Faculty Profile

Systems Neurobiology Group (Scammell), Beth Israel Deaconess Medical Center

Our research focuses on the neurobiology of narcolepsy. Narcolepsy is caused by destruction of the hypothalamic neurons that make the neuropeptides orexin/hypocretin. We have found that the orexin-producing neurons are active during wakefulness, and we have identified the numerous inputs to these cells. Now, we are identifying the critical pathways through which orexin promotes wakefulness and suppresses cataplexy. We have produced mice with inducible, focal expression of the orexin receptors. Using adeno-associated vectors and genetic approaches, we can induce eutopic expression of orexin receptors in neurochemically specific populations to identify which brain regions are essential for the wake-promoting effects of orexin. We have also created novel viral vectors to trace neuronal connections between specific groups of neurons. Additional experiments seek to identify how drugs used in the treatment of narcolepsy improve sleepiness and cataplexy. Through these experiments, we hope to gain a detailed understanding of the neurobiology of orexin that will result in highly effective therapies for patients with narcolepsy and enhance our knowledge of sleep.

Takatoshi Mochizuki, PhD
Sandor Kantor, PhD
Cecilia Diniz Behn, PhD
Chloe Alexandre, PhD
Liz Clain
Brian Ko

2001-2006 NIH/R01 Principle Investigator
Circadian and Aminergic Regulation of Orexin Neurons
2003-2008 NIH/P01 Principle Investigator for Project 5
Harvard Center on Sleep Neurobiology and Sleep Apnea
2003-2008 Takeda Pharmaceuticals Principle Investigator
Consolidation of sleep and wakefulness in narcoleptic mice by ramelteon
2007-2012 NIH/R01 Principle Investigator
Orexin and the control of cataplexy

"Human Nervous System and Behavior", Harvard Medical School, lecturer on "Sleep and Sleep Disorders"

"Circadian Biology: From Cellular Oscillators to Sleep Regulation", Biol. 186, Harvard College, lecturer on, "Neurophysiology and Genetic Regulation of Mammalian Sleep"

"Advances in the Treatment of Sleep Disorders", sponsored by the Division of Sleep Medicine, HMS, lecturer on, "Narcolepsy"

"Advanced Sleep Medicine Course", sponsored by the American Academy of Sleep Medicine, lecturer on, "Neurobiology of Wakefulness and Sleep" and "Narcolepsy"

Baumann CR, Bassetti CL, Valko PO, Haybaeck J, Keller M, Clark E, Stocker R, Tolnay M, Scammell TE. Loss of hypocretin (orexin) neurons with traumatic brain injury.
Ann Neurol. 2009 Oct;66(4):555-559. [PMID: 19847903]

Arrigoni E, Mochizuki T, Scammell TE. Activation of the basal foredbrain by the orexinhypocretin neurons.
Acta Physiol (Oxf). 2009 Sep 1. [Epub ahead of print] [PMID: 19723027]

Kantor S, Mochizuki T, Janisiewicz AM, Clark E, Nishino S, Scammell TE. Orexin neurons are necessary for the circadian control of REM sleep.
Sleep. 2009 Sep 1;32(9):1127-34. [PMID: 19750917]

Clark EL, Baumann CR, Cano G, Scammell TE, Mochizuki T. Feeding-elicited cataplexy in orexin knockout mice.
Neuroscience. 2009 Jul 21;161(4):970-7. Epub 2009 Apr 8. [PMID: 19362119]

Scammell TE, Mochizuki T. Is low histamine a fundamental cause of sleepiness in narcolepsy and idiopathic hypersomnia?
Sleep. 2009 Feb 1;32(2):133-4. [PMID: 19238797]

Scammell TE, Willie JT, Guilleminault C, Siegel JM; International Working Group on Rodent Models of Narcolepsy. A consensus definition of cataplexy in mouse models of narcolepsy.
Sleep. 2009 Jan 1;32(1):111-6. [PMID: 19189786]

Diniz Behn CG, Kopell N, Brown EN, Mochizuki T, Scammell TE.  Delayed orexin signaling consolidates wakefulness and sleep: physiology and modeling.
J Neurophysiol. 2008 Jun;99(6):3090-103. [PMID: 18417630]

Baumann CR, Clark EL, Pedersen NP, Hecht JL, Scammell TE. Do enteric neurons make hypocretin?
Regul Pept. 2008 Apr 10;147(1-3):1-3. [PMID: 18191238 ]

Baumann CR, Scammell TE, Bassetti CL.
Parkinson's disease, sleepiness and hypocretin/orexin.
Brain. 2008 Mar;131(Pt 3):e91. [PMID: 17898005]

España, R, McCormack, S, Mochizuki, T,  Scammell, TE. Running and the effects of running wheels in orexin knockout mice.
Sleep. 2007 Nov 1;30(11):1417-25. [PMID: 18041476]

Diniz Behn, C, Brown, EN, Scammell, TE, Kopell, N. A mathematical model of network dynamics governing mouse sleep-wake behavior.
J Neurophysiol. 2007 Jun;97(6):3828-40. Epub 2007 Apr 4. [PMID: 17409167]

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

Mochizuki, M, Klerman, EB, Sakurai, T,  Scammell, TE. Elevated body temperature during sleep in orexin knockout mice.
Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R533-40. [PMID: 16556901]

Grady, S, Nishino, S, Czeisler, C, Hepner, D,  Scammell, TE. Diurnal variation in CSF orexin-A in healthy male subjects.
Sleep. 2006 Mar 1;29(3):295-7. [PMID: 16553014]

Scammell TE. The frustrating and mostly fruitless search for an autoimmune cause of narcolepsy.
Sleep. 2006 May 1;29(5):601-2. [PMID: 16774147]

Yoshida K, McCormack S, Espana RA, Crocker A, and Scammell TE. Afferents to the orexin neurons of the rat brain.
J Comp Neurol. 2006 Feb 10;494(5):845-61. [PMID: 16374809]

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

Crocker, A, España, RA, Papadopoulou, M, Saper, CB, Faraco, J, Sakurai, T, Honda, M, Mignot, E, and Scammell, TE. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology. 2005 Oct 25;65(8):1184-8. Epub 2005 Sep 14. [PMID: 16247044]

Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, and Scammell TE. Behavioral state instability in orexin knock-out mice.
J Neurosci. 2004 Jul 14;24(28):6291-300. [PMID: 15254084]

Scammell, TE, Thompson, MA, Saper, CB, and Greene, R. 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]

Scammell, TE. The neurobiology, diagnosis, and treatment of narcolepsy.
Ann Neurol. 2003 Feb;53(2):154-66. [PMID: 12557281]

Saper, CB, Chou, TC and Scammell, TE. The sleep switch: hypothalamic control of sleep and wakefulness.
Trends Neurosci. 2001 Dec;24(12):726-31. [PMID: 11718878]

Estabrooke, IV, McCarthy, MT, Ko, E, Chou, T, Chemelli, R, Yanagisawa, M, Saper, CB, Scammell, TE. Fos expression in orexin neurons varies with behavioral state.
J Neurosci. 2001 Mar 1;21(5):1656-62. [PMID: 11222656]

Scammell, TE, Estabrooke, IV, McCarthy, MT, Chemelli, R, Yanagisawa, M, Miller, MS, and Saper, CB. Hypothalamic arousal regions are activated during modafinil-induced wakefulness.
J Neurosci. 2000 Nov 15;20(22):8620-8. [PMID: 11069971]

Chemelli, RM, Willie, JT, Sinton, CM, Elmquist, JK, Scammell, T, Lee, C, Richardson, JA, Williams, SC, Xiong, Y, Kisanuki, Y, Fitch, TE, Nakazato, M, Hammer, RE, Saper, CB, and Yanagisawa, M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
Cell. 1999 Aug 20;98(4):437-51. [PMID: 10481909

Scammell, TE, Gerashchenko, D, Urade, Y, Onoe, H, Saper, C, Hayaishi, O. Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2.
Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7754-9. [PMID: 9636223]