Thomas E. Scammel - Harvard Medical School, Boston, USA.
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El jueves y viernes 18 y 19 de enero del 2018 se organizó en la Fundación Ramón Areces un Simposio Internacional: Patología del Sueño: de la Neurobiología a las manifestaciones sistémicas. En colaboración con la Sociedad Española de Sueño.
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Thomas E. Scammel - Harvard Medical School, Boston, USA.
- 1. Brain Circuitry of Narcolepsy: Mechanistic and Therapeutic insights Tom Scammell, MD Harvard Medical School Boston Children’s Hospital Beth Israel Deaconess Medical Center
- 2. Symptoms of narcolepsy 1) Excessive daytime sleepiness: often moderate to severe, 4x increased risk motor vehicle accidents 2) Cataplexy: brief, emotionally-triggered episodes of muscle weakness in type 1 narcolepsy 3) Other REM sleep-like phenomena – Sleep paralysis in 40-80% – Hypnagogic and hypnopompic hallucinations in 40- 80% 1) Other symptoms – Fragmented sleep, depression, mild obesity
- 3. Two types of narcolepsy Narcolepsy Type I (Narcolepsy with Cataplexy) •Sleepiness •At least one of the following: – Cataplexy and a positive Multiple Sleep Latency Test (MSLT)* – Low CSF orexin-A concentrations Narcolepsy Type 2 (Narcolepsy without Cataplexy) •Sleepiness •Positive MSLT Hypnagogic hallucinations, sleep paralysis, and fragmented sleep are more common in Type 1 narcolepsy. * Positive MSLT : mean sleep latency of ≤8 minutes and ≥2 sleep- onset REM perdiods. REM sleep latency < 15min on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.
- 4. Orexins/ Hypocretins Ox2ROx1R Orexin-A Orexin-B prepro-orexin mRNA Hcrt-1 Hcrt-2 Sakurai, et al, 1998; de Lecea, et al, 1998
- 5. Orexins activate arousal regions and suppress REM sleep PPT/LDT & SLD REM-on neurons( )
- 6. Loss of orexin neurons in narcolepsy Peyron, et al 2000; Thannickal, et al, 2000; Crocker, et al, 2005; Valko, et al, 2013 3V Control Narcolepsy with cataplexy
- 7. 24 hour polysomnograms in control and untreated narcolepsy patient Adapted from Rogers et al. Sleep. 1994;17:590. Time of day Control Untreated narcolepsy Time of day 2000 2400 0400 0800 1200 1600 W REM 1 2 3/4 2000 2400 0400 0800 1200 1600 W REM 1 2 3/4 MT MT
- 8. • What causes sleepiness in narcolepsy? • What is cataplexy? • How do positive emotions trigger cataplexy?
- 9. What causes sleepiness in narcolepsy?
- 10. Poorly maintained wake and sleep in orexin knockout mice 100 50 0 7 PM7 AM7 PM 100 50 0 Wild-type Orexin knockout %Wake%Wake%wake%wake Mochizuki, et al, 2004 Wild-type Orexin knockout
- 11. Poor maintenance of wake in mice lacking orexin neurons Branch, et al, 2016 progressive orexin neuron loss
- 12. Orexins excite many wake-promoting brain regions orexin laterodorsal and pedunculopontine tegmental nuclei locus coeruleus dorsal raphe ventral tegmental area tuberomammillary nucleus basal forebrain
- 13. Reversible disruption of orexin signaling MAZ (pausing sequence) loxPloxP Splice Acceptor β-geo (β-galactosidase-NeoR fusion) poly A Exon 1 OX1R OX2R SV40 promoter Exon 3 Exon 4 Exon 2 Transcription disrupter (TD) cassette (2.9 kb) ATG ATG Mochizuki, et al, 2011
- 14. Local expression of Cre recombinase to induce local expression of orexin receptors orexin tuberomammillary nucleus adeno-associated viral vector coding for Cre
- 15. Ox2R signaling in the tuberomammillary region rescues sleepiness
- 16. Expression of Ox1R and Ox2R in the basal forebrain improves sleepiness Alexandre, et al, unpublished <0.5 0.5-1 1-2.5 2.5-5.0 5.0-10.5 10.5-21.2 21.2-42.5 >42.5 Duration of wake bouts (min)
- 17. Ox1R signaling in the locus coeruleus region rescues sleepiness Hasegawa, et al, 2014 Injection into LC region of AAV with EF1α promoter driving OX1R expression Wakeepisodeduration(sec)
- 18. What is the underlying physiology of cataplexy?
- 19. Cataplexy • Muscle weakness triggered by strong emotions - especially laughter and joking, but also intense frustration or anger • Consciousness is preserved, though long episodes may transition into REM sleep
- 20. Physiology of cataplexy • Lapses of tone at onset resemble asterixis • Intermittent atonia opposed by postural reflexes can resemble arrhythmic tremor falling 1 sec Rubboli, et al, 2000
- 21. Isolated cataplexy • Cataplexy and vomiting from pilocytic astrocytoma at the dorsal ponto-medullary junction • A few additional cases cataplexy with lesions in the pons Stahl, et al, 1980; Fernandez, et al, 1995; D’Cruz, et al, 1994, O’Neil, et al, 1994
- 22. REM dissociation hypothesis • Cataplexy resembles the atonia of REM sleep (sparing extraocular and respiratory muscles) • People with narcolepsy have Sleep-Onset REM periods (SOREMs), esp. people with cataplexy • Most drugs that suppress cataplexy also suppress REM sleep • Cataplexy less common in narcoleptic dogs and mice with REM sleep in prior 10-20 min
- 23. Orexins promote wake and suppress REM sleep PPT/LDT & SLD REM-on neurons( )
- 24. Histamine neurons remain active during cataplexy 1.6 1.2 0.8 0.4 0 QuietwakeNREM REMcataplexy dischargerate(Hz) Active wake dorsal raphe 1.6 1.2 0.8 0.4 0 Quietwake NREM REMcataplexy dischargerate(Hz) Active wake locus coeruleus John, et al, 2004 Active wake 8 6 4 2 0 Quietwake NREM REMcataplexy dischargerate(Hz) tuberomammillary nucleus
- 25. Problems with the REM dissociation hypothesis • Emotions do not trigger REM sleep • Even in healthy people, laughter transiently reduces the H reflex and deep tendon reflexes • Sodium oxybate (GHB) reduces cataplexy without affecting REM sleep • Sulpiride (D2/D3 antagonist) reduces cataplexy without affecting REM sleep in narcoleptic dogs
- 26. Tonic immobility (feigned death, playing possum) • Immobility when faced with imminent death • Atonia and loss of deep tendon reflexes (rabbits, guinea pigs, ducks, chickens, grass snakes, sharks) • Consciousness is probably preserved (immobility ends when predator looks away); EEG consistent with wake Milius, 2006
- 27. Tonic immobility is widespread and varied • Occurs in many species – Mammals (rabbits, guinea pigs, pigs, bison) – Marsupials (opossum) – Birds (chickens, ducks, quail) – Reptiles (snakes) – Crustaceans (brittle star) – Insects (grasshoppers, beetles) • Some species have high tone (opossums, hognose snake, grasshoppers) Milius, 2006
- 28. Explanations for tonic immobility • Predator loses interest – Cats prefer moving quail – Some atonic ducks survive fox attack – Beetles bred for tonic immobility more likely to survive spider attack • Prey more difficult to swallow – Awkward postures in grasshoppers • Sends a signals that no escape is needed as the prey has other defenses (toxic chemicals, etc) (Miyatake, 2004; Honma, 2006)
- 29. How do positive emotions trigger cataplexy?
- 30. Cataplexy triggers Overeem, et al, 2011
- 31. Adapted from E. Nestler How can we read emotions in mice?
- 32. Cataplexy in mice may be associated with positive emotions • Cataplexy in orexin knockout mice is increased by: – Tasty food (Froot Loops, peanuts, chocolate) – Running wheels España, et al, 2007; Clark, et al, 2009
- 33. Reunification with siblings increases cataplexy Mahoney, et al, unpublished Reunification doubles cataplexy in male and female orexin knockout mice.
- 34. Amygdala activation increases cataplexy Expression of hM3 DREADD receptor in GABAergic neurons of the central nucleus. n=21. DREADD: Designer Receptor Exclusively Activated by Designer Drug Mahoney, et al, 2017
- 35. Amygdala inactivation reduces cataplexy Mahoney, et al, 2017 hM4 inhibitory DREADD in GABAergic neurons of the central nucleus of the amygdala 7PM 9PM 11PM 1AM Chow Chocolate 6 4 2 0 #cataplexybouts 7PM 9PM 11PM 1AM Saline CNO 1 mg/kg Saline CNO 1 mg/kg* * * * *, p<0.05
- 36. Proposed model for cataplexy Amygdala Orexin vlPAG /LPT SLD Cataplexy - Atonia blocker( ) vlPAG/LPT: ventrolateral periaqueductal grey and lateral pontine tegmentum SLD: sublaterodorsal nucleus + - Medial prefrontal cortex + +
- 37. Conclusions • Narcolepsy with cataplexy is caused by loss of the orexin/hypocretin neurons. • Orexins likely promote wake through the tuberomammillary nucleus and locus coeruleus. • The medial prefrontal cortex and amygdala are necessary for cataplexy. • Unanswered questions: – Does an autoimmune process kill the orexin neurons? – What causes narcolepsy without cataplexy? – What are the key neurons that mediate sleepiness and cataplexy? – Can these be targeted therapeutically? – Can we develop ways to restore orexin signaling?
- 38. Acknowledgements Harvard Medical School/BIDMC Carrie Mahoney Caroline Woods Danielle Hawryluk Christian Burgess Yo Oishi Chloe Alexandre Takatoshi Mochizuki Megan Steele Lindsay Agostinelli Jack Thundercliffe Daniel Kroeger Marta Morawska Elda Arrigoni Clif Saper Support from: NINDS, NHLBI Wake Up Narcolepsy Foundation for Prader-Willi Research Collaborators: Christian Baumann, Philipp Valko – Univ. of Zurich Claudio Bassetti – Univ. of Bern Masashi Yanagisawa - UTSW Medical School Emmanuel Mignot - Stanford Univ. Jerry Siegel – UCLA Takeshi Sakurai - Kanazawa Univ. Akihiro Yamanaka - Nagoya Univ. Akira Terao- Tokai Univ.
Editor's Notes
- Orexins/hypocretins discovered by Yanagisawa, Sakurai, deLecea 1998
- Christelle Peyron and Tom Kilduff mapped out the projections of the orexin neurons and found they strongly innervate many wake promoting brain regions including….
- Sleep is disrupted in patients with narcolepsy The disrupted nature of sleep in narcolepsy is evident in these 24-hour polysomnographic (PSG) recordings of an untreated patient with narcolepsy (bottom) and an individual with a normal sleep pattern (top). The Control subject has a regular pattern of REM and NREM stages confined to a 7.5-hour sleep interval. In contrast, the untreated patient with narcolepsy experiences a more fragmented sleep pattern, has REM sleep at evening sleep onset, and has REM sleep intruding even during usual waking hours.
- Orexin signaling through neurons in the TMN region is sufficient to rescue the sleepiness of narcolepsy.
- Distribution of Wake bouts index = amount of
- So restoring orexin signaling in the TMN and LC regions is sufficient, but there may still be other important sites and it remains unclear which sites are truly necessary for orexin’s effects
- Christelle Peyron and Tom Kilduff mapped out the projections of the orexin neurons and found they strongly innervate many wake promoting brain regions including….