Pontine and hypothalamic pathways and transmitters involved in the regulation of paradoxical sleep

 

Lucienne Léger, Romuald Boissard, Romain Goutagny, Laure Verret, Damien Lapray, Emilie Sapin, Christelle Peyron and Pierre-Hervé Luppi

Physiopathology of waking and sleep networks, CNRS UMR 5167, IFNL 19, Lyon, France

 

            Since the early transection studies by Jouvet and his collaborators more than forty years ago, it has been known that the brainstem is necessary and sufficient to trigger and maintain paradoxical (PS or REM) sleep. The importance of the mesopontine cholinergic neurons as PS-inducing (or PS-ON) neurons has been emphasized in the reciprocal interaction model of McCarley and Hobson (1975). The onset of PS also requires the cessation of firing of the monoaminergic neurons (PS-OFF neurons) located in the locus coeruleus and raphe nuclei. Recent work, performed in our laboratory in head-restrained rats with a combination of electrophysiology and local pharmacology by microiontophoresis, indicates that neurons synthetizing GABA are also important players. Indeed, PS can be induced with a short latency either by injection of muscimol (a GABA A receptor agonist) in the ventrolateral quadrant of the periaqueductal gray (vlPAG) or of bicuculline (a GABA A antagonist) in the subcoeruleus nucleus (SLD). In addition, the progressive silencing of the monoaminergic neurons, which occurs from waking to slow-wave sleep (SWS) and to PS, would be due to an increased GABAergic tone on these neurons. Thanks to the combination of tract-tracing and immunohistochemical techniques, the neurons potentially responsible for these effects have been localized in several distant areas, namely the lateral preoptic area, lateral hypothalamus, vlPAG and mesencephalic, pontine and dorsomedial medullary reticular formation. Even if local interneurons are not to be overlooked, these results show that the rostral brain certainly plays an important role in the control of PS.

            Although neglected for several decades, the role of the hypothalamus is being more and more substantiated. The first indication that this part of the brain could be important for sleep came from the anatomo-pathological observations by von Economo, almost one century ago. From these observations and later experimental work, the anterior hypothalamus and preoptic area were recognized as a sleep center, whereas the posterior hypothalamus (PH) was determined as a waking center. Indeed, the histaminergic neurons lying in the tuberomammillary nucleus and the more recently identified orexinergic neurons encompassing the perifornical nucleus, are strongly active during waking and are necessary for the animals to respond properly to a novel environment and maintain a consolidated waking state. However, neurons firing specifically during PS have been recorded among the orexinergic neurons and in the lateral and dorsal caudal hypothalamus. Data from our laboratory suggest that part of these neurons might synthetize the neuropeptide melanin-concentrating hormone (MCH). Indeed, during the PS recovery following a specific PS deprivation in the rat, more than half of the MCH neurons express the activation marker Fos. In addition, the intraventricular administration of MCH induces a significant increase of PS during the 8 hours following the injection. A significant increase in SWS is also noted during 6 hours. MCH neurons co-express GABA and send very ramified axons to most parts of the brain, including the neighbouring orexinergic neurons and the distant monoaminergic and brainstem reticular formation neurons. MCH by itself is known to depress synaptic activity, whether excitatory or inhibitory. The fastest actions of MCH neurons would be exerted by GABA. In this case, we propose that MCH neurons facilitate PS by inhibiting the local wake-promoting orexinergic and histaminergic neurons, the brainstem monoaminergic neurons and/or the population of GABAergic neurons afferent to the SLD. The mechanisms of release of the MCH peptide versus that of GABA at the MCH/GABA terminals are not known. Although present in moderate density, receptors for MCH have been visualized in all the nuclei involved in the regulation of the sleep-waking cycle. Further studies are needed to disclose the location and chemical nature of the target PS-ON neurons.

 

The studies mentioned were supported by CNRS (UMR 5167).