From waking to sleeping: neuronal and chemical substrates

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Multiple arousal systems maintain waking through the actions of chemical neurotransmitters that are released from broadly distributed nerve terminals when the neurons fire. Among these, noradrenaline-, histamine- and orexin-containing neurons fire during waking with behavioral arousal, decrease firing during slow-wave sleep (SWS) and cease firing during paradoxical sleep (PS), which is also known as rapid-eye-movement sleep. By contrast, acetylcholine (ACh)-containing neurons discharge during waking, decrease firing during SWS and fire at high rates during PS in association with fast cortical activity. Neurons that do not contain ACh, including GABA-containing neurons in the basal forebrain and preoptic area, are active in a reciprocal manner to the neurons of the arousal systems: one group discharges with slow cortical activity during SWS, and another discharges with behavioral quiescence and loss of postural muscle tone during SWS and PS. The reciprocal activities and interactions of these wake-active and sleep-active cell groups determine the alternation between waking and sleeping. Selective enhancement and attenuation of their discharge, transmitter release and postsynaptic actions comprise the substrates for the major stimulant and hypnotic drugs.

Section snippets

The neuronal basis of the sleep–wake cycle

From early pharmacological and lesion studies, and more-recent gene-knockout studies, we know that wakefulness is maintained by multiple neuronal systems that use different chemical neurotransmitters (reviewed in [1]) (Figure 1). These multiple systems are partially redundant because no one system appears to be absolutely necessary for wakefulness, although each contributes in a unique way to its generation and maintenance [1]. They include glutamate-, noradrenaline (NA)-, dopamine (DA)-,

Ascending reticular activating system

As established by the early work of Moruzzi and Magoun in the 1940s and 1950s, the brainstem reticular formation (RF) is crucial for maintaining cortical activation and behavioral arousal of waking (reviewed in [1]). Projections from neurons concentrated in the oral pontine and mesencephalic RF ascend into the forebrain where they stimulate cortical activation via a dorsal relay in the thalamus and a ventral relay through the hypothalamus and basal forebrain (Figure 1). Neurons concentrated in

GABA-containing neurons in the basal forebrain and preoptic area

Since early studies in the 20th century it has been known that neurons in the basal forebrain and preoptic area have an important role in promoting sleep because lesions in these areas result in insomnia (reviewed in 1, 45). Neurons were also recorded in these areas that discharge at higher rates during sleep than during waking 46, 47, 48, 49. In the basal forebrain, a sleep-promoting role is, presumably, fulfilled by neurons that co-distribute with ACh-containing neurons that promote cortical

Concluding remarks

Waking is maintained by multiple, parallel, partially redundant arousal systems that use discrete neurotransmitters. Several of these, including NA-containing neurons in the LC, histamine-containing neurons in the TM and Orx-containing neurons in the hypothalamus, discharge during behavioral arousal and waking, and cease discharge during SWS and PS. By diffuse projections and excitatory actions, these neurons simultaneously stimulate cortical activation, behavioral arousal and postural-muscle

Acknowledgements

Most of the recent research presented was funded by grants from the Canadian Institutes of Health Research (CIHR) and U.S. National Institutes of Health (NIH) and performed at the Montreal Neurological Institute (MNI) by Maan Gee Lee, Ian Manns, Oum Hassani, Mandana Modirrousta, Pablo Henny and Lynda Mainville to whom I am most grateful. I am also thankful to my collaborators, Angel Alonso at the MNI and Michel Muhlethaler and colleagues at the Centre Medicale Universitaire (CMU) in Geneva,

References (71)

  • L. Lin

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

    Cell

    (1999)
  • L. Bayer

    Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices

    Neuroscience

    (2005)
  • B.Y. Mileykovskiy

    Behavioral correlates of activity in identified hypocretin/orexin neurons

    Neuron

    (2005)
  • B.E. Jones

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

    Prog. Brain Res.

    (2004)
  • M. Modirrousta

    GABAergic neurons with alpha2-adrenergic receptors in basal forebrain and preoptic area express c-Fos during sleep

    Neuroscience

    (2004)
  • R. Szymusiak et al.

    Sleep-waking discharge of basal forebrain projection neurons in cats

    Brain Res. Bull.

    (1989)
  • R. Szymusiak

    Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats

    Brain Res.

    (1998)
  • 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)
  • T. Sakurai

    Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice

    Neuron

    (2005)
  • B.E. Jones et al.

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

    Neuroscience

    (1989)
  • C. Gottesmann

    GABA mechanisms and sleep

    Neuroscience

    (2002)
  • W.B. Mendelson

    Hypnotic medications: mechanisms of action and pharmacologic effects

  • J.M. Fritschy et al.

    Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications

    Pharmacol. Ther.

    (2003)
  • P. Krogsgaard-Larsen

    GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic

    Biochem. Pharmacol.

    (2004)
  • S.A. Shefner et al.

    GABAA and GABAB receptors and the ionic mechanisms mediating their effects on locus coeruleus neurons

    Prog. Brain Res.

    (1991)
  • Jones, B.E. (1995) Reticular formation. Cytoarchitecture, transmitters and projections. In The Rat Nervous System...
  • F. Fujiyama

    Immunocytochemical localization of candidates for vesicular glutamate transporters in the rat cerebral cortex

    J. Comp. Neurol.

    (2001)
  • Henny, P. and Jones, B.E. (2004) Differential innervation of prefrontal cortex by cholinergic, GABAergic, and...
  • U. Rudolph et al.

    Molecular and neuronal substrates for general anaesthetics

    Nat. Rev. Neurosci.

    (2004)
  • R.W. McCarley et al.

    Neuronal excitability modulation over the sleep cycle: a structural and mathematical model

    Science

    (1975)
  • 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.E. Nelson

    The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects

    Anesthesiology

    (2003)
  • T. Gallopin

    Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study

    Sleep

    (2004)
  • J. Mirenowicz et al.

    Preferential activation of midbrain dopamine neurons by appetitive rather than aversive stimuli

    Nature

    (1996)
  • K. Maloney

    c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery

    Eur. J. Neurosci.

    (2002)
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