Research Laboratories and Divisions

Scammell Lab

Department of Neurology, Beth Israel Deaconess Medical Center
Director: Thomas E. Scammell, MD

Thomas Scammell Lab: Research

Research in the Scammell Lab
focuses on the neurobiology of
scammell figure 1 20180801

The orexin neurons innervate many brain regions that promote wakefulness and suppress REM sleep, including the basal forebrain and monoaminergic nuclei.

sleep and the neural basis of narcolepsy. Narcolepsy is caused by an extensive and selective loss of the hypothalamic neurons that produce the orexin neuropeptides(also known as hypocretins). This cell loss generally occurs in the teens or young adulthood and results in lifelong sleepiness and cataplexy, brief episodes of muscle weakness that are similar to the paralysis that occurs during REM sleep. Much of our current work focuses on mouse models  of narcolepsy because mice lacking orexins also have sleepiness and frequent episodes of cataplexy. We hypothesize that orexins normally stabilize the activity of wake-promoting brain regions, but absence of orexins produces behavioral state instability, with rapid transitions from wakefulness into sleep, and intrusions into wakefulness of REM sleep elements such as cataplexy or hallucinations.

Our major goals are to identify the neural mechanisms through which the orexin system controls sleep and wakefulness and to determine how loss of the orexin peptides results in sleepiness and cataplexy. We are pursuing these questions in several ongoing studies:

1. Cataplexy is generally triggered by strong,
scammell figure 2 201807

An injection of the excitatory M3 DREADD receptor into the central nucleus of the amygdala (CeA), just lateral to the optic tract (opt) and medial to the basolateral nucleus (BLA).

positive emotions such as laughing at a great
joke. The amygdala is a key site through which
emotions trigger motor responses, and we are
working to identify just which neurons in the
amygdala mediate cataplexy. Using engineered
DREADD receptors, we found that activation of
GABAergic neurons in the central nucleus of the
amygdala roughly doubles the amount of
cataplexy whereas inhibition of these cells
reduces cataplexy. We are now focused on
identifying just which GABAergic neurons
mediatethis response to develop more targeted
therapies for cataplexy.

2. The pedunculopontine tegmental (PPT)
nucleus has long been implicated in the
regulation of cortical activity and behavioral
states, including rapid eye-movement (REM)
sleep. Though these effects have been
linked with the activity of cholinergic PPT
neurons, the PPT also includes intermingled
scammell figure 3 2018

Conditional anterograde tracing with channelrhodopsin shows that PPT glutamatergic neurons densely innervate the substantia innominata (SI), just below the anterior commissure (ac), and lateral to the optic chiasm (oc).

glutamatergic and GABAergic cell populations, and the precise
roles of cholinergic, glutamatergic,
and GABAergic PPT cell groups in regulating cortical activity and
behavioral state remain unknown.
Using a chemogenetic approach
in three Cre-driver mouse lines, we
foundthat selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons
suppressed lower-frequency
electroencephalogram rhythms
during NREM sleep. Last, activation
of GABAergic PPT neurons slightly reduced REM sleep.
We are now using optogenetics to determine the key pathways through which the glutamatergic PPT neurons promote wakefulness.

3. In collaboration with Dr. Elda Arrigoni’s lab, we are examining the electrophysiologic effects of orexin and dynorphin peptides on neurons of the basal forebrain and other regions. These studies use patch clamp recordings and channelrhodopsins to identify the precise mechanisms through which these peptides influence their targets.

4. Researchers have little understanding of just when the orexin neuropeptides are released and for how long they increase the activity of neurons bearing the orexin receptors. Defining the kinetics of orexin signaling is fundamental for understanding normal neurobiology, especially in relation to variations in arousal and sleep/wake regulation. We are using engineered cells that fluoresce when exposed to orexins to measure orexin tone in relation to changes in behavioral state, reward, and other behaviors.


5. In studies of human brains, we
scammell figure 4 20180

Noradrenergic neurons of the locus coeruleus in humans are heavily innervated by orexin-containing nerve terminals.

have
found that loss of the orexin neurons
in narcolepsy is also accompanied by a
large increase in the number of neurons
producing histamine. This may be a
compensatory response that helps
produce wakefulness after loss of the
orexin neurons. In related work, we are
also examining whether loss of the
orexin neurons and other wake-
promoting systems contributes to
the sleepiness often seen after traumatic
brain injury.

6. In collaboration with Dr. Clifford
Woolf’s lab, we are also examining the interactions of sleep and pain. We have found that reductions in sleep increase behavioral responses to painful stimuli and these responses are normalized with wake-promoting medications. In addition, we have found that mice with neuropathic pain have fragmented sleep, which may be a useful biomarker of spontaneous pain.

Our lab uses a variety of
anatomic,
scammell figure 5 201807 (4)

Axons from GABAergic basal forebrain neurons (red) heavily innervate the lateral parabrachial nucleus, but avoid the external lateral subnucleus dense in catecholamine axons (green). Cholinergic neurons are labeled in blue.

physiologic, andmolecular techniques. We frequently study sleep/wake behavior in mice using detailed analysis of the electroencephalogram
in conjunction with optogenetics, photometry, DREADDs, recordings of muscle activity,locomotion, behavior, and body temperature. We have
also developed new mathematical techniques for analysis of the transitions between behavioral states and examinationof intermediate states. We trace neural pathways using noveland conventional anterograde and retrograde tracers, and we perform immunostaining and in situ hybridization histochemistryto map the distribution of neurotransmitters, receptors, and other molecules. We also use a variety of molecular techniques to design and produce novel recombinant mice.

Through these approaches, we hope to gain a detailed understanding of orexin neurobiology that will result in highly effective therapies for patients with narcolepsy and enhance our knowledge of sleep.



Affiliated Faculty

Lab Members

TScammell 201807
Tom Scammell, MD
Principle Investigator
DKroeger
Daniel Kroeger, PhD
Instructor
CMahoney 20180
Carrie Mahoney, PhD
Instructor


MMorawska 201807
Marta Morawska, PhD
Postdoctoral fellow
ACoffey 201807
Alissa Coffey, PhD
Postdoctoral fellow


STrinh 201807
Sherry Trinh, BS
Research Assistant
SBragg 201807
Sam Bragg, BS
Research Assistant

Alumni and Collaborators

CAlexandre 201807                   
Chloe Alexandre, PhD
Assistant Professor
Johns Hopkins University

LAgostinelli 201807
Lindsay Agostinelli, BS
MD/PhD student
University of Iowa
JGeerling 201807
Joel Geerling, MD, PhD
Assistant Professor
University of Iowa
TMochizuki 201807
Takatoshi Mochizuki, PhD
Intellectual Property Management Group
Kyushu University
CBurgess 201807
Christian Burgess, PhD
Assistant Professor
University of Michigan
YOishi 201807
Yo Oishi, PhD
Assistant Professor
University of Tsukuba
PValko 201807
Philipp Valko, MD
Assistant Professor
University of Zurich
REspana 201807
Rodrigo España, PhD
Assistant Professor
Drexel University College of Medicine
CDinizBehn
Cecilia Diniz Behn, PhD
Assistant Professor
Colorado School of Mines
CBaumann 201807
Christian Baumann, MD
Professor
University of Zurich


Lab Publications

Insight Into Reduction of Wakefulness by Suvorexant in Patients With Insomnia: Analysis of Wake Bouts. Svetnik V, Snyder ES, Tao P, Scammell TE, Roth T, Lines C, Herring WJ. Sleep. 2018 Jan 1;41(1). PMID: 29112763

Dysregulation of Sleep Behavioral States in Narcolepsy. Schoch SF, Werth E, Poryazova R, Scammell TE, Baumann CR, Imbach LL. Sleep. 2017 Dec 1;40(12). PMID: 29029348

Decreased alertness due to sleep loss increases pain sensitivity in mice. Alexandre C, Latremoliere A, Ferreira A, Miracca G, Yamamoto M, Scammell TE, Woolf CJ. Nat Med. 2017 Jun;23(6):768-774. PMID: 28481358
 
Cataplexy and Its Mimics: Clinical Recognition and Management. Pillen S, Pizza F, Dhondt K, Scammell TE, Overeem S. Curr Treat Options Neurol. 2017 Jun;19(6):23. PMID: 28478511

GABAergic Neurons of the Central Amygdala Promote Cataplexy. Mahoney CE, Agostinelli LJ, Brooks JN, Lowell BB, Scammell TE. J Neurosci. 2017 Apr 12;37(15):3995-4006. PMID: 28235898

Neural Circuitry of Wakefulness and Sleep. Scammell TE, Arrigoni E, Lipton JO. Neuron. 2017 Feb 22;93(4):747-765. PMID: 28231463

Complementary roles of gasotransmitters CO and H2S in sleep apnea. Peng YJ, Zhang X, Gridina A, Chupikova I, McCormick DL, Thomas RJ, Scammell TE, Kim G, Vasavda C, Nanduri J, Kumar GK, Semenza GL, Snyder SH, Prabhakar NR. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1413-1418. PMID: 28115703

Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice. Kroeger D, Ferrari LL, Petit G, Mahoney CE, Fuller PM, Arrigoni E, Scammell TE. J Neurosci. 2017 Feb 1;37(5):1352-1366. PMID: 28039375
 
Descending projections from the basal forebrain to the orexin neurons in mice. Agostinelli LJ, Ferrari LL, Mahoney CE, Mochizuki T, Lowell BB, Arrigoni E, Scammell TE. J Comp Neurol. 2017 May 1;525(7):1668-1684. PMID: 27997037

Dynamic GABAergic afferent modulation of AgRP neurons. Garfield AS, Shah BP, Burgess CR, Li MM, Li C, Steger JS, Madara JC, Campbell JN, Kroeger D, Scammell TE, Tannous BA, Myers MG Jr, Andermann ML, Krashes MJ, Lowell BB. Nat Neurosci. 2016 Dec;19(12):1628-1635. PMID: 27643429
 
Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury. Valko PO, Gavrilov YV, Yamamoto M, Noaín D, Reddy H, Haybaeck J, Weis S, Baumann CR, Scammell TE. Sleep. 2016 Jun 1;39(6):1249-52. PMID: 27091531

Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area. Gavrilov YV, Ellison BA, Yamamoto M, Reddy H, Haybaeck J, Mignot E, Baumann CR, Scammell TE, Valko PO. Sleep. 2016 May 1;39(5):1059-62. PMID: 26951397

Narcolepsy. Scammell TE. N Engl J Med. 2015 Dec 31;373(27):2654-62. PMID: 26716917

Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure. Perez MV, Pavlovic A, Shang C, Wheeler MT, Miller CL, Liu J, Dewey FE, Pan S, Thanaporn PK, Absher D, Brandimarto J, Salisbury H, Chan K, Mukherjee R, Konadhode RP, Myers RM, Sedehi D, Scammell TE, Quertermous T, Cappola T, Ashley EA. J Am Coll Cardiol. 2015 Dec 8;66(22):2522-33. PMID: 26653627

Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms. Ferrari LL, Agostinelli LJ, Krashes MJ, Lowell BB, Scammell TE, Arrigoni E. J Physiol. 2016 Feb 15;594(4):1069-85. PMID: 26613645
 
Genetic identity of thermosensory relay neurons in the lateral parabrachial nucleus. Geerling JC, Kim M, Mahoney CE, Abbott SB, Agostinelli LJ, Garfield AS, Krashes MJ, Lowell BB, Scammell TE. Am J Physiol Regul Integr Comp Physiol. 2016 Jan 1;310(1):R41-54. PMID: 26491097

Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals. Bonsall DR, Kim H, Tocci C, Ndiaye A, Petronzio A, McKay-Corkum G, Molyneux PC, Scammell TE, Harrington ME. PLoS One. 2015 Oct 15;10(10):e0140678. PMID: 26469939

Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness. Branch AF, Navidi W, Tabuchi S, Terao A, Yamanaka A, Scammell TE, Diniz Behn C. Sleep. 2016 Feb 1;39(2):369-77. PMID: 26446125

Bradysomnia in Parkinson's disease. Imbach LL, Sommerauer M, Poryazova R, Werth E, Valko PO, Scammell TE, Baumann CR. Clin Neurophysiol. 2016 Feb;127(2):1403-1409. PMID: 26419612

Overview of sleep: the neurologic processes of the sleep-wake cycle. Scammell TE. J Clin Psychiatry. 2015 May;76(5):e13. PMID: 26035194

The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep. Oishi Y, Yoshida K, Scammell TE, Urade Y, Lazarus M, Saper CB. Brain Behav Immun. 2015 Jul;47:172-7. PMID: 25532785

Damage to histaminergic tuberomammillary neurons and other hypothalamic neurons with traumatic brain injury. Valko PO, Gavrilov YV, Yamamoto M, Finn K, Reddy H, Haybaeck J, Weis S, Scammell TE, Baumann CR. Ann Neurol. 2015 Jan;77(1):177-82.  PMID: 25363332

Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population. Reiter J, Katz E, Scammell TE, Maski K. Sleep. 2015 Jun 1;38(6):859-65.  PMID: 25325489

SCOPRISM: a new algorithm for automatic sleep scoring in mice. Bastianini S, Berteotti C, Gabrielli A, Del Vecchio F, Amici R, Alexandre C, Scammell TE, Gazea M, Kimura M, Lo Martire V, Silvani A, Zoccoli G. J Neurosci Methods. 2014 Sep 30;235:277-84.  PMID: 25092499

Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, Dauvilliers Y, Honda M, Owens JA, Plazzi G, Scammell TE. Sleep. 2014 Jun 1;37(6):1035-42.  PMID: 24882898

Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. Williams RH, Chee MJ, Kroeger D, Ferrari LL, Maratos-Flier E, Scammell TE, Arrigoni E. J Neurosci. 2014 Apr 23;34(17):6023-9.  PMID: 24760861

Delusional confusion of dreaming and reality in narcolepsy. Wamsley E, Donjacour CE, Scammell TE, Lammers GJ, Stickgold R. Sleep. 2014 Feb 1;37(2):419-22.  PMID: 24501437

Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord. Weng FJ, Williams RH, Hawryluk JM, Lu J, Scammell TE, Saper CB, Arrigoni E. J Physiol. 2014 Apr 1;592(7):1601-17.  PMID: 24344163

Emerging therapeutics in sleep. Saper CB, Scammell TE. Ann Neurol. 2013 Sep;74(3):435-40.  PMID: 24038193

Increase of histaminergic tuberomammillary neurons in narcolepsy. Valko PO, Gavrilov YV, Yamamoto M, Reddy H, Haybaeck J, Mignot E, Baumann CR, Scammell TE. Ann Neurol. 2013 Dec;74(6):794-804.  PMID: 24006291

Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Kantor S, Mochizuki T, Lops SN, Ko B, Clain E, Clark E, Yamamoto M, Scammell TE. Sleep. 2013 Aug 1;36(8):1129-38.  PMID: 23904672

Role of the medial prefrontal cortex in cataplexy. Oishi Y, Williams RH, Agostinelli L, Arrigoni E, Fuller PM, Mochizuki T, Saper CB, Scammell TE. J Neurosci. 2013 Jun 5;33(23):9743-51.  PMID: 23739971

Amygdala lesions reduce cataplexy in orexin knock-out mice. Burgess CR, Oishi Y, Mochizuki T, Peever JH, Scammell TE. J Neurosci. 2013 Jun 5;33(23):9734-42.  PMID: 23739970

Control of arousal by the orexin neurons. Alexandre C, Andermann ML, Scammell TE. Curr Opin Neurobiol. 2013 Oct;23(5):752-9. 15. Review. PMID: 23683477

Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Poli F, Overeem S, Lammers GJ, Plazzi G, Lecendreux M, Bassetti CL, Dauvilliers Y, Keene D, Khatami R, Li Y, Mayer G, Nohynek H, Pahud B, Paiva T, Partinen M, Scammell TE, Shimabukuro T, Sturkenboom M, van Dinther K, Wiznitzer M, Bonhoeffer J. Vaccine. 2013 Jan 30;31(6):994-1007. PMID: 23246545

Inter-hemispheric oscillations in human sleep. Imbach LL, Werth E, Kallweit U, Sarnthein J, Scammell TE, Baumann CR. PLoS One. 2012;7(11):e48660. PMID: 23144920

Narcolepsy: neural mechanisms of sleepiness and cataplexy. Burgess CR, Scammell TE. J Neurosci. 2012 Sep 5;32(36):12305-11. PMID: 22956821

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

Sleep neurobiology from a clinical perspective. España RA, Scammell TE. Sleep. 2011 Jul 1;34(7):845-58.  PMID: 21731134

Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, Nestler EJ, Elmquist JK, Lutter M. Behav Brain Res. 2011 Sep 23;222(2):289-94.  PMID: 21377495



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