Faculty Profile

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

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

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

NHLBI, PI, SCOR on Sleep and Sleep Apnea, Project 4 Leader, Cognitive and metabolic responses to sleep disruption
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

Scammell TE and Saper, CB. Orexins: looking forward to sleep, back at addiction.
Nature Medicine, 2007, 13:126-128.

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, and Saper CB.  The Neuroanatomy of Sleep: Sleep Architecture, Circadian Regulation and Regulatory Feedback. 
J Biol Rhythms. 21 (6) 482-493, 2006

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]

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] 

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]