Segment 4

Wake & REM: Monoamines

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

Monoaminergic Components of the Ascending Reticular Activating System

Jacobs and Fornal, in Handbook of Behavioral State Control, CRC Press 1999, p. 184

Serotonin, Norepinephrine, and Histamine Neurons Cease Discharging in REM Sleep

WAKE NREM REM

Neuron

EEG

MuscleEyes

Serotonergic, noradrenergic, and histaminergic neurons all have a Wake-On/REM-Off discharge pattern

However, each of these neurochemical cell types has waking discharge patterns that differ from the other cell types

Serotonergic DR Neurons Discharge Regularly During Wakefulness

Lydic et al., Am J Physiol 247:R135-R145, 1984

NE-LC Neurons Discharge Irregularly During Wakefulness

Takahashi et al., 2010 Neuroscience 169: 1115-26

EEGEMG

Unit

500 V500 V1 mV

HA-TMN Neurons Slow Firing Rate from Active to Quiet Wakefulness

Takahashi et al., J Neurosci 26:10292-10298, 2006

AcBve Waking

Quiet Waking

EEGEMG

Unit

EEGEMG

Unit

Serotonergic, noradrenergic, and histaminergic neurons also discharge with dierent phase relaBonships to changes in behavioral state

NE-LC Neurons Resume Discharging Before the Onset of Wakefulness

Takahashi et al., Neuroscience 169:1115-1126, 2010

Takahashi et al., J Neurosci 26:10292-10298, 2006

HA-TMN Neurons Resume Discharging After the Onset of Wakefulness

Parmentier et al., J Neurosci 22:7695-7711, 2002

Histamine Promotes Wakefulness Knockout mice lacking the histidine

decarboxylase gene show an increase in REM sleep, a slowing of EEG frequencies during wakefulness, and a short sleep latency when placed in a new environment

HDC +/+

HDC -/-

Parmentier et al., J Neurosci 22:7695-7711, 2002

Histamine Promotes Wakefulness Knockout mice lacking the histidine

decarboxylase gene show an increase in REM sleep, a slowing of EEG frequencies during wakefulness, and a short sleep latency when placed in a new environment

This finding supports a role for histamine in maintaining wakefulness

In every brain region studied, levels of serotonin, norepinephrine, and histamine are greater during wakefulness than during sleep

State-Specific Changes in Brain Levels of Monoamines

Wakefulness NREM Sleep REM Sleep

Use of optogenetic tools to inhibit LC neurons: decreased the duration of wakefulness episodes increased the number of wake-to-NREM transitions increased cortical slow wave activity during wakefulness

Use of optogenetic tools to stimulate LC neurons: caused immediate transitions to wakefulness from NREM

and REM sleepCarter et al., Nat Neurosci 13: 1526-1533, 2010

NE LC Neurons Maintain the Normal Duration of Wakefulness

Monoamines Promote Wakefulness: Clinical Relevance Selective serotonin (SSRIs) and serotonin-

norepinephrine (SNRIs) enhance the actions of these two wake-promoting neurotransmitters

SSRIs and SNRIs are widely used for the treatment of depression

Insomnia or disturbed sleep are common side effects of SSRIs and SNRIs

Monoamines Promote Wakefulness: Clinical Relevance Patients with major depressive disorder often

have coexisting insomnia that does not improve with antidepressant treatment

Combining the use of an SSRI (fluoxetine) with a sleeping medication (eszopiclone) increases the antidepressant response and improves sleep (Fava et al., Biol Psychiatry 59:1052-1060, 2006)

Monoamines Promote Wakefulness: Clinical Relevance Doxepin improves sleep in adults (Roth et al., Sleep

30:1555-1561, 2007; Krystal et al., Sleep 34:1433-1442, 2011) and elderly (Krystal et al., Sleep 33:1553-1561, 2010) with primary insomnia

Modafinil increases the activity of wakefulness-promoting histaminergic neurons in the TMN (Scammell et al., J Neurosci 15:8620-8628, 2000)