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Neurobiology of Sleep and

Wakefulness

Helen A. Baghdoyan, Ph.D.


Professor of Psychology & Anesthesiology, University of Tennessee
Professor Emerita, Anesthesiology, Pharmacology, & Psychiatry,
University of Michigan

Segment 1
Learning Points

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

Learning Point
States of sleep and wakefulness are
generated by complex interactions
between many neurotransmitters
and neuromodulators acting at
multiple sites within the brain

Multiple Transmitters Regulate Sleep

norepinephrine (NE) - locus coeruleus (LC)


serotonin (5-HT) - dorsal raph (DR)
acetylcholine (ACh) laterodorsal and pedunculopontine
tegmental nuclei (LDT/PPT); basal forebrain (BF)
dopamine (DA) - ventral tegmental area (VTA); substantia nigra
(SN)
-aminobutyric acid (GABA) - ventrolateral preoptic area (VLPO);
median preoptic nucleus (MnPN); anterior hypothalamus (AH)
glutamate (Glu) pontine reticular formation (PRF); BF
histamine (HA) - tuberomammillary nucleus (TMN) of the
posterior hypothalamus (PH)
adenosine (Ado) - basal forebrain (BF)
hypocretin/orexin - lateral hypothalamus (LH)

PFC (Glu)
BF (ACh, GABA)

LH (Hcrt/Ox)
Thalamus
(ACh,Glu)

LDT/PPT (ACh)
DR (5-HT)
VLPO (GABA)
LC (NE)
TMN (HA)
PRF
VTA/SN (DA) (Glu, GABA)

Thalamus LDT/PPT
PFC (Glu) (ACh,Glu) (ACh) DR (5-HT)
LC (NE)
BF (ACh,
GABA)

VLPO
(GABA)
LH (Hcrt/Ox)
PRF
TMN (HA) VTA/SN (DA) (Glu, GABA)

Learning Point
Sleep neurobiology phenotypes
neurons based on chemical
identity, discharge patterns,
projection pathways, transmitter
release, and receptors expressed

Learning Point
Neurochemical identity, discharge
patterns, and transmitter release
patterns are some of the lower level
phenotypes generating the higher
level phenotypes of sleep and
wakefulness

State-Specific Discharge Patterns


REM-On

Spikes/sec

Spikes/sec

Wake-On/REM-O

WAKE NREM REM

WAKE NREM REM

Wake-On/REM-On
Spikes/sec

Spikes/sec

NREM-On

WAKE NREM REM

WAKE NREM REM

State-Specific Discharge Patterns


REM-On

Spikes/sec

Spikes/sec

Wake-On/REM-O

WAKE NREM REM

WAKE NREM REM

Wake-On/REM-On
Spikes/sec

Spikes/sec

NREM-On

WAKE NREM REM

WAKE NREM REM

State-Specific Discharge Patterns


REM-On

Spikes/sec

Spikes/sec

Wake-On/REM-O

WAKE NREM REM

WAKE NREM REM

Wake-On/REM-On
Spikes/sec

Spikes/sec

NREM-On

WAKE NREM REM

WAKE NREM REM

State-Specific Discharge Patterns


REM-On

Spikes/sec

Spikes/sec

Wake-On/REM-O

WAKE NREM REM

WAKE NREM REM

Wake-On/REM-On
Spikes/sec

Spikes/sec

NREM-On

WAKE NREM REM

WAKE NREM REM

State-Specific Transmitter Release

Baghdoyan & Lydic, in Basic Neurochemistry ed: Brady et al., Elsevier, 2012, p. 985

Some Neurotransmitters Regulating


Sleep and Wakefulness
Wakefulness

NREM Sleep

REM Sleep

Acetylcholine

GABA

Acetylcholine

Serotonin
Norepinephrine
Histamine

Adenosine

Dopamine
HypocreFn/Orexin
Glutamate

Glutamate (?)

Clinical Relevance
New medications developed to enhance
sleep or wakefulness will be most
effective if they act on multiple
transmitter systems
Medications used to treat other medical
conditions negatively impact sleep

Learning Points
Interactions between transmitters determine
behavioral state at any moment in time
The same transmitter may have opposite
effects on sleep and wakefulness depending
on site of action within the brain
For example

Brain-Region-Specific Effects of GABA


GABA in the posterior hypothalamus
promotes sleep (Lin et al., Brain Res 479:225-240,
1989)

GABA in the pontine reticular


formation promotes wakefulness (Xi et al.,
J Neurophysiol 82:2015-2019, 1999)