Neurobiology of Sleep and Wakefulness

Tom Scammell, MDNeurology, BIDMC

• Circadian regulation of sleep (Saper)

• The neurobiology of sleep

• Narcolepsy and other sleep disorders

3 Stages of Behavior

• Wakefulness - awareness of self and one’s environment

• Rapid Eye Movement (REM) Sleep - unconscious but cortex active, dreaming, paralysis, saccadic eye movements

• Non-REM Sleep - unconscious with little cortical activity

The electroencephalogram

EEG waves differ across behavioral states

Alpha (8-13 Hz)

Theta (4-7 Hz)

Delta (< 4 Hz)

Stage 1

Stage 2

Stage 3

Stage 4

REM

NREM

The Sleep Cycle

REM

12 1 2 3 4 5 6Clock time

2 major determinants of sleep:

• Homeostatic component- long sleep compensates for prolonged wakefulness

• Circadian component - alertness varies with time of day

Sleep homeostasis: adenosine

• ATP ADP AMP Adenosine• Dependent on glucose, glycogen, and O2

• Brain glycogen falls with sleep deprivation • Adenosine concentration rises during wake and falls during

sleep• Caffeine blocks adenosine receptors

• Other somnogens: PGD2, TNF...

Wake-promoting pathways

periaqueductal grey(dopamine)

Ventral

REM sleep

• Cortical activation

• Dreams are vivid, emotional, and bizarre

• Paralysis

• Rapid eye movements

• Autonomic fluctuations

Mechanisms of REM sleep

See Saper lab Nature 2006

Non-REM sleep

• Cortical synchrony

• Difficult to wake out of deep NREM sleep

• Dreams brief and less vivid

• Increased parasympathetic activity

Mechanisms of non-REM sleep

VLPO lesions produce insomnia

Lu, et al, 2000

Amines and carbachol inhibit the VLPO

Gallopin, et al, 00

The flip-flop and bistability

Saper, et al, 01

What stabilizes wake and sleep?

OrexinHypocretin

Brief bouts of wake and sleep with orexin deficiency

% Wake

% Wake

100

50

0

7 PM7 AM7 PM

100

50

0

Wild-type

Orexinknockout

% Wake

% Wake

%w

ake

%w

ake

Mochizuki, et al, 04

Orexin activates arousal regions

REM-onneurons( )

Orexin excites orexin neurons

Li, et al, 02

Orexin may stabilize sleep/wake behavior

Amines (locus coeruleus, dorsal raphe,tuberomammillary nucleus)

Acetylcholine (LDT/PPT, basal forebr.)

Orexin/Hypocretin

GABA (ventrolateral preoptic nucleus)

Wake Non-REM REM

O

O

O

O

O

Activity of state-regulatory nuclei

Sleep disorders are clinically important

• 15% of adults have chronic insomnia

• 24% of adults have chronic sleepiness

• 25% of motor vehicle accidents with loss of consciousness are due to falling asleep

• 60% of fatal truck accidents are due to sleepiness

• A 23 year old woman is referred for excessive sleepiness after having fallen asleep while driving. She reports that her sleepiness has been present since high school, and she often struggles to remain awake. She occasionally feels weak in the knees when laughing. Once, she fell to the ground while laughing during a party and could not get up for 1-2 minutes. If she is sleepy while driving, she may imagine seeing an animal in the road. Once she was terrified to find herself unable to move for a minute after awakening.

Narcolepsy

Daytime sleepiness

Disrupted nighttime sleep

Fragments of REM sleepCataplexy - sudden, brief episodes of muscular weakness

Hypnagogic hallucinations - vivid, dream-like hallucinations at the beginning or end of sleep

Sleep paralysis - inability to move upon awakening

Polysomnograms in control anduntreated narcolepsy patient

Adapted from Rogers et al. Sleep. 1994;17:590.

Time of day

Co

ntr

ol

Un

trea

ted

nar

cole

psy

Time of day

2000 2400 0400 0800 1200 1600

W

REM

12

3/4

2000 2400 0400 0800 1200 1600

W

REM

12

3/4

MT

MT

Loss of orexin in human narcolepsy

Crocker, et al, 05

Impaired orexin signaling and narcolepsy

Daytime sleepinessFragmented sleepCataplexySleep paralysisHypnagogic hallucinations

Loss of orexin neurons

HumansMice/Rats/Dogs

Lack of orexinLoss of orexin neuronsLack of orexin receptors

Narcolepsy

Cataplexy in orexin knockout mice

Probable mechanisms of narcolepsy

LDT/PPTREM-on cells

motor neurons

LCraphe

noorexin

What causes narcolepsy?

• Most narcoleptics do not have mutations in the genes coding for orexin or its receptors

• Only 1/3 of monozygotic twins will both develop narcolepsy

• 85% of narcoleptics with cataplexy have HLA DQB1* 0602 compared to only about 25% of the general population

What causes narcolepsy?

• Narcoleptics may have gliosis (scarring) in the orexin neuron region

• HLA DQB1* 0602 and other genes may confer a susceptibility for some individuals to develop narcolepsy, possibly through an autoimmune attack on the orexin neurons

Orexin neurons respond to metabolic factors

Yamanaka, et al, 03

Hunger-induced wake requires the orexin neurons

Yamanaka, et al, 03

Narcolepsy and Metabolism

• People with narcolepsy are mildly obese (BMI=28) but eat less than normal

• Thus, metabolic rate may be reduced in narcolepsy

Drugs: tricyclic antidepressants ModafiniltrazedoneAmphetaminesGamma hydroxy butyrate

Orexin/ataxin-3 mice

Orexin/ataxin-3 mice are overweight but eat less than normal

decreased metabolic rate and locomotor activity?less motivation to eat?

Orexin and drug addiction

• Addiction to amphetamines appears to be quite rare in people with narcolepsy

• Orexin neurons activate brain regions implicated in drug-seeking (ventral tegmental area, nucleus accumbens) and makes VTA neurons more excitable

• Mice lacking orexin have almost no conditioned place preference to morphine

• …Maybe orexin provides the impetus to seek rewarding stimuli like food and drugs

VTA

Motivation,drug-seeking

ArcVMH

Feeding

VLM

Increased sympathetic activity

LC

Wakefulness,reduced REM sleep

raphe

orexin

• Waking is due to the coordinated action of neurons producing amines, acetylcholine, and orexin

• Pontine pathways regulate REM sleep, and preoptic nuclei promote non-REM sleep

• Orexin deficiency produces narcolepsy

• Orexin may promote many aspects of arousal

Orexin KO run less but the diurnal pattern is normal

Orexin KO spend less time running

Still, orexin KO mice initiate wheel running as often and run as fast as WT mice

KO fall asleep or have cataplexy soon after running

28% of running bouts are soon followed by cataplexy

Why do orexin KO mice run less?

• Sleepiness• Imminent cataplexy• Less motivated to keep running

(perhaps running is less rewarding)