest-activity patterns in elderly individuals using a state transition analysis.
Sleep. 2011 Nov 1;34(11):1569-81. [PMID: 22043128]

Parvizi J, Le S, Foster BL, Bourgeois B, Riviello JJ, Prenger E, Saper C, Kerrigan JF. Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients.
Brain. 2011 Oct;134(Pt 10):2960-8. [PMID: 21975589]

Fuller PM, Sherman D, Pedersen NP, Saper CB, Lu J. Reassessment of the structural basis of the ascending arousal system.
J Comp Neurol. 2011 Apr 1;519(5):933-56. [PMID: 21280045]

Gompf HS, Mathai C, Fuller PM, Wood DA, Pedersen NP, Saper CB, Lu J. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment.
J Neurosci. 2010 Oct 27;30(43):14543-51. [PMID: 20980612]

Saper CB, Lenkinski R. MR spectroscopy in translational neuroscience.
J Comp Neurol. 2010 Oct 15;518(20):4089-90. [ PMID: 20878777]

Gautron L, Lazarus M, Scott MM, Saper CB, Elmquist JK. Identifying the efferent projections of leptin-responsive neurons in the dorsomedial hypothalamus using a novel conditional tracing approach.
J Comp Neurol. 2010 Jun 1;518(11):2090-108. [PMID: 20394060]

Saper CB. A treasure trove of gene expression patterns.
Nat Neurosci. 2010 Jun;13(6):658-9. [PMID: 20498685]

Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome.
J Comp Neurol. 2010 Feb 1;518(3):277-91. [PMID: 19941350]

Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light.
Nat Neurosci. 2010 Feb;13(2):239-45. [PMID: 20062053]

Saper CB. The dance of the perivascular and endothelial cells: mechanisms of brain response to immune signaling.
Neuron. 2010 Jan 14;65(1):4-6 [PMID: 20152108]

Chamberlin NL, Saper CB. The agony of the ecstasy: serotonin and obstructive sleep apnea.
Neurology. 2009 Dec 8;73(23):1947-8 [PMID: 19955498]

Arrigoni E, Lu J, Vetrivelan R, Saper CB. Long-term synaptic plasticity is impaired in rats with lesions of the ventrolateral preoptic nucleus.
Eur J Neurosci. 2009 Dec 3;30(11):2112-20. [PMID: 20128848]

Saper CB. Opening up the JCN toolbox.
J Comp Neurol. 2009 Oct 20;516(6):455. [PMID: 19672981]

Yoshida K, Li X, Cano G, Lazarus M, Saper CB. Parallel preoptic pathways for thermoregulation.
J Neurosci. 2009 Sep 23;29(38):11954-64. [PMID: 19776281]

Saper CB, Maunsell JH. The neuroscience peer review consortium.
Brain Struct Funct. 2009 Sep;213(4-5):359-61. [PMID: 19308445]

Fuller PM, Lu J, Saper CB. Standards of evidence in chronobiology: A response.
J Circadian Rhythms. 2009 Jul 22;7:9. [PMID: 19624818]

Saper CB, Maunsell JH; NPRC Editors and Publishers. The Neuroscience Peer Review Consortium.
Neurosci Lett. 2009 Jun 19;457(1):1-2. [PMID: 19410133]

Saper CB, Maunsell JH. The Neuroscience Peer Review Consortium.
Neuroinformatics. 2009 Jun;7(2):89-91. [PMID: 19172416]

Branco LG, Moreira TS, Guyenet PG, Lalley PM, Kawai A, Putnam RW, Chamberlin NL, Saper CB, Gourine AV, Kanamaru M, Homma I. Commentaries on Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites.
J Appl Physiol. 2009 Apr;106(4):1467-70. [PMID: 19336680]

Saper CB, Maunsell JH. The Neuroscience Peer Review Consortium.
Neural Dev. 2009 Mar 12;4:10. [PMID: 19284614]

Jhou TC, Fields HL, Baxter MG, Saper CB, Holland PC. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.
Neuron. 2009 Mar 12;61(5):786-800. [PMID: 19285474]

Saper CB. The Neuroscience Peer Review Consortium.
Neurobiol Dis. 2009 Mar;33(3):313-4. [PMID: 19218038]

Bohland JW, Wu C, Barbas H, Bokil H, Bota M, Breiter HC, Cline HT, Doyle JC, Freed PJ, Greenspan RJ, Haber SN, Hawrylycz M, Herrera DG, Hilgetag CC, Huang ZJ, Jones A, Jones EG, Karten HJ, Kleinfeld D, Kötter R, Lester HA, Lin JM, Mensh BD, Mikula S, Panksepp J, Price JL, Safdieh J, Saper CB, Schiff ND, Schmahmann JD, Stillman BW, Svoboda K, Swanson LW, Toga AW, Van Essen DC, Watson JD, Mitra PP. A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.
PLoS Comput Biol. 2009 Mar;5(3):e1000334. Epub 2009 Mar 27. [PMID: 19325892]

Saper CB, Maunsell JH. The Neuroscience Peer Review Consortium.
Eur J Neurosci. 2009 Feb;29(3):435-6. [PMID: 19222555]

Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB, Woolf CJ, Fitzgerald GA, Samad TA. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice.
J Clin Invest. 2009 Feb;119(2):287-94. [PMID: 19127021]

Saper CB, Maunsell JH. The Neuroscience Peer Review Consortium.
Neuropharmacology. 2009 Jan 19. [PMID: 19272338]

Saper CB, Maunsell JH, Sagvolden T. The neuroscience peer review consortium.
Behav Brain Funct. 2009 Jan 16;5:4. [PMID: 19149887]

Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB, Woolf CJ, Fitzgerald GA, Samad TA. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice.
J Clin Invest. 2009 Feb;119(2):287-94. Epub 2009 Jan 5. [PMID: 19127021]

Orser BA, Saper CB. Multimodal anesthesia and systems neuroscience: the new
Anesthesiology. 2008 Dec;109(6):948-50. [PMID: 19034087]

Cano G, Mochizuki T, Saper CB. Neural circuitry of stress-induced insomnia in rats.
J Neurosci. 2008 Oct 1;28(40):10167-84. [PMID: 18829974]

Pedersen NP, Fuller PM, Lu J, Saper CB. In the flicker of an eye.
J Physiol. 2008 Jul 15;586(14):3305-6. [PMID: 18625803]

Lu J, Nelson LE, Franks N, Maze M, Chamberlin NL, Saper CB. Role of endogenous sleep-wake and analgesic systems in anesthesia.
J Comp Neurol. 2008 Jun 1;508(4):648-62. [PMID: 18383504]

Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms.
Science. 2008 May 23;320(5879):1074-7. [PMID: 18497298]

Tsuchiya H, Oka T, Nakamura K, Ichikawa A, Saper CB, Sugimoto Y. Prostaglandin E2 attenuates preoptic expression of GABAA receptors via EP3 receptors.
J Biol Chem. 2008 Apr 18;283(16):11064-71. [PMID: 18292084]

Scammell TE, Saper CB. Orexins: looking forward to sleep, back at addiction.
Nat Med. 2007 Feb;13(2):126-8. [PMID: 17290266]

Lazarus M, Saper C. The Differential Role of Prostaglandin E2 Receptors in the CNS Response to Systemic Immune Challenge. In: Ader R, editor. Psychoneuroimmunology. Boston, MA: Academic Press; 2006. p. 319-336.

Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep arhitecture, circadian regulation and regulatory feedback.
J Biol Rhythms 2006; 21:482-493. [PMID: 17107938]

Arrigoni E, Chamberlin NL, Saper CB, McCarley RW. Adenosine inhibits basal forebrain cholinergic and noncholinergic neurons in vitro.
Neuroscience. 2006 Mar 14; [Epub ahead of print] [PMID: 16542780] 

Gooley JJ, Schomer A, Saper CB. The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms.
Nat Neurosci. 2006 Mar;9(3):398-407. Epub 2006 Feb 19. [PMID: 16491082]

Lu J, Jhou TC, Saper CB. Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter.
J Neurosci. 2006 Jan 4;26(1):193-202. [PMID: 16399687]

Arrigoni E, Crocker AJ, Saper CB, Greene RW, Scammell TE. Deletion of presynaptic adenosine A1 receptors impairs the recovery of synaptic transmission after hypoxia.
Neuroscience. 2005;132(3):575-80. [PMID: 15837119] 

Chou TC, Rotman SR, Saper CB. Lateral hypothalamic acetylcholinesterase-immunoreactive neurons co-express either orexin or melanin concentrating hormone.
Neurosci Lett. 2004 Nov 11;370(2-3):123-6. [PMID: 15488307]

Chou TC, Scammell TE, Gooley JJ, Gaus SE, Saper CB, Lu J. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms.
J Neurosci. 2003 Nov 19;23(33):10691-702. [PMID: 14627654] 

Gooley JJ, Lu J, Fischer D, Saper CB. A broad role for melanopsin in nonvisual photoreception.
J Neurosci. 2003 Aug 6;23(18):7093-106. [PMID: 12904470] 

Scammell TE, Arrigoni E, Thompson MA, Ronan PJ, Saper CB, Greene RW. Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector.
J Neurosci. 2003 Jul 2;23(13):5762-70. [PMID: 12843280] 

Oka T, Oka K, Kobayashi T, Sugimoto Y, Ichikawa A, Ushikubi F, Narumiya S, Saper CB. Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EP3 receptors.
J Physiol. 2003 Sep 15;551(Pt 3):945-54. Epub 2003 Jul 1. [PMID: 12837930]

Torrealba F, Yanagisawa M, Saper CB. Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats.
Neuroscience. 2003;119(4):1033-44. [PMID: 12831862]

Chamberlin NL, Arrigoni E, Chou TC, Scammell TE, Greene RW, Saper CB. Effects of adenosine on gabaergic synaptic inputs to identified ventrolateral preoptic neurons.
Neuroscience. 2003;119(4):913-8. [PMID: 12831851] 

Zhang YH, Lu J, Elmquist JK, Saper CB. Specific roles of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide-induced fever and Fos expression in rat brain.
J Comp Neurol. 2003 Aug 11;463(1):3-12. [PMID: 12811798] 

Oka T, Oka K, Saper CB. Contrasting effects of E type rostaglandin (EP) receptor agonists on core body temperature in rats.
Brain Res. 2003 Apr 11;968(2):256-62. [PMID: 12663095] 

Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects.
Anesthesiology. 2003 Feb;98(2):428-36. [PMID: 12552203] 

Gaus SE, Strecker RE, Tate BA, Parker RA, Saper CB. Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species.
Neuroscience. 2002;115(1):285-94. [PMID: 12401341] 

Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB. Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep.
J Neurosci. 2002 Jun 1;22(11):4568-76. [PMID: 12040064] 

Chou TC, Bjorkum AA, Gaus SE, Lu J, Scammell TE, Saper CB. Afferents to the ventrolateral preoptic nucleus.
J Neurosci. 2002 Feb 1;22(3):977-90. [PMID: 11826126]


Saper CB, Romanovsky AA, Scammell TE. Neural circuitry engaged by prostaglandins during the sickness syndrome.
Nat Neurosci. 2012 Jul 26;15(8):1088-95. Review. [ PMID: 22837039]

Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching.
Neuron. 2010 Dec 22;68(6):1023-42. Review. [PMID: 21172606]

Saper CB. A Guide to the Perplexed on the Specificity of Antibodies.
J Histochem Cytochem. 2009 Jan;57(1):1-5. Review. [PMID:18854594]

Saper CB, Cano G, Scammell TE. Homeostatic, circadian, and emotional regulation of sleep.
J Comp Neurol. 2005 Dec 5;493(1):92-8. Review. [PMID: 16254994]

Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms.
Nature. 2005 Oct 27;437(7063):1257-63. Review. [PMID: 16251950]

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