Post on 01-Nov-2015
description
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)