The Experts below are selected from a list of 738 Experts worldwide ranked by ideXlab platform
Clifford B. Saper - One of the best experts on this subject based on the ideXlab platform.
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galanin neurons in the Ventrolateral Preoptic area promote sleep and heat loss in mice
Nature Communications, 2018Co-Authors: Daniel Kroeger, Thomas E. Scammell, Elda Arrigoni, Lorisl . Ferrari, Gianna Absi, Celia Gagliardi, Sathyajit S Bandaru, Joseph C Madara, Heike Munzberg, Clifford B. SaperAbstract:The Preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neurons in the Ventrolateral Preoptic Nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POAGAL neurons was shown to paradoxically cause waking, not sleep. Here we report that photostimulation of VLPOGAL neurons in mice promotes sleep with low frequency stimulation (1–4 Hz), but causes conduction block and waking at frequencies above 8 Hz. Further, optogenetic inhibition reduces sleep. Chemogenetic activation of VLPOGAL neurons confirms the increase in sleep, and also reduces body temperature. In addition, chemogenetic activation of VLPOGAL neurons induces short-latency sleep in an animal model of insomnia. Collectively, these findings establish a causal role of VLPOGAL neurons in both sleep induction and heat loss. Anatomical lesions of the Preoptic area (POA) can cause sleep loss while electrical, chemical, or thermal stimulation of POA can induce sleep. To better understand the exact neural function of the POA, this study shows that galanin and GABA+ inhibitory neurons in the Ventrolateral POA that project to the wake-promoting tuberomammillary Nucleus promote sleep in a stimulation frequency dependent manner.
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sleep is related to neuron numbers in the Ventrolateral Preoptic intermediate Nucleus in older adults with and without alzheimer s disease
Brain, 2014Co-Authors: Andrew S P Lim, Brian A Ellison, Joshua L Wang, Julie A Schneider, Aron S Buchman, David A Bennett, Clifford B. SaperAbstract:Fragmented sleep is a common and troubling symptom in ageing and Alzheimer’s disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic Ventrolateral Preoptic Nucleus cause fragmented sleep. We previously proposed that the intermediate Nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the Ventrolateral Preoptic Nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate Nucleus is important for human sleep, then intermediate Nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer’s disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer’s disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate Nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer’s disease had fewer galaninergic intermediate Nucleus neurons than those without (estimate −2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate Nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate −0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer’s disease, and similar associations were not seen for two other cell populations near the intermediate Nucleus. These data are consistent with the intermediate Nucleus being the human homologue of the Ventrolateral Preoptic Nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate Nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer’s disease.
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Sleep is related to neuron numbers in the Ventrolateral Preoptic/intermediate Nucleus in older adults with and without Alzheimer's disease.
Brain, 2014Co-Authors: Andrew S P Lim, Brian A Ellison, Joshua L Wang, Julie A Schneider, Aron S Buchman, David A Bennett, Clifford B. SaperAbstract:Fragmented sleep is a common and troubling symptom in ageing and Alzheimer’s disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic Ventrolateral Preoptic Nucleus cause fragmented sleep. We previously proposed that the intermediate Nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the Ventrolateral Preoptic Nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate Nucleus is important for human sleep, then intermediate Nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer’s disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer’s disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate Nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer’s disease had fewer galaninergic intermediate Nucleus neurons than those without (estimate −2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate Nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was
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The neurobiology of sleep.
Continuum (Minneapolis Minn.), 2013Co-Authors: Clifford B. SaperAbstract:The basic circuitries that regulate wake-sleep cycles are described, along with how these are affected by different disease states and how those alterations lead to the clinical manifestations of those disorders. The discovery of both sleep-promoting neurons in the Ventrolateral Preoptic Nucleus and wake-promoting neurons, such as the lateral hypothalamic orexin (also called hypocretin) neurons, has allowed us to recognize that these two populations of neurons are mutually antagonistic (ie, inhibit each other) and form a "flip-flop switch," a type of circuit that results in rapid and complete transition in behavioral state. The same principle applies to the circuitry controlling transitions between REM sleep and non-REM (NREM) sleep. The flip-flop switch circuitry of the wake-sleep regulatory system produces the typical sleep pattern seen in healthy adults, with consolidated waking during the day and alternation between NREM and REM sleep at night. Breakdown in this circuitry both results in and explains the manifestations of a variety of sleep disorders including insomnia, narcolepsy with cataplexy, and REM sleep behavior disorder.
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the Ventrolateral Preoptic Nucleus is not required for isoflurane general anesthesia
Brain Research, 2011Co-Authors: Matthias Eikermann, Clifford B. Saper, Ramalingam Vetrivelan, Mark Henry, Ulrike Hoffmann, Shigefumi Yokota, Martina Grossesundrup, Nancy L. ChamberlinAbstract:Neurons of the Ventrolateral Preoptic Nucleus (VLPO) promote sleep and VLPO loss produces insomnia. Previous studies show that general anesthetics including isoflurane activate VLPO neurons, and may contribute to their sedative effects. However, it is not clear to what extent the activation of VLPO neurons contributes to general anesthesia. We tested whether destruction of the VLPO neurons would affect the onset, depth, or recovery from isoflurane's general anesthetic effects. The VLPO was ablated in 25 rats by bilateral local injection of orexin-saporin, and polysomnography was performed to measure baseline sleep loss and responses to isoflurane anesthesia at 1% and 2%. Eight rats received sham (saline) injections. We measured isoflurane effects on time to loss of righting reflex, onset of continuous slow wave activity, and burst suppression; burst-suppression ratio; and time to recovery of righting reflex and desynchronized EEG. VLPO neuron cell loss was quantified by post hoc histology. Loss of VLPO neurons as well as lesion size were associated with cumulative sleep loss (r = 0.77 and r = 0.62, respectively), and cumulative sleep loss was the strongest predictor of high sensitivity to anesthesia, expressed as decreased time to loss of righting reflex (− 0.59), increased burst-suppression ratio (r = 0.52) , and increased emergence time (r = 0.54); an interaction-effect of isoflurane dose was observed (burst-suppression ratio: p < 0.001). We conclude that the sleep loss caused by ablation of VLPO neurons sensitizes animals to the general anesthetic effects of isoflurane, but that the sedation produced by VLPO neurons themselves is not required for isoflurane anesthesia.
Patrice Fort - One of the best experts on this subject based on the ideXlab platform.
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Sleep–wake physiology
Handbook of Clinical Neurology, 2019Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:Abstract This chapter presents hypotheses on the mechanisms responsible for the succession of the three vigilance states, namely waking, nonrapid eye movement (non-REM) (slow-wave sleep—SWS), and REM sleep (paradoxical sleep—PS). It can be proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus. However, additional GABAergic systems have been described, localized in the parafacial, accumbens, and reticular thalamic nuclei, and these are also presented. In addition, the chapter discusses the fact that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Sleep-wake physiology.
Handbook of clinical neurology, 2019Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:This chapter presents hypotheses on the mechanisms responsible for the succession of the three vigilance states, namely waking, nonrapid eye movement (non-REM) (slow-wave sleep-SWS), and REM sleep (paradoxical sleep-PS). It can be proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus. However, additional GABAergic systems have been described, localized in the parafacial, accumbens, and reticular thalamic nuclei, and these are also presented. In addition, the chapter discusses the fact that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Neuroanatomical and Neurochemical Bases of Vigilance States
Handbook of experimental pharmacology, 2018Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:In the present chapter, hypotheses on the mechanisms responsible for the genesis of the three vigilance states, namely, waking, non-rapid eye movement (non-REM) also called slow-wave sleep (SWS), and REM sleep also called paradoxical sleep (PS), are presented. A huge number of studies first indicate that waking is induced by the activation of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons would be activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus (VLPO). However, new GABAergic systems recently described localized in the parafacial, accumbens, and reticular thalamic nuclei will be also presented. In addition, we will show that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Glucose Induces Slow-Wave Sleep by Exciting the Sleep-Promoting Neurons in the Ventrolateral Preoptic Nucleus: A New Link between Sleep and Metabolism
Journal of Neuroscience, 2015Co-Authors: Christophe Varin, Armelle Rancillac, Patrice Fort, Hélène Geoffroy, Sébastien Arthaud, Thierry GallopinAbstract:Sleep-active neurons located in the Ventrolateral Preoptic Nucleus (VLPO) play a crucial role in the induction and maintenance of slow-wave sleep (SWS). However, the cellular and molecular mechanisms responsible for their activation at sleep onset remain poorly understood. Here, we test the hypothesis that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons. We find that infusion of a glucose concentration into the VLPO of mice promotes SWS and increases the density of c-Fos-labeled neurons selectively in the VLPO. Moreover, we show in patch-clamp recordings from brain slices that VLPO neurons exhibiting properties of sleep-promoting neurons are selectively excited by glucose within physiological range. This glucose-induced excitation implies the catabolism of glucose, leading to a closure of ATP-sensitive potassium (KATP) channels. The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status. Together, these results provide evidence that glucose may participate in the mechanisms of SWS promotion and/or consolidation. SIGNIFICANCE STATEMENT: Although the brain circuitry underlying vigilance states is well described, the molecular mechanisms responsible for sleep onset remain largely unknown. Combining in vitro and in vivo experiments, we demonstrate that glucose likely contributes to sleep onset facilitation by increasing the excitability of sleep-promoting neurons in the Ventrolateral Preoptic Nucleus (VLPO). We find here that these neurons integrate energetic signals such as ambient glucose directly to regulate vigilance states accordingly. Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the fundamental and intimate link between sleep and metabolism.
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Networks of Normal and Disordered Sleep
Neuronal Networks in Brain Function CNS Disorders and Therapeutics, 2014Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:In the present chapter, we are providing state-of-the-art hypotheses on the mechanisms responsible for the succession of the three vigilance states: waking; non–rapid eye movement (non-REM, or NREM) sleep, also called slow-wave sleep (SWS); and REM sleep, also called paradoxical sleep (PS). It is proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. In contrast, a number of studies indicate that the GABAergic neurons that induce SWS are all localized in the Ventrolateral Preoptic Nucleus (VLPO) and surrounding structures. At the onset of sleep, the PS sleep neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. Finally, we review data strongly suggesting that the switch from SWS to PS sleep is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the hypothalamus and the brainstem.
Armelle Rancillac - One of the best experts on this subject based on the ideXlab platform.
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Structural and functional connections between the median and the Ventrolateral Preoptic Nucleus
Brain Structure and Function, 2019Co-Authors: Augustin Walter, Lorijn Spek, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Armelle RancillacAbstract:The median Preoptic Nucleus (MnPO) and the Ventrolateral Preoptic Nucleus (VLPO) are two brain structures that contain neurons essential for promoting non-rapid eye movement (NREM) sleep. However, their connections are still largely unknown. Here, we describe for the first time a slice preparation with an oblique coronal slicing angle at 70° from the horizontal in which their connectivity is preserved. Using the in vivo iDISCO method following viral infection of the MnPO or ex vivo biocytin crystal deposition in the MnPO of mouse brain slices, we revealed a strong axonal pathway from the MnPO to the VLPO. Then, to further explore the functionality of these projections, acute 70° slices were placed on multielectrode arrays (MEAs) and electrical stimulations were performed near the MnPO. Recordings of the signals propagation throughout the slices revealed a preferential pathway from the MnPO to the VLPO. Finally, we performed an input–output curve of field responses evoked by stimulation of the MnPO and recorded in the VLPO. We found that field responses were inhibited by GABA_A receptor antagonist, suggesting that afferent inputs from the MnPO activate VLPO neuronal networks by disinhibition.
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Neuropeptide S promotes wakefulness through the inhibition of sleep-promoting Ventrolateral Preoptic Nucleus neurons.
Sleep, 2019Co-Authors: Frédéric Chauveau, Augustin Walter, Eléonore Hardy, Nathalie Rouach, Christophe Varin, Damien Claverie, Emma Lardant, Frédéric Canini, Armelle RancillacAbstract:Study objectives The regulation of sleep-wake cycles is crucial for the brain's health and cognitive skills. Among the various substances known to control behavioral states, intraventricular injection of neuropeptide S (NPS) has already been shown to promote wakefulness. However, the NPS signaling pathway remains elusive. In this study, we characterized the effects of NPS in the Ventrolateral Preoptic Nucleus (VLPO) of the hypothalamus, one of the major brain structures regulating non-rapid eye movement (NREM) sleep. Methods We combined polysomnographic recordings, vascular reactivity, and patch-clamp recordings in mice VLPO to determine the NPS mode of action. Results We demonstrated that a local infusion of NPS bilaterally into the anterior hypothalamus (which includes the VLPO) significantly increases awakening and specifically decreases NREM sleep. Furthermore, we established that NPS application on acute brain slices induces strong and reversible tetrodotoxin (TTX)-sensitive constriction of blood vessels in the VLPO. This effect strongly suggests that the local neuronal network is downregulated in the presence of NPS. At the cellular level, we revealed by electrophysiological recordings and in situ hybridization that NPSR mRNAs are only expressed by non-Gal local GABAergic neurons, which are depolarized by the application of NPS. Simultaneously, we showed that NPS hyperpolarizes sleep-promoting neurons, which is associated with an increased frequency in their spontaneous IPSC inputs. Conclusion Altogether, our data reveal that NPS controls local neuronal activity in the VLPO. Following the depolarization of local GABAergic neurons, NPS indirectly provokes feed-forward inhibition onto sleep-promoting neurons, which translates into a decrease in NREM sleep to favor arousal.
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Neuropeptide S promotes wakefulness through the inhibition of sleep-promoting VLPO neurons
SLEEP, 2019Co-Authors: Frédéric Chauveau, Augustin Walter, Eléonore Hardy, Nathalie Rouach, Christophe Varin, Damien Claverie, Emma Lardant, Frédéric Canini, Armelle RancillacAbstract:STUDY OBJECTIVES: The regulation of sleep-wake cycles is crucial for the brain's health and cognitive skills. Among the various substances known to control behavioral states, intraventricular injection of neuropeptide S (NPS) has already been shown to promote wakefulness. However, the NPS signaling pathway remains elusive. In this study, we characterized the effects of NPS in the Ventrolateral Preoptic Nucleus (VLPO) of the hypothalamus, one of the major brain structures regulating non-rapid eye movement (NREM) sleep. METHODS: We combined polysomnographic recordings, vascular reactivity, and patch-clamp recordings in mice VLPO to determine the NPS mode of action. RESULTS: We demonstrated that a local infusion of NPS bilaterally into the anterior hypothalamus (which includes the VLPO) significantly increases awakening and specifically decreases NREM sleep. Furthermore, we established that NPS application on acute brain slices induces strong and reversible TTX-sensitive constriction of blood vessels in the VLPO. This effect strongly suggests that the local neuronal network is downregulated in the presence of NPS. At the cellular level, we revealed by electrophysiological recordings and in situ hybridization that NPSR mRNAs are only expressed by non-Gal local GABAergic neurons, which are depolarized by the application of NPS. Simultaneously, we showed that NPS hyperpolarizes sleep-promoting neurons, which is associated with an increased frequency in their spontaneous IPSC inputs. CONCLUSION: Altogether, our data reveal that NPS controls local neuronal activity in the VLPO. Following the depolarization of local GABAergic neurons, NPS indirectly provokes feed-forward inhibition onto sleep-promoting neurons, which translates into a decrease in NREM sleep to favor arousal.
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Structural and functional connections between the median and the Ventrolateral Preoptic Nucleus. : The MnPO-VLPO pathway
Brain Structure and Function, 2019Co-Authors: Augustin Walter, Eléonore Hardy, Alexis Pierre Bemelmans, Nathalie Rouach, Lorijn Van Der Spek, Armelle RancillacAbstract:The median Preoptic Nucleus (MnPO) and the Ventrolateral Preoptic Nucleus (VLPO) are two brain structures that contain neurons essential for promoting non-rapid eye movement (NREM) sleep. However, their connections are still largely unknown. Here, we describe for the first time a slice preparation with an oblique coronal slicing angle at 70° from the horizontal in which their connectivity is preserved. Using the in vivo iDISCO method following viral infection of the MnPO or ex vivo biocytin crystal deposition in the MnPO of mouse brain slices, we revealed a strong axonal pathway from the MnPO to the VLPO. Then, to further explore the functionality of these projections, acute 70° slices were placed on multielectrode arrays (MEAs) and electrical stimulations were performed near the MnPO. Recordings of the signals propagation throughout the slices revealed a preferential pathway from the MnPO to the VLPO. Finally, we performed an input-output curve of field responses evoked by stimulation of the MnPO and recorded in the VLPO. We found that field responses were inhibited by GABAA receptor antagonist, suggesting that afferent inputs from the MnPO activate VLPO neuronal networks by disinhibition.
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Serotonin differentially modulates excitatory and inhibitory synaptic inputs to putative sleep-promoting neurons of the Ventrolateral Preoptic Nucleus
Neuropharmacology, 2016Co-Authors: Aude Sangare, Romain Dubourget, Thierry Gallopin, Hélène Geoffroy, Armelle RancillacAbstract:The role of serotonin (5-HT) in sleep-wake regulation has been a subject of intense debate and remains incompletely understood. In the Ventrolateral Preoptic Nucleus (VLPO), the main structure that triggers non-rapid eye movement (NREM) sleep, putative sleep-promoting (PSP) neurons were shown ex vivo to be either inhibited (Type-1) or excited (Type-2) by 5-HT application. To determine the complex action of this neurotransmitter on PSP neurons, we recorded spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, sIPSCs, mEPSCs and mIPSCs) in response to bath application of 5-HT. We established in mouse acute VLPO slices that 5-HT reduces spontaneous and miniature EPSC and IPSC frequencies to Type-1 neurons, whereas 5-HT selectively increases sIPSC and mIPSC frequencies to Type-2 VLPO neurons. We further determined that Type-1 neurons display a lower action potential threshold and a smaller soma size than Type-2 neurons. Finally, single-cell RT-PCR designed to identify the 13 serotonergic receptor subtypes revealed the specific mRNA expression of the 5-HT1A,B,D,F receptors by Type-1 neurons. Furthermore, the 5-HT2A-C,4,7 receptors were found to be equivalently expressed by both neuronal types. Altogether, our results establish that the excitatory and inhibitory inputs to Type-1 and Type-2 VLPO PSP neurons are differentially regulated by 5-HT. Electrophysiological, morphological and molecular differences were also identified between these two neuronal types. Our results provide new insights regarding the orchestration of sleep regulation by 5-HT release, and strongly suggest that Type-2 neurons could play a permissive role, whereas Type-1 neurons could have an executive role in sleep induction and maintenance.
Pierre-hervé Luppi - One of the best experts on this subject based on the ideXlab platform.
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Sleep-wake physiology.
Handbook of clinical neurology, 2019Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:This chapter presents hypotheses on the mechanisms responsible for the succession of the three vigilance states, namely waking, nonrapid eye movement (non-REM) (slow-wave sleep-SWS), and REM sleep (paradoxical sleep-PS). It can be proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus. However, additional GABAergic systems have been described, localized in the parafacial, accumbens, and reticular thalamic nuclei, and these are also presented. In addition, the chapter discusses the fact that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Sleep–wake physiology
Handbook of Clinical Neurology, 2019Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:Abstract This chapter presents hypotheses on the mechanisms responsible for the succession of the three vigilance states, namely waking, nonrapid eye movement (non-REM) (slow-wave sleep—SWS), and REM sleep (paradoxical sleep—PS). It can be proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus. However, additional GABAergic systems have been described, localized in the parafacial, accumbens, and reticular thalamic nuclei, and these are also presented. In addition, the chapter discusses the fact that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Neuroanatomical and Neurochemical Bases of Vigilance States
Handbook of experimental pharmacology, 2018Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:In the present chapter, hypotheses on the mechanisms responsible for the genesis of the three vigilance states, namely, waking, non-rapid eye movement (non-REM) also called slow-wave sleep (SWS), and REM sleep also called paradoxical sleep (PS), are presented. A huge number of studies first indicate that waking is induced by the activation of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. At the onset of sleep, the SWS-active neurons would be activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. A number of studies support the hypothesis that SWS results from the activation of GABAergic neurons localized in the Ventrolateral Preoptic Nucleus (VLPO). However, new GABAergic systems recently described localized in the parafacial, accumbens, and reticular thalamic nuclei will be also presented. In addition, we will show that a large body of data strongly suggests that the switch from SWS to PS is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the posterior hypothalamus and the brainstem.
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Networks of Normal and Disordered Sleep
Neuronal Networks in Brain Function CNS Disorders and Therapeutics, 2014Co-Authors: Pierre-hervé Luppi, Patrice FortAbstract:In the present chapter, we are providing state-of-the-art hypotheses on the mechanisms responsible for the succession of the three vigilance states: waking; non–rapid eye movement (non-REM, or NREM) sleep, also called slow-wave sleep (SWS); and REM sleep, also called paradoxical sleep (PS). It is proposed that waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems. In contrast, a number of studies indicate that the GABAergic neurons that induce SWS are all localized in the Ventrolateral Preoptic Nucleus (VLPO) and surrounding structures. At the onset of sleep, the PS sleep neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking. Finally, we review data strongly suggesting that the switch from SWS to PS sleep is due to the interaction of multiple populations of glutamatergic and GABAergic neurons localized in the hypothalamus and the brainstem.
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Neurochemical aspects of sleep regulation with specific focus on slow-wave sleep.
The World Journal of Biological Psychiatry, 2010Co-Authors: Pierre-hervé LuppiAbstract:The purpose of this review is to outline the mechanisms responsible for the succession of the three vigilance states, namely waking, non rapid eye movement (nonREM) and REM (paradoxical) sleep over 24 h. The latest hypothesis on the mechanisms by which cortical activity switches from an activated state during waking to a synchronised state during nonREM sleep is presented. It is proposed that the activated cortical state during waking is induced by the activity of multiple waking systems, including the serotonergic, noradrenergic, cholinergic and hypocretin systems located at different subcortical levels. In contrast, the neurons inducing nonREM sleep are all localized in a single small Nucleus named the Ventrolateral Preoptic Nucleus (VLPO) situated above the optic chiasm. These neurons all contain the inhibitory neurotransmitter gamma-aminobutyric acid. The notion that the switch from waking to nonREM sleep is due to the inhibition of the waking systems by the VLPO sleep-active neurons is introduced. At the onset of sleep, the sleep neurons are activated by the circadian clock localized in the suprachiasmatic Nucleus and a hypnogenic factor, adenosine, which progressively accumulates in the brain during waking.
Thomas E. Scammell - One of the best experts on this subject based on the ideXlab platform.
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galanin neurons in the Ventrolateral Preoptic area promote sleep and heat loss in mice
Nature Communications, 2018Co-Authors: Daniel Kroeger, Thomas E. Scammell, Elda Arrigoni, Lorisl . Ferrari, Gianna Absi, Celia Gagliardi, Sathyajit S Bandaru, Joseph C Madara, Heike Munzberg, Clifford B. SaperAbstract:The Preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neurons in the Ventrolateral Preoptic Nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POAGAL neurons was shown to paradoxically cause waking, not sleep. Here we report that photostimulation of VLPOGAL neurons in mice promotes sleep with low frequency stimulation (1–4 Hz), but causes conduction block and waking at frequencies above 8 Hz. Further, optogenetic inhibition reduces sleep. Chemogenetic activation of VLPOGAL neurons confirms the increase in sleep, and also reduces body temperature. In addition, chemogenetic activation of VLPOGAL neurons induces short-latency sleep in an animal model of insomnia. Collectively, these findings establish a causal role of VLPOGAL neurons in both sleep induction and heat loss. Anatomical lesions of the Preoptic area (POA) can cause sleep loss while electrical, chemical, or thermal stimulation of POA can induce sleep. To better understand the exact neural function of the POA, this study shows that galanin and GABA+ inhibitory neurons in the Ventrolateral POA that project to the wake-promoting tuberomammillary Nucleus promote sleep in a stimulation frequency dependent manner.
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Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area
Sleep, 2016Co-Authors: Yury V. Gavrilov, Thomas E. Scammell, Brian A Ellison, Mihoko Yamamoto, Hasini Reddy, Johannes Haybaeck, Emmanuel Mignot, Christian R. Baumann, Philipp O. ValkoAbstract:STUDY OBJECTIVES To examine the integrity of sleep-promoting neurons of the Ventrolateral Preoptic Nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. METHODS Postmortem examination of five narcolepsy and eight control brains. RESULTS VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544). CONCLUSIONS A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease.
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optogenetic mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal
The Journal of Neuroscience, 2014Co-Authors: Rhîannanh . Williams, Thomas E. Scammell, Lorisl . Ferrari, Melissa J Chee, Daniel Kroeger, Eleftheria Maratosflier, Elda ArrigoniAbstract:Histaminergic neurons in the tuberomammillary Nucleus (TMN) are an important component of the ascending arousal system and may form part of a “flip–flop switch” hypothesized to regulate sleep and wakefulness. Anatomical studies have shown that the wake-active TMN and sleep-active Ventrolateral Preoptic Nucleus (VLPO) are reciprocally connected, suggesting that each region can inhibit its counterpart when active. In this study, we determined how histamine affects the two branches of this circuit. We selectively expressed channelrhodopsin-2 (ChR2) in TMN neurons and used patch-clamp recordings in mouse brain slices to examine the effects of photo-evoked histamine release in the Ventrolateral TMN and VLPO. Photostimulation decreased inhibitory GABAergic inputs to the Ventrolateral TMN neurons but produced a membrane hyperpolarization and increased inhibitory synaptic input to the VLPO neurons. We found that in VLPO the response to histamine was indirect, most likely via a GABAergic interneuron. Our experiments demonstrate that release of histamine from TMN neurons can disinhibit the TMN and suppresses the activity of sleep-active VLPO neurons to promote TMN neuronal firing. This further supports the sleep–wake “flip–flop switch” hypothesis and a role for histamine in stabilizing the switch to favor wake states.
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Delayed orexin signaling consolidates wakefulness and sleep: physiology and modeling.
Journal of neurophysiology, 2008Co-Authors: C. G. Diniz Behn, Nancy Kopell, Emery N. Brown, Takatoshi Mochizuki, Thomas E. ScammellAbstract:Orexin-producing neurons are clearly essential for the regulation of wakefulness and sleep because loss of these cells produces narcolepsy. However, little is understood about how these neurons dynamically interact with other wake- and sleep-regulatory nuclei to control behavioral states. Using survival analysis of wake bouts in wild-type and orexin knockout mice, we found that orexins are necessary for the maintenance of long bouts of wakefulness, but orexin deficiency has little impact on wake bouts 1 min) of functional effects. This delay has important implications for understanding the control of wakefulness and sleep because increasing evidence suggests that different mechanisms are involved in the production of brief and sustained wake bouts. We incorporated these findings into a mathematical model of the mouse sleep/wake network. Orexins excite monoaminergic neurons and we hypothesize that orexins increase the monoaminergic inhibition of sleep-promoting neurons in the Ventrolateral Preoptic Nucleus. We modeled orexin effects as a time-dependent increase in the strength of inhibition from wake- to sleep-promoting populations and the resulting simulated behavior accurately reflects the fragmented sleep/wake behavior of narcolepsy and leads to several predictions. By integrating neurophysiology of the sleep/wake network with emergent properties of behavioral data, this model provides a novel framework for investigating network dynamics and mechanisms associated with normal and pathologic sleep/wake behavior.
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Homeostatic, circadian, and emotional regulation of sleep.
The Journal of comparative neurology, 2005Co-Authors: Clifford B. Saper, Georgina Cano, Thomas E. ScammellAbstract:A good night's sleep is one of life's most satisfying experiences, while sleeplessness is stressful and causes cognitive impairment. Yet the mechanisms that regulate the ability to sleep have only recently been subjected to detailed investigation. New studies show that the control of wake and sleep emerges from the interaction of cell groups that cause arousal with other nuclei that induce sleep such as the Ventrolateral Preoptic Nucleus (VLPO). The VLPO inhibits the ascending arousal regions and is in turn inhibited by them, thus forming a mutually inhibitory system resembling what electrical engineers call a "flip-flop switch." This switch may help produce sharp transitions between discrete behavioral states, but it is not necessarily stable. The orexin neurons in the lateral hypothalamus may help stabilize this system by exciting arousal regions during wakefulness, preventing unwanted transitions between wakefulness and sleep. The importance of this stabilizing role is apparent in narcolepsy, in which an absence of the orexin neurons causes numerous, unintended transitions in and out of sleep and allows fragments of REM sleep to intrude into wakefulness. These influences on the sleep/wake system by homeostatic and circadian drives, as well as emotional inputs, are reviewed. Understanding the pathways that underlie the regulation of sleep and wakefulness may provide important insights into how the cognitive and emotional systems interact with basic homeostatic and circadian drives for sleep.
