Neurobiology of waking and sleeping

doi:10.1016/B978-0-444-52006-7.00009-5

Handbook of Clinical Neurology

Volume 98, 2011, Pages 131-149

https://doi.org/10.1016/B978-0-444-52006-7.00009-5 Get rights and content

Publisher Summary

This chapter discusses the neurobiology of waking and sleeping. Waking and sleeping are actively generated by neuronal systems distributed through the brainstem and forebrain with different projections, discharge patterns, neurotransmitters, and receptors. Specific ascending systems stimulate cortical activation, characterized by fast, particularly gamma activity that occurs during waking and rapid eye movement (REM) sleep. In addition to glutamatergic neurons of the reticular formation and thalamus, cholinergic pontomesencephalic and basal forebrain neurons are integral components of the ascending activating system. Sleeping is initiated by inhibition of the activating and arousal systems. This inhibition is effected at multiple levels through particular GABAergic neurons which become active during sleep. Neurons in the preoptic area and basal forebrain play a particularly important role in this process. Some become active during slow-wave sleep (SWS), promoting deactivation, and slow-wave activity in the cerebral cortex. Others discharge at progressively increasing rates during SWS and REM sleep, promoting behavioral quiescence, and diminishing muscle tone. Through their projections and inhibitory neurotransmitter, they have the capacity to inhibit the monoaminergic neurons and orexin (Orx)neurons in the brainstem and hypothalamus.

Section snippets

Historical Background

Over the course of the 20th century, concepts evolved as evidence accumulated concerning the existence and delineation of intrinsic neural systems controlling waking and sleeping. Waking was once thought to be maintained by sensory inputs and sleep to result from the cessation of sensory inputs to the brain (Bremer, 1929, Kleitman, 1939). Yet, from variable alterations of waking and sleeping that occurred with cerebral lesions clinically in humans or experimentally in animals, both waking and

Forebrain projecting reticular neurons

The neurons of the reticular formation with ascending projections are concentrated in the oral pontine and mesencephalic reticular formation, although they are present in smaller numbers in the caudal pontine and medullary reticular formation (Jones and Yang, 1985). They project rostrally to the midline and intralaminar thalamic nuclei which form the nonspecific thalamocortical projection system that project in turn in a widespread manner to the cerebral cortex (Figure 9.1). The reticular

The nonspecific thalamocortical projection system

The midline and intralaminar nuclei of the thalamus, unlike the sensory and motor relay nuclei, project to multiple regions of the cerebral cortex in a thus nonspecific manner, often in highest density to frontal regions, though for some nuclei in a truly diffuse manner in high density to all regions (Herkenham, 1986) (Figure 9.1). They discharge at their highest rate in association with cortical activation during waking and REM sleep. Their discharge is generally tonic and relatively fast

Diffusely Projecting Arousal Systems

The reticular formation and cholinergic pontomesencephalic tegmental neurons have the capacity to influence widespread areas of the forebrain and cortex through their projections to the major subcortical relay stations. Some also give rise to branching axons with descending as well as ascending projections of some distance, thus allowing simultaneous influence upon forebrain and spinal cord systems (Jones and Yang, 1985). It is thus likely that some neurons of the reticular formation can

Sleep-Promoting Systems

Although it is clear that thalamic neurons play an important role in shaping the activity of the cortex across waking and sleeping, their influence depends upon their pattern of discharge, which is tonic and fast during waking and becomes bursting and slow during sleep. In contrast, there are neurons in the forebrain and brainstem which are selectively active during sleep and thus appear to play a specific role in promoting sleep.

Summary

Waking and sleeping are actively generated by neuronal systems distributed through the brainstem and forebrain with different projections, discharge patterns, neurotransmitters, and receptors. Specific ascending systems stimulate cortical activation, characterized by fast, particularly gamma, activity which occurs during waking and REM sleep. In addition to glutamatergic neurons of the reticular formation and thalamus, cholinergic pontomesencephalic and basal forebrain neurons are integral

Acknowledgments

Most of the recent research of the author presented in this article was funded by grants from the Canadian Institutes of Health Research and US National Institutes of Health and performed at the Montreal Neurological Institute by Maan Gee Lee, Ian Manns, Oum Hassani, Mandana Modirrousta, Pablo Henny, Frederic Brischoux, and Lynda Mainville, to whom I am most grateful. I am also thankful to my collaborators Michel Muhlethaler and colleagues at the Centre Médicale Universitaire in Geneva, whose

References (163)

M.N. Alam et al.
Preoptic/anterior hypothalamic neurons: thermosensitivity in wakefulness and non rapid eye movement sleep
Brain Res
(1996)
H.A. Baghdoyan et al.
Site-specific enhancement and suppression of desynchronized sleep signs following cholinergic stimulation of three brainstem regions
Brain Res
(1984)
H. Barbeau et al.
The effects of serotonergic drugs on the locomotor pattern and on cutaneous reflexes of the adult chronic spinal cat
Brain Res
(1990)
L. Bayer et al.
Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices
Neuroscience
(2005)
R.M. Chemelli et al.
Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation
Cell
(1999)
M. Denoyer et al.
Neurotoxic lesion of the mesencephalic reticular formation and/or the posterior hypothalamus does not alter waking in the cat
Brain Res
(1991)
L. Descarries et al.
Noradrenergic axon terminals in the cerebral cortex of rat. III. Topometric ultrastructural analysis
Brain Res
(1977)
E.F. Domino et al.
Role of cholinergic mechanisms in states of wakefulness and sleep
Progr Brain Res
(1968)
E. Eggermann et al.
Orexins/hypocretins excite basal forebrain cholinergic neurones
Neuroscience
(2001)
R.A. Espana et al.
Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin
Brain Res
(2002)

R.T. Fremeau et al.

The expression of vesicular glutamate transporters defines two classes of excitatory synapse

Neuron

(2001)

C. Gottesmann

GABA mechanisms and sleep

Neuroscience

(2002)

J. Hara et al.

Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity

Neuron

(2001)

C.J. Holmes et al.

Importance of cholinergic, GABAergic, serotonergic and other neurons in the medullary reticular formation for sleep–wake states studied by cytotoxic lesions in the cat

Neuroscience

(1994)

J.C. Holstege et al.

A glycinergic projection from the ventromedial lower brainstem to spinal motoneurons. An ultrastructural double labeling study in rat

Brain Res

(1991)

B.L. Jacobs et al.

Activity of serotonergic neurons in behaving animals

Neuropsychopharmacology

(1999)

B.L. Jacobs et al.

Single-unit and physiological analyses of brain norepinephrine function in behaving animals

Progr Brain Res

(1991)

J. John et al.

Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior

Neuron

(2004)

B.E. Jones

Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex

Progr Brain Res

(2004)

B.E. Jones

From waking to sleeping: neuronal and chemical substrates

Trends Pharmacol Sci

(2005)

B.E. Jones et al.

Afferents to the basal forebrain cholinergic cell area from pontomesencephalic – catecholamine, serotonin, and acetylcholine – neurons

Neuroscience

(1989)

B.E. Jones et al.

Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study

Brain Res

(1977)

B.E. Jones et al.

The effect of lesions of catecholamine-containing neurons upon monoamine content of the brain and EEG and behavioral waking in the cat

Brain Res

(1973)

B.E. Jones et al.

Effects of locus coeruleus lesions upon cerebral monoamine content, sleep–wakefulness states and the response to amphetamine

Brain Res

(1977)

T. Kaneko et al.

Glutaminase-like immunoreactivity in the lower brainstem and cerebellum of the adult rat

Neuroscience

(1989)

Y. Kayama et al.

Firing of “possibly” cholinergic neurons in the rat laterodorsal tegmental nucleus during sleep and wakefulness

Brain Res

(1992)

A. Khateb et al.

Cholinergic nucleus basalis neurons are excited by histamine in vitro

Neuroscience

(1995)

Y. Koyama et al.

Firing of neurons in the preoptic/anterior hypothalamic areas in rat: its possible involvement in slow wave sleep and paradoxical sleep

Neurosci Res

(1994)

L. Kubin et al.

Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat

Neurosci Lett

(1992)

J.S. Lin et al.

Evidence for histaminergic arousal mechanisms in the hypothalamus of cats

Neuropharmacol

(1988)

J.S. Lin et al.

Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat

Brain Res

(1992)

L. Lin et al.

The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene

Cell

(1999)

D.B. Lindsley et al.

Behavioral and EEG changes following chronic brain stem lesions

Electroencephalogr Clin Neurophysiol

(1950)

M. Lubkin et al.

Independent feeding and metabolic actions of orexins in mice

Biochem Biophys Res Commun

(1998)

D.A. McCormick

Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity

Prog Neurobiol

(1992)

D.A. McCormick

Actions of acetylcholine in the cerebral cortex and thalamus and implications for function

Prog Brain Res

(1993)

D. McGinty et al.

Dorsal raphe neurons: depression of firing during sleep in cats

Brain Res

(1976)

K. Akert et al.

Sleep produced by electrical stimulation of the thalamus

Am J Physiol

(1952)

G. Aston-Jones et al.

Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

J Neurosci

(1981)

L. Bayer et al.

Orexins (hypocretins) directly excite tuberomammillary neurones

Eur J Neurosci

(2001)

L. Bayer et al.

Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons

J Neurosci

(2002)

L. Bayer et al.

Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons

J Neurosci

(2004)

C. Beaulieu et al.

Enrichment of cholinergic synaptic terminals on GABAergic neurons and coexistence of immunoreactive GABA and choline acetyltransferase in the same synaptic terminals in the striate cortex of the cat

J Comp Neurol

(1991)

C. Blanco-Centurion et al.

Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone

Eur J Neurosci

(2004)

C. Blanco-Centurion et al.

Adenosine and sleep homeostasis in the basal forebrain

J Neurosci

(2006)

C. Blanco-Centurion et al.

Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake

J Neurosci

(2007)

R. Boissard et al.

The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study

Eur J Neurosci

(2002)

F. Bremer

Cerveau ‘isolé’ et physiologie du sommeil

C R Soc Biol (Paris)

(1929)

S. Burlet et al.

Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy

J Neurosci

(2002)

E.G. Cape et al.

Differential modulation of high frequency gamma electroencephalogram activity and sleep–wake state by noradrenaline and serotonin microinjections into the region of cholinergic basalis neurons

J Neurosci

(1998)

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Chapter 9 - Neurobiology of waking and sleeping

Publisher Summary

Section snippets

Historical Background

Forebrain projecting reticular neurons

The nonspecific thalamocortical projection system

Diffusely Projecting Arousal Systems

Sleep-Promoting Systems

Summary

Acknowledgments

Brain Res

Brain Res

Brain Res

Neuroscience

Cell

Brain Res

Brain Res

Progr Brain Res

Neuroscience

Brain Res

Neuron

Neuroscience

Neuron

Neuroscience

Brain Res

Neuropsychopharmacology

Progr Brain Res

Neuron

Progr Brain Res

Trends Pharmacol Sci

Neuroscience

Brain Res

Brain Res

Brain Res

Neuroscience

Brain Res

Neuroscience

Neurosci Res

Neurosci Lett

Neuropharmacol

Brain Res

Cell

Electroencephalogr Clin Neurophysiol

Biochem Biophys Res Commun

Prog Neurobiol

Prog Brain Res

Brain Res

Sleep produced by electrical stimulation of the thalamus

Am J Physiol

Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

J Neurosci

Orexins (hypocretins) directly excite tuberomammillary neurones

Eur J Neurosci

Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons

J Neurosci

Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons

J Neurosci

Enrichment of cholinergic synaptic terminals on GABAergic neurons and coexistence of immunoreactive GABA and choline acetyltransferase in the same synaptic terminals in the striate cortex of the cat

J Comp Neurol

Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone

Eur J Neurosci

Adenosine and sleep homeostasis in the basal forebrain

J Neurosci

Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake

J Neurosci

The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study

Eur J Neurosci

Cerveau ‘isolé’ et physiologie du sommeil

C R Soc Biol (Paris)

Direct and indirect excitation of laterodorsal tegmental neurons by hypocretin/orexin peptides: implications for wakefulness and narcolepsy

J Neurosci

Differential modulation of high frequency gamma electroencephalogram activity and sleep–wake state by noradrenaline and serotonin microinjections into the region of cholinergic basalis neurons

J Neurosci