Research Laboratories and Divisions

Systems Neurobiology Group (Scammell)

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 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. To identify the critical pathways through which orexins promote wakefulness and suppress cataplexy, we have produced mice in which local expression of Cre recombinase induces local expression of the orexin receptors. Using adeno-associated viral vectors and genetic techniques, we induce expression of orexin receptors in specific brain regions such as the basal forebrain or in neurochemically specific nuclei such as the histamine-producing neurons. We have found that orexin signaling through the basal forebrain or posterior hypothalamus substantially improves the sleepiness of narcolepsy, and we are now identifying the specific cells that mediate this improvement.

Wake

Some of the key pathways that promote wakefulness. Monoaminergic systems (green) diffusely innervate the forebrain, and cholinergic signals (blue) project to the forebrain and thalamus from the pons and basal forebrain.


Orexin Loss

The orexin neurons promote wakefulness and regulate REM sleep, but these cells are lost in narcolepsy. This loss of orexin signaling probably causes sleepiness through reduced activity of the basal forebrain and monoaminergic systems. In the absence of orexins, REM sleep is poorly controlled, resulting in episodes of paralysis and dream-like hallucinations during wakefulness.

Human LC

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

2. In humans, cataplexy is triggered by strong, positive emotions, and we seek to identify the mechanisms through which emotions trigger cataplexy. We have found that cataplexy in narcoleptic mice is increased by rewarding stimuli such as running wheels, highly palatable food, and group housing, and we are now mapping the pathways through which these presumably positive stimuli trigger cataplexy.







in situ

Double-label in situ hybridization shows that the orexin neurons (prepro-orexin mRNA labeled red) also contain dynorphin (pre-prodynorphin labeled with silver grains, white dots).

3. We have found that the orexin neurons also produce dynorphin and glutamate, and we are using electrophysiologic techniques, mathematical modeling, and new lines of mice to determine the functions of these co-neurotransmitters.











4. 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.

5. Using an adeno-associated viral vector that drives expression of the orexin peptides, we are testing whether gene therapy can improve the symptoms of narcolepsy in mice that lack the orexin-producing neurons. We are finding that ectopic expression of orexins markedly improves the sleepiness of these mice and reduces the severity of their cataplexy.

6. We have found that the orexin-producing neurons are active during wakefulness, and we are using novel methods to trace these the inputs and electrophysiologic mechanisms through which this occurs.

7. Other new projects are determining how cholinergic neurons of the pons regulate sleep and how pain disrupts sleep.

Our lab uses a variety of anatomic, physiologic, and molecular techniques. We frequently study sleep/wake behavior in mice using detailed analysis of the electroencephalogram in conjunction with 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 examination of intermediate states. We trace neural pathways using novel and conventional anterograde and retrograde tracers, and we perform immunostaining and in situ hybridization histochemistry to 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
Thomas E. Scammell, MD
Tom Scammell, MD
Principle Investigator

Mochizuki
Takatoshi Mochizuki, PhD
Assistant Professor
Alexandre
Chloé Alexandre, PhD
Postdoctoral Fellow

Clark
Erika Clark, MS
Research Assistant
Mihoko
Mihoko Yamamoto, MS
Research Assistant
Brian Ko
Senior Thesis Student

Collaborators

Elda Arrigoni, PhD
Assistant Professor
Christian Baumann, MD
Assistant Professor
University of Zurich

Sandor Kantor
Sandor Kantor, PhD
Research Associate
Institute of Experimental Medicine
Hungarian Academy of Sciences

Diniz Behn
Cecilia Diniz Behn, PhD
Assistant Professor
Univ. of Michigan
Espana
Rodrigo España, PhD
Assistant Professor
Wake Forest University




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