sleep.02.07

Segment 7

Wake & REM: Orexin

Neurobiology of Sleep and Wakefulness

Learning Points & Defining Behavioral States Historical Overview: Brainstem & Forebrain Wakefulness and REM Sleep: Monoamines,

Acetylcholine & GABA, Hypocretin/Orexin NREM Sleep: GABA, Adenosine Summary

modified from Peyron et al., J Neurosci 18:9996-10015, 1998

Hypocretin/Orexin-Containing Neurons and Their Projections

Lateral hypothalamus

Hypocretin/Orexin Neurons Project to Arousal-Related Nuclei

tuberomammillary nucleus/posterior hypothalamus

locus coeruleus, dorsal raph nucleus pontine and medullary reticular

formation laterodorsal tegmental area

(Peyron et al., J Neurosci 18:9996-10015, 1998)

Hypocretin/Orexin Neurons Receive Arousal-Related Input from:

basal forebrain glutamatergic and GABAergic neurons (Peyron et al., J Neurosci 18:9996-10015, 1998)

VTA, LC, DR, SCN via DMH, amygdala, BST (Sakurai, Nat Neurosci 8:171-181, 2007)

peripheral metabolic cues (glucose, ghrelin, leptin) (Sakurai, Nat Neurosci 8:171-181, 2007)

modied from Sakurai Nat Neurosci 8:171-181, 2007

Hypocretin/Orexin Neurons: Afferent & Efferent Connections Permit Behavioral State Modulation

Hypocretin/Orexin and Narcolepsy Canine narcolepsy is caused by a

mutation in the hypocretin (orexin) receptor 2 gene (Lin et al., Cell 98:365-376, 1999)

Hypocretin/orexin knockout mice show periods of behavioral arrest similar to narcolepsy (Chemelli et al., Cell 98:437-451, 1999)

Hypocretin/orexin is not detectable in the CSF of human narcoleptics (Nishino et al., Lancet 355:39-40, 2000)

Postmortem brains of human narcoleptics show a reduced number of hypocretin/orexin neurons (Thannickal et al., Neuron 27:469-474, 2000)

Hypocretin/Orexin and Narcolepsy

Low hypocretin/orexin levels in CSF are now known to occur in patients that have narcolepsy with cataplexy (reviewed in Nishino and Kanbayasi, Sleep Med Rev 9:269-310, 2005)


Transgenic mice that loose hypocretin-containing neurons during development show a phenotype similar to narcolepsy, including periods of behavioral arrest, REM sleep onset periods, fragmented sleep, and late onset obesity (Hara et al., Neuron 30:345-354, 2001)


Symptoms of narcolepsy (cataplexy, fragmented sleep, REM sleep onset periods) in orexin/ataxin-3-transgenic mice are reversed by ectopic production of orexin from a prepro-orexin transgene or by i.c.v. administration of orexin-A (Mieda et al., Proc Natl Acad Sci USA 101:4649-4654, 2004)


Microinjection of hypocretin-1/orexin-A into locus coeruleus increases wakefulness and decreases sleep (Bourgin et al., J Neurosci 20:7760-7765, 2000)

Hypocretin/orexin depolarizes (i.e., activates) wake-promoting neurons in LC, DR, LDT/PPT, PH, SI) (reviewed in Sakurai, Sleep Med Rev 9:231-214, 2005)

Hypocretin/Orexin and Wakefulness

Hypocretin/orexin concentrations in the cerebrospinal fluid of animals are significantly greater during active waking than during quiet waking (Kiyashchenko et al., J Neurosci 22:5282-5286, 2002)

Hypocretin/Orexin and Motor Control

State-Dependent Discharge Rate of Hypocretin/Orexin Neurons

Mileykovshiy et al., Neuron 46:787-798, 2005

AcHve Waking (grooming)



Quiet Waking



Slow Wave Sleep



REM Sleep

Lee et al., J Neurosci 25:6716-6720, 2005


aW qW tS S tR R

Spike

s/se

c

1

3

5

Hypocretin/Orexin and Wakefulness Greatest hypocretin/orexin levels and

neuronal discharge rates during active waking are consistent with a role for hypocretin/orexin in promoting wakefulness and activating motor systems

Hypocretin/Orexin and Wakefulness Optogenetic stimulation of hcrt neurons:

decreased the latency to wake onset from both SWS and REM sleep

increased the number of transitions from both SWS and REM sleep to wake

The photostimulation effects were blocked by a hypocretin receptor 1 antagonist

Adamantidis et al., Nature 450:420-425, 2007

Hypocretin/Orexin and Wakefulness Activation of hypocretin/orexin-

containing neurons promotes the initiation of wakefulness from sleep

This process is mediated by hypocretin/orexin receptors

Adamantidis et al., Nature 450:420-425, 2007

Hypocretin: Clinical Relevance Insomnia

Suvorexant, an orally available, dual orexin receptor antagonist (DORA), promotes sleep at doses that do not disrupt cognition in rats and rhesus monkeys (Uslaner et al., Sci Transl Med 5(179):179ra44, 2013)

FDA News Release, August 13, 2014: suvorexant (Belsomra) approved for the treatment of insomnia

Hypocretin: Clinical Relevance Drug Abuse

Sleep disruption increases the risk of addiction relapse (Brower & Perron Med Hypotheses 74:928-933, 2010)

Dual orexin receptor antagonists block behavioral and genetic changes caused by amphetamine and nicotine (Winrow et al., Neuropharmacology 58:185-194, 2010)

sleep.02.07

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