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ABSTRACT: 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.
PLoS ONE 01/2012; 7(12):e52525. · 4.09 Impact Factor
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ABSTRACT: 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.
Journal of chemical neuroanatomy 03/2010; 39(4):262-71. · 1.75 Impact Factor
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ABSTRACT: Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.
PLoS ONE 02/2009; 4(1):e4272. · 4.09 Impact Factor
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ABSTRACT: Noradrenaline is known to induce waking (W) and to inhibit paradoxical sleep (PS or REM). Both roles have been exclusively attributed to the noradrenergic neurons of the locus coeruleus (LC, A6), shown to be active during W and inactive during PS. However, the A1, A2, A5 and A7 noradrenergic neurons could also be responsible. Therefore, to determine the contribution of each of the noradrenergic groups in W and in PS inhibition, 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. Thirty percent of the LC noradrenergic cells were found to be Fos-positive after exposure to the novel environment and less than 2% after PS deprivation. In contrast, a significant number of double-labeled neurons (up to 40% of the noradrenergic neurons) were observed in the A1/C1, A2 and A5 groups, after both novel environment and PS deprivation. After PS recovery and in control condition, less than 1% of the noradrenergic neurons were Fos-immunoreactive, regardless of the noradrenergic group. These results indicate that the brainstem noradrenergic cell groups are activated during W and silent during PS. They further suggest that the inhibitory effect of noradrenaline on PS may be due to the A1/C1, A2 and to a lesser degree to A5 neurons but not from those of the LC as previously hypothesized.
Journal of chemical neuroanatomy 01/2009; 37(3):149-57. · 1.75 Impact Factor
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ABSTRACT: Growing amounts of data indicate involvement of the posterior hypothalamus in the regulation of sleep, especially paradoxical sleep (PS). Accordingly, we previously showed that the melanin-concentrating hormone (MCH)-producing neurons of the rat hypothalamus are selectively activated during a PS rebound. In addition, intracerebroventricular infusion of MCH increases total sleep duration, suggesting a new role for MCH in sleep regulation. To determine whether activation of the MCH system promotes sleep, we studied spontaneous sleep and its homeostatic regulation in mice with deletion of the MCH-receptor 1 gene (MCH-R1-/- vs. MCH-R1+/+) and their behavioural response to modafinil, a powerful antinarcoleptic drug. Here, we show that the lack of functional MCH-R1 results in a hypersomniac-like phenotype, both in basal conditions and after total sleep deprivation, compared to wild-type mice. Further, we found that modafinil was less potent at inducing wakefulness in MCH-R1-/- than in MCH-R1+/+ mice. We report for the first time that animals with genetically inactivated MCH signaling exhibit altered vigilance state architecture and sleep homeostasis. This study also suggests that the MCH system may modulate central pathways involved in the wake-promoting effect of modafinil.
European Journal of Neuroscience 05/2008; 27(7):1793-800. · 3.63 Impact Factor
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ABSTRACT: 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.
Neuroreport 08/2005; 16(10):1069-73. · 1.66 Impact Factor
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ABSTRACT: Acetylcholine is crucial for the regulation of paradoxical sleep (PS) and EEG theta activity. To determine the contribution of individual muscarinic receptors to these events, we analyzed the sleep-waking cycle and EEG activities of mice lacking functional M(3) or M(2)/M(4 )receptors. Daily PS amounts were significantly decreased in M3-/- (-22%) but not in M2/M4-/- mice. Further, the theta peak frequency for PS was significantly increased in both M2/M4-/- and M3-/- mice. This study supports the potential role of M(3) rather than M(2) and M(4) muscarinic receptors in the modulation of PS in mice and strengthens the idea that multiple muscarinic receptors contribute to the regulation of the EEG theta activity during PS.
Neuropsychobiology 02/2005; 52(3):140-6. · 2.67 Impact Factor
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ABSTRACT: 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.
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.
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.
BMC Neuroscience 10/2003; 4:19. · 3.04 Impact Factor
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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 alpha (peri-LCalpha 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.
Journal of Physiology-Paris 100(5-6):271-83. · 1.31 Impact Factor
