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

Scammell Diagram 1
The orexin neurons innervate many brain regions that promote wakefulness and suppress REM sleep, including the basal forebrain and monoaminergic nuclei.

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:

Scammell Diagram 2
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).

1. Cataplexy is generally triggered by strong, 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 mediate this response to develop more targeted therapies for cataplexy.

Scammell Diagram 3
Conditional anterograde tracing with channelrhodopsin show that PPT glutamatergic neurons densely innervate the substantia innominata (SI), just below the anterior commissure (ac), and lateral to the optic chiasm (oc).

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 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 found that 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.

Scammell Diagram 4
Noradrenergic neurons of the locus coeruleus in humans are heavily innervated by orexin-containing nerve terminals.

5. In studies of human brains, we 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, physiologic, and molecular 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 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.


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