Which structure generates paradoxical (REM) sleep: The brainstem, the hypothalamus, the amygdala or the cortex?

Paradoxical or Rapid eye movement (REM) sleep (PS) is a state characterized by REMs, EEG activation and muscle atonia. In this review, we discuss the contribution of brainstem, hypothalamic, amygdalar and cortical structures in PS genesis. We propose that muscle atonia during PS is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD) projecting to glycinergic/GABAergic pre-motoneurons localized in the ventro-medial medulla (vmM). The SLD PS-on neurons are inactivated during wakefulness and slow-wave sleep by PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray (vPAG) and the adjacent deep mesencephalic reticular nucleus. Melanin concentrating hormone (MCH) and GABAergic PS-on neurons localized in the posterior hypothalamus would inhibit these PS-off neurons to initiate the state. Finally, the activation of a few limbic cortical structures during PS by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would also contribute to PS expression. Accumulating evidence indicates that the activation of these limbic structures plays a role in memory consolidation and would communicate to the PS-generating structures the need for PS to process memory. In summary, PS generation is controlled by structures distributed from the cortex to the medullary level of the brain.

Melanin-concentrating hormone-expressing neurons adjust slow-wave sleep dynamics to catalyze paradoxical (REM) sleep.

Study Objectives: Experimental studies over the last 15 years established a role in sleep of the tuberal hypothalamic neurons that express melanin-concentrating hormone (MCH). Controversies still remain regarding their actual contribution to both slow-wave sleep (SWS) and paradoxical sleep (PS also known as REM sleep) or PS alone. Methods: To address this point, we compared effects of chemogenetic activation and inhibition of MCH neurons on SWS and PS amounts and EEG rhythmic activities in transgenic Pmch-cre mice. Results: In agreement with recently reported optogenetic data, the activation of MCH neurons invariably facilitates PS onset and maintenance. Our chemogenetic experiments further disclose that the ultradian rhythm of SWS is also notably related to the activity of MCH neurons. We observed that the mean duration of SWS episodes is significantly extended when MCH neurons are inhibited. Conversely, when they were excited, SWS bouts were drastically shortened and depicted substantial changes in δ rhythmic activities in electroencephalographic recording likely reflecting a deeper SWS. Conclusions: According to these original findings, we propose that when MCH neurons are physiologically recruited, SWS depth is increased and the extinction of SWS episodes is accelerated, two joint physiological processes strengthening the probability for natural SWS to PS transition and likely facilitating PS onset.

Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder.

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus.

New aspects in the pathophysiology of rapid eye movement sleep behavior disorder: the potential role of glutamate, gamma-aminobutyric acid, and glycine.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the occurrence of intense movements during rapid eye movement (REM) sleep, also named paradoxical sleep. The neuronal dysfunctions at the origin of the loss of atonia in RBD patients are not known. One possibility is that RBD is due to the degeneration of neurons inducing the muscle atonia of REM sleep. Therefore, in our paper we review data on the populations of neurons responsible for the atonia of REM sleep before discussing their potential role in RBD. We first review evidence that motoneurons are tonically hyperpolarized by gamma-aminobutyric acid (GABA) and glycine and phasically excited by glutamate during REM sleep. Then, we review data indicating that the atonia of REM sleep is induced by glycinergic/GABAergic REM-on premotoneurons contained within the raphe magnus and the ventral and alpha gigantocellular reticular nuclei localized in the ventral medullary reticular formation. These neurons are excited during REM sleep by a direct projection from glutamatergic REM-on neurons localized in the pontine sublaterodorsal tegmental nucleus (SLD). From these results, we discuss the possibility that RBD is due to a specific degeneration of descending REM-on glutamatergic neurons localized in the caudal SLD or that of the REM-on GABA/glycinergic premotoneurons localized in the ventral medullary reticular formation. We then propose that movements of RBD are induced by descending projections of cortical motor neurons before discussing possible modes of action of clonazepam and melatonin.

Paradoxical (REM) sleep genesis by the brainstem is under hypothalamic control.

The purpose of this review is to outline our latest hypothesis on the mechanisms responsible for the genesis of paradoxical (REM) sleep (PS). On the basis of recent data, we propose that the onset and maintenance of PS are due to the activation by intrinsic and extrinsic factors of MCH/GABAergic neurons located in the lateral hypothalamic area. These neurons would inhibit during PS, GABAergic PS-off neurons located in the ventrolateral periaqueductal gray region. A number of results strongly suggest that these PS-off neurons gate the activation of the PS-on glutamatergic neurons located in the sublaterodorsal tegmental nucleus (SLD) and responsible for cortical activation and muscle atonia via descending projections to GABA/glycinergic neurons localized in the ventral medullary reticular nuclei.

Tuberal hypothalamic neurons secreting the satiety molecule Nesfatin-1 are critically involved in paradoxical (REM) sleep homeostasis.

The recently discovered Nesfatin-1 plays a role in appetite regulation as a satiety factor through hypothalamic leptin-independent mechanisms. Nesfatin-1 is co-expressed with Melanin-Concentrating Hormone (MCH) in neurons from the tuberal hypothalamic area (THA) which are recruited during sleep states, especially paradoxical sleep (PS). To help decipher the contribution of this contingent of THA neurons to sleep regulatory mechanisms, we thus investigated in rats whether the co-factor Nesfatin-1 is also endowed with sleep-modulating properties. Here, we found that the disruption of the brain Nesfatin-1 signaling achieved by icv administration of Nesfatin-1 antiserum or antisense against the nucleobindin2 (NUCB2) prohormone suppressed PS with little, if any alteration of slow wave sleep (SWS). Further, the infusion of Nesfatin-1 antiserum after a selective PS deprivation, designed for elevating PS needs, severely prevented the ensuing expected PS recovery. Strengthening these pharmacological data, we finally demonstrated by using c-Fos as an index of neuronal activation that the recruitment of Nesfatin-1-immunoreactive neurons within THA is positively correlated to PS but not to SWS amounts experienced by rats prior to sacrifice. In conclusion, this work supports a functional contribution of the Nesfatin-1 signaling, operated by THA neurons, to PS regulatory mechanisms. We propose that these neurons, likely releasing MCH as a synergistic factor, constitute an appropriate lever by which the hypothalamus may integrate endogenous signals to adapt the ultradian rhythm and maintenance of PS in a manner dictated by homeostatic needs. This could be done through the inhibition of downstream targets comprised primarily of the local hypothalamic wake-active orexin- and histamine-containing neurons.

The neuronal network responsible for paradoxical sleep and its dysfunctions causing narcolepsy and rapid eye movement (REM) behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a sub-population of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic pre-motoneurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A phasic glutamatergic excitatory pathway from the central amygdala to the SLD PS-on neurons activated during emotion would induce such activation. In normal conditions, the glutamate excitation would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus, gating the activation of the PS-on SLD neurons.

Dopaminergic neurons expressing Fos during waking and paradoxical sleep in the rat.

Formerly believed to contribute to behavioural waking (W) alone, dopaminergic (DA) neurons are now also known to participate in the regulation of paradoxical sleep (PS or REM) in mammals. Indeed, stimulation of postsynaptic DA1 receptors with agonists induces a reduction in the daily amount of PS. DA neurons in the ventral tegmental area were recently shown to fire in bursts during PS, but nothing is known about the activity of the other DA cell groups in relation to waking or PS. To fulfil this gap, we used a protocol in which rats were maintained in continuous W for 3h in a novel environment, or specifically deprived of PS for 3 days with some of them allowed to recover from this deprivation. A double immunohistochemical labeling with Fos and tyrosine hydroxylase was then performed. DA neurons in the substantia nigra (A9) and ventral tegmental area (A10), and its dorsocaudal extension in the periaqueductal gray (A10dc), almost never showed a Fos-immunoreactive nucleus, regardless of the experimental condition. The caudal hypothalamic (A11) group showed a moderate activation after PS deprivation and novel environment. During PS-recovery, the zona incerta (A13) group contained a significant number and percentage of double-labeled neurons. These results suggest that some DA neurons (A11) could participate in waking and/or the inhibition of PS during PS deprivation whereas others (A13) would be involved in the control of PS.

Role of the melanin-concentrating hormone neuropeptide in sleep regulation.

Melanin-concentrating hormone (MCH), a neuropeptide secreted by a limited number of neurons within the tuberal hypothalamus, has been drawn in the field of sleep only fairly recently in 2003. Since then, growing experimental evidence indicates that MCH may play a crucial role in the homeostatic regulation of paradoxical sleep (PS). MCH-expressing neurons fire specifically during PS. When injected icv MCH induces a 200% increase in PS quantities in rats and the lack of MCH induces a decrease in sleep quantities in transgenic mice. Here, we review recent studies suggesting a role for MCH in the regulation of the sleep-wake cycle, in particular PS, including insights on (1) the specific activity of MCH neurons during PS; (2) how they might be controlled across the sleep-wake cycle; (3) how they might modulate PS; (4) and finally whether MCH might take part in the expression of some symptoms observed in primary sleep disorders.

GABAergic control of hypothalamic melanin-concentrating hormone-containing neurons across the sleep-waking cycle.

The perifornical-lateral hypothalamic area is implicated in regulating waking and paradoxical sleep. The blockade of GABAA receptors by iontophoretic applications of bicuculline (or gabazine) into the perifornical-lateral hypothalamic area induced a continuous quiet waking state associated to a robust muscle tone in head-restrained rats. During the effects, sleep was totally suppressed. In rats killed at the end of a 90 min ejection of bicuculline, Fos expression was induced in approximately 28% of the neurons immunoreactive for hypocretin and in approximately 3% of the neurons immunostained for melanin-concentrating hormone within the ejection site. These results suggest that neurons containing melanin-concentrating hormone are not active during waking and that the lack of a potent GABAergic influence during waking is consistent with their role in sleep regulation.

A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep.

BACKGROUND: Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation. RESULTS: Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats). Further, we show that ICV administration of MCH induces a dose-dependent increase in PS (up to 200%) and slow wave sleep (up to 70%) quantities. CONCLUSION: These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system.