Neurophysiology of Sleep

Definition 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)

Types of sleep:
Classification based on three physiologic measurements i.e., EEG, EOG & EMG Non-Rapid Eye Movement Sleep (NREM) Rapid Eye Movement Sleep (REM)

 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
DOPAMINE

RAPHE NUCLEUS
VENTRAL TEGMENTAL AREA

ACETYLCHOLINE
HISTAMINE

BASAL FOREBRAIN
POSTERIOR HYPOTHALAMUS

GLUTAMATE

RETICULAR FORMATION AND CORTICAL PROJECTION NEURONS

 This group of aminergic neurons fire maximally duringWakefulness, 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)

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 chemicals 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. Luppis model 3. Lu and coworkers model

McCarley-Hobson model of reciprocal inhibition

REM on Neurons PPT/LDT- Cholinergic neuronsFire 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 atonia

Stimulation of REMon 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.

Luppis 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

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