Elsevier

Journal of Physiology-Paris

Volume 100, Issues 5–6, November–December 2006, Pages 271-283
Journal of Physiology-Paris

Paradoxical (REM) sleep genesis: The switch from an aminergic–cholinergic to a GABAergic–glutamatergic hypothesis

https://doi.org/10.1016/j.jphysparis.2007.05.006Get rights and content

Abstract

In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in “pontine cats” in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus α (peri-LCα in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset. It was then proposed that the onset and maintenance of PS is due to a reciprocal inhibitory interaction between neurons presumably cholinergic specifically active during PS localized in this region and monoaminergic neurons. In the last decade, we have tested this hypothesis with our model of head-restrained rats and functional neuroanatomical studies. Our results confirmed that the SLD in rats contains the neurons responsible for the onset and maintenance of PS. They further indicate that (1) these neurons are non-cholinergic possibly glutamatergic neurons, (2) they directly project to the glycinergic premotoneurons localized in the medullary ventral gigantocellular reticular nucleus (GiV), (3) the main neurotransmitter responsible for their inhibition during waking (W) and slow wave sleep (SWS) is GABA rather than monoamines, (4) they are constantly and tonically excited by glutamate and (5) the GABAergic neurons responsible for their tonic inhibition during W and SWS are localized in the deep mesencephalic reticular nucleus (DPMe). We also showed that the tonic inhibition of locus coeruleus (LC) noradrenergic and dorsal raphe (DRN) serotonergic neurons during sleep is due to a tonic GABAergic inhibition by neurons localized in the dorsal paragigantocellular reticular nucleus (DPGi) and the ventrolateral periaqueductal gray (vlPAG). We propose that these GABAergic neurons also inhibit the GABAergic neurons of the DPMe at the onset and during PS and are therefore responsible for the onset and maintenance of PS.

Section snippets

The identification of the brainstem executive structures

Back in 1959, Michel Jouvet and François Michel discovered in cats a phase of sleep characterized by a complete disappearance of the muscle tone, and paradoxically associated with a cortical activation and rapid eye movements (REM) (Jouvet and Michel, 1959). In view of its singularity, they proposed to call this state paradoxical sleep (PS). It corresponded to REM sleep, the state described in 1953 by Aserinsky and Kleitman and that correlates with dream activity in humans (Aserinsky and

The reciprocal aminergic–cholinergic interaction model

Hobson et al. (1975) were the first to propose that the onset of PS was due to a reciprocal inhibitory interaction between cholinergic PS-on neurons and monoaminergic PS-off neurons. They were soon followed by Sakai et al. (1981) who proposed a slightly revised model. This well-accepted hypothesis was formulated following the findings that serotonergic neurons from the dorsal raphe nucleus (DRN) and noradrenergic neurons from the locus coeruleus (LC) cease firing specifically during PS, i.e.

Evidence that the neurons responsible for PS genesis are glutamatergic instead of cholinergic

We first demonstrated in cats that the great majority of the neurons in the peri-LCα projecting to the GiV are not cholinergic (Luppi et al., 1988). We more recently showed that carbachol iontophoresis into the SLD, the rat equivalent of the peri-LCα, induces a W state with increased muscle activity and has no effect on SLD PS-on neurons (Boissard et al., 2002). These results indicate important differences between rats and cats in the pharmacological sensitivity of the SLD PS-on neurons. In

Demonstration that GABAergic neurons localized in the deep mesencephalic reticular nucleus (DPMe) gate the onset of PS

We reported that a long-lasting PS-like hypersomnia can be induced with a short latency in the head-restrained rat by microiontophoretic applications of bicuculline or gabazine, both GABAA antagonists, specifically within the SLD (Boissard et al., 2002). We also recorded in the SLD neurons that are specifically active during PS and excited by bicuculline or gabazine iontophoresis (Boissard et al., 2000). Studies in freely moving rats have reproduced our results (Pollock and Mistlberger, 2003,

Evidence that SLD neurons responsible for PS onset and maintenance are tonically excited by glutamate

We recently showed that the iontophoretic injection of kainic acid (a glutamate agonist) in the SLD excites the PS-on neurons and induces a PS-like state (Boissard et al., 2002). Further, the PS-like state induced by bicuculline iontophoresis in the SLD was reversed by the application of kynurenate, a wide spectrum antagonist of excitatory amino acids (Boissard et al., 2002). In agreement with these results, the microdialysis injection of kainic acid in the cat peri-LCα induces a PS-like state (

GABAergic neurons responsible for the inactivation of monoaminergic neurons during PS

According to the classical “reciprocal interaction” model (McCarley and Hobson, 1975, Sakai et al., 1981), the cessation of firing of the noradrenergic and serotonergic neurons at the onset of PS is the result of active PS-specific inhibitory processes originating from PS-on cells. These neurons were first hypothesized to be cholinergic and localized in the peri-LCα, LDT and PPT. However, acetylcholine excites LC noradrenergic neurons and is only weakly inhibitory on serotonergic DRN neurons (

Beyond the glutamatergic–GABAergic neuronal network

As described above, great progresses were made in the recent years to identify the neuronal network responsible for PS onset and maintenance. There are however a number of questions remaining for the future: (1) by which mechanisms and pathways the brain switches from SWS to PS and (2) what are the mechanisms responsible for the homeostasis of PS, i.e. the occurrence of a recovery of PS quantities after deprivation?

We indeed need to determine the mechanisms responsible for the “switch on” of

Conclusion: a new network model for the onset and maintenance of PS (Fig. 1)

Based on our and others results, we propose the following model (Fig. 1). The activation of PS-on glutamatergic neurons from the SLD underlies the onset and maintenance of PS. Ascending SLD PS-on glutamatergic neurons induce cortical activation via their projections to intralaminar thalamic relay neurons in conjunction with W/PS-on cholinergic and glutamatergic neurons of the LDT and PPT, mesencephalic and pontine reticular nuclei and the basal forebrain. Descending PS-on glutamatergic SLD

Acknowledgments

This work was supported by CNRS (UMR 5167 and FRE 2469) and Université Claude Bernard Lyon 1.

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      Genetic inactivation or damage to SLD prevents motor suppression of REM sleep, while electrical or pharmacological stimulation of the SLD region can induce REM sleep-like motor suppression (Valencia et al., 2017; Provini et al., 2004). The SLD is a region of the dorsal pons that plays a central role in the induction of motor suppression during REM sleep (Boissard et al., 2002, 2003; Clément et al., 2011; Luppi et al., 2006). SLD plays a role in synchronizing motor activity and brain state, suppressing motor neuron activity during natural REM sleep, but also uncoupling brain state and motor tone during wakefulness (Krenzer et al., 2011).

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