Neurophysiology of Sleep

Neurophysiology of Sleep

• A recurring state characterized by:– Reduced awareness of and interaction with the

external environment– Reduced mobility and muscular activity– Partial or complete cessation of voluntary behavior

and awareness of self in the environment (reversible)

Definition of sleep:

• Classification based on three physiologic

measurements i.e., EEG, EOG & EMG

• Non-Rapid Eye Movement Sleep (NREM)

• Rapid Eye Movement Sleep (REM)

Types of sleep:

• Rechtschaffen and Kales (1968)– Developed the first manual giving rules for sleep

staging • “A manual of standardized terminology, techniques, and

scoring system for sleep stages of human subjects”

– Used EEG, EOG and EMG for defining stages of sleep

• From “A manual for the scoring of sleep and associated events” – American Academy of Sleep Medicine [AASM], 2007

In adults:

•Stage W (wakefulness)

•Stage N1 (NREM 1)

•Stage N2 (NREM 2)

•Stage N3 (NREM 3 & 4)

•Stage R (REM)

In children:

•Stage W (wakefulness)

•Stage N1 (NREM 1)

•Stage N2 (NREM 2)

•Stage N3 (NREM 3 & 4)

•Stage N (NREM)

•Stage R (REM)

• Wakefulness- RAS and Posterior Hypothalamus

• NREM Sleep- Anterior Hypothalamus

• REM Sleep- Pons

• Drugs and NT system

Wakefulness

• Moruzzi, Magoun, and colleagues confirmed that waking behavior is indeed maintained by an “ascending reticular activating system”

• One branch innervates the thalamus, activating relay neurons and reticular nuclei essential for thalamocortical transmission

• Two cholinergic structures-• In the brainstem and basal forebrain serve as

the origin of these projections to the principal thalamic nuclei

PPT/LDT nuclei• They fire during wakefulness and REM sleep

• The other branch of the ascending arousal system projects-

• To the lateral hypothalamus, basal forebrain, and the cerebral cortex

NOREPINEPHRINE LOCUS CERULEUS AND LATERAL TEGMENTAL AREA

SEROTONIN RAPHE NUCLEUS

DOPAMINE VENTRAL TEGMENTAL AREA

ACETYLCHOLINE BASAL FOREBRAIN

HISTAMINE POSTERIOR HYPOTHALAMUS

GLUTAMATE RETICULAR FORMATION AND CORTICAL PROJECTION NEURONS

NOREPINEPHRINE LOCUS CERULEUS AND LATERAL TEGMENTAL AREA

SEROTONIN RAPHE NUCLEUS

DOPAMINE VENTRAL TEGMENTAL AREA

ACETYLCHOLINE BASAL FOREBRAIN

HISTAMINE POSTERIOR HYPOTHALAMUS

GLUTAMATE RETICULAR FORMATION AND CORTICAL PROJECTION NEURONS

• This group of aminergic neurons fire maximally during-

Wakefulness, Slow down during NREM sleep and Nearly stop firing in REM sleep

– HYPOCRETIN: NT for Wakefulness

• A peptide also known as orexin, produced by neurons whose cell bodies are located in the lateral hypothalamus

• Their destruction causes narcolepsy and difficulty in sleeping for extended time

• Involved in regulating the sleep on/off cells in the ventro lateral preoptic area (VLPA)

– HYPOCRETIN: NT for Wakefulness

• A peptide also known as orexin, produced by neurons whose cell bodies are located in the lateral hypothalamus

• Their destruction causes narcolepsy and difficulty in sleeping for extended time

• Involved in regulating the sleep on/off cells in the ventro lateral preoptic area (VLPA)

NREM Sleep(neurogenic theory)

The ventrolateral preoptic area (VLPA) in the anterior hypothalamus is mainly responsible for the generation of of NREM sleep.

The transmitters: GABA and Galanin

Copyright © 2004 Allyn and Bacon

Copyright © 2004 Allyn and Bacon

As the day advances

Orexin levels fall

Stimuli to arousal system will decrease

This leads to less inhibition of VLPA

Therefore activity in VLPA increases

This further inhibits the arousal systems

Thereby producing a state of NREM Sleep

Other Hands on the Flip-Flop Switch

• Homeostatic influence

• Circadian influence

• Allostatic influence

Homeostatic Influence

Adenosine is implicated in the production of NREM sleep

Adenosine level increases during periods of wakefulness

During wakefulness

Adenosine levels increase

It inhibits the arousal systems

As a result activity in VLPA increases

(Flip-Flop switch is off)

It further inhibits the arousal systems

And NREM Sleep is generated

Other chemical’s affecting sleep

• Interleukin-1

• Growth Hormone Releasing Hormone

• Prostaglandin D-2

• Nitric Oxide

Circadian influence•SCN does not send direct projection to VLPA

•SCN sends projection to DMH

•DMH sends GABAergic projections to VLPA

•DMH sends Glutaminergic projections to Orexinergic neurons

•Thereby promoting wakefullness

•In mice damage to DMH causes wake-sleep cycle to become ultradian, with 7-8 wake-sleep cycles per day

Allostatic influence

• Food deprivation• Behavioral stress

During NREM sleep,

sleep-spindles are generated by the thalamic circuitry.

slow EEG waves are generated by the thalamocortical circuitry and the cortical activity.

The rhythmic activity of thalamic and cortical cells prevents the sensory informations to the cortex.

Functions of NREM Sleep

• Neocortical maintenance• Energy conservation• Protection against Oxidative stress

REM Sleep

• Three models

1. McCarley-Hobson model of reciprocal inhibition

2. Luppi’s model

3. Lu and coworkers model

McCarley-Hobson model of reciprocal inhibition

• REM on Neurons – PPT/LDT- Cholinergic neurons- Fire during REM sleep.

• REM off neurons- LC/DRN-Aminergic – Fire during wakefulness

• REM wake-on neurons- Fire during wakefulness and REM sleep- responsible for rapid eye movements and muscle twitches

• GABA ergic neurons also play a role in REM Sleep

Mechanism of muscle atoniaMechanism of muscle atonia

Stimulation of REM–on neurons produces atonia.Excessive firing of REM-on neurons during wakefulness causes sudden loss of muscle tone (cataplexy), one of the features of narcolepsy.

Excessive firing of REM-on neurons during sleep may result in collapse of the airway, resulting in sleep apnea.

Insufficient activity of REM-on neurons during REM sleep may result in release of the motor activity during REM sleep, a disorder called REM sleep behavior disorder.

Luppi’s model

• Cholinergic neurons do not play a crucial role in activation of REM executive neurons

Lu and coworkers model

• Cholinergic and aminergic neurons play a modulatory role and are not part of Flip-flop switch

• Two mutually inhibitory circuits cannot explain the REM periodicity

• Does not explain the gradually increasing duration of REM sleep throughout the night and absence of REM sleep during daytime naps

• Brooks and Peever have challenged the GABAergic and Glycinergic mechanism of REM muscle atonia

• REM atonia persists even when Glycine and GABA receptors are blocked

• There may be multiple biochemical pathways controlling muscle tone during REM Sleep

Functions of REM Sleep

• Memory consolidation• Brain development• Regulation of monoaminergic systems

THE MYSTERY

Of Sleep continues

Thank you