Letteratura scientifica selezionata sul tema "Ventrolateral preoptic nucleus (VLPO)"

For over a century, the role of the preoptic hypothalamus and adjacent basal forebrain in sleep–wake regulation has been recognized. However, for years, the identity and location of sleep- and wake-promoting neurons in this region remained largely unresolved. Twenty-five years ago, Saper and colleagues uncovered a small collection of sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) of the preoptic hypothalamus, and since this seminal discovery the VLPO has been intensively investigated by labs around the world, including our own. Herein, we first review the history of the preoptic area, with an emphasis on the VLPO in sleep–wake control. We then attempt to synthesize our current understanding of the circuit, cellular and synaptic bases by which the VLPO both regulates and is itself regulated, in order to exert a powerful control over behavioral state, as well as examining data suggesting an involvement of the VLPO in other physiological processes.

Background There is much evidence that the sedative component of anesthesia is mediated by gamma-aminobutyric acid type A (GABA(A)) receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These GABA(A) receptors are targeted by gamma-aminobutyric acid-mediated (GABAergic) neurons in the ventrolateral preoptic area (VLPO): When these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to GABA(A). The authors explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Methods Spontaneous excitatory postsynaptic currents were recorded from VLPO cells-principally mechanically isolated, but also in slices from rats. Results In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. The action of propofol was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at GABA(A) receptors. It was also suppressed by bumetanide, a blocker of Na-K-Cl cotransporter-mediated inward Cl transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Conclusion Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in the VLPO, indirectly by activation of GABA(A) receptors on glutamatergic afferents: Because these axons/terminals have a relatively high internal Cl concentration, they are depolarized by GABAergic agents such as propofol, which thus enhance glutamate release.

The present experiment investigated the expression of the nuclear phosphoprotein Fos over the 24-h light-dark cycle in regions of the rat brain related to sleep and vigilance, including the ventrolateral preoptic area (VLPO), the paraventricular thalamic nucleus (PVT), and the central medial thalamic nucleus (CMT). Immunocytochemistry for Fos, an immediate-early gene product used as an index of neuronal activity, was carried out on brain sections from rats perfused at zeitgeber time (ZT) 1, ZT 5, ZT 12.5, and ZT 17 (lights on ZT 0–ZT 12). The number of Fos-immunopositive (Fos+) cells in the VLPO was elevated at ZT 5 and 12.5 (i.e., during or just after the rest phase of the cycle). Fos+cell number increased at ZT 17 and ZT 1 in the PVT and CMT, 180° out of phase with the VLPO. A positive correlation was found between the numbers of Fos+ cells in the PVT and CMT, and Fos expression in each thalamic nucleus was negatively correlated with VLPO Fos+ cell number. The VLPO, PVT, and CMT may integrate circadian and homeostatic influences to regulate the sleep-wake cycle.

The ventrolateral preoptic nucleus (VLPO) is a key nucleus involved in the homeostatic regulation of sleep-wakefulness. Little is known, however, about the cellular mechanisms underlying its role in sleep regulation and how the neurotransmitters, such as GABA and noradrenaline (NA), are involved. In the present study we investigated GABAergic transmission to acutely dissociated VLPO neurons using an enzyme-free, mechanical dissociation procedure in which functional terminals remained adherent and we investigated how this GABAergic transmission was modulated by NA. As previously reported in slices, NA hyperpolarized multipolar VLPO neurons and depolarized bipolar VLPO neurons. NA also inhibited the release of GABA onto multipolar VLPO neurons but had no effect on GABAergic transmission to bipolar neurons. The inhibition of release was mediated by presynaptic α2 adrenoceptors coupled to N-ethylmaleimide (NEM)-sensitive G-proteins which appeared to act via inhibition of adenylate cyclase and subsequent decreases in protein kinase A activity. The inhibition of GABA release did not, however, involve an inhibition of external Ca2+ influx. The results indicate that all VLPO neurons contain GABAergic inputs and that the different morphological subgroups of VLPO neurons are correlated not only to different postsynaptic responses to NA but also to different presynaptic NA responses. Furthermore our results demonstrate an additional mechanism by which NA can modulate the excitability of multipolar VLPO neurons which may have important implications for its role in regulating sleep/wakefulness.

Sexual function and orientation is a complex platform of human personality which is being modulated by several brain circuities which is less understood currently. Recently, several studies have demonstrated interesting results regarding the role of several brain locations in sexual behaviors and orientation. Sexual arousal in homosexual men is associated with activation of the left angular gyrus, left caudate nucleus, Ventrolateral Preoptic (VLPO) Nucleus of Hypothalamus and right pallidum; while it is associated with bilateral lingual gyrus, right hippocampus, and right parahippocampal gyrus in heterosexual men. We postulate that sexual-orientation behaviors are being mediated by several circuits in the brain in the center of which the VLPO is playing an indistinguishable role. We hypothesize that the different aspects of the sexual dysfunction could be associated with innate or acquired lesions of VLPO. Accordingly, the electrical stimulation of the nucleus in those with sexual dysfunction would be a treatment option. Thus the VLPO could be considered a target for Deep Brain Stimulation (DBS) in individuals with impaired sexual function.

The preoptic hypothalamus is implicated in sleep regulation. Neurons in the median preoptic nucleus (MnPO) and the ventrolateral preoptic area (VLPO) have been identified as potential sleep regulatory elements. However, the extent to which MnPO and VLPO neurons are activated in response to changing homeostatic sleep regulatory demands is unresolved. To address this question, we continuously recorded the extracellular activity of neurons in the rat MnPO, VLPO and dorsal lateral preoptic area (LPO) during baseline sleep and waking, during 2 h of sleep deprivation (SD) and during 2 h of recovery sleep (RS). Sleep-active neurons in the MnPO ( n = 11) and VLPO ( n = 13) were activated in response to SD, such that waking discharge rates increased by 95.8 ± 29.5% and 59.4 ± 17.3%, respectively, above waking baseline values. During RS, non-rapid eye movement (REM) sleep discharge rates of MnPO neurons initially increased to 65.6 ± 15.2% above baseline values, then declined to baseline levels in association with decreases in EEG delta power. Increase in non-REM sleep discharge rates in VLPO neurons during RS averaged 40.5 ± 7.6% above baseline. REM-active neurons ( n = 16) in the LPO also exhibited increased waking discharge during SD and an increase in non-REM discharge during RS. Infusion of A2A adenosine receptor antagonist into the VLPO attenuated SD-induced increases in neuronal discharge. Populations of LPO wake/REM-active and state-indifferent neurons and dorsal LPO sleep-active neurons were unresponsive to SD. These findings support the hypothesis that sleep-active neurons in the MnPO and VLPO, and REM-active neurons in the LPO, are components of neuronal circuits that mediate homeostatic responses to sustained wakefulness.

Preoptic area (POA) neuronal activity promotes sleep, but the localization of critical sleep-active neurons is not completely known. Thermal stimulation of the POA also facilitates sleep. This study used the c-Fos protein immunostaining method to localize POA sleep-active neurons at control (22°C) and mildly elevated (31.5°C) ambient temperatures. At 22°C, after sleep, but not after waking, we found increased numbers of c-Fos immunoreactive neurons (IRNs) in both rostral and caudal parts of the median preoptic nucleus (MnPN) and in the ventrolateral preoptic area (VLPO). In animals sleeping at 31.5°C, significantly more Fos IRNs were found in the rostral MnPN compared with animals sleeping at 22°C. In VLPO, Fos IRN counts were no longer increased over waking levels after sleep at the elevated ambient temperature. Sleep-associated Fos IRNs were also found diffusely in the POA, but counts were lower than those made after waking. This study supports a hypothesis that the MnPN, as well as the VLPO, is part of the POA sleep-facilitating system and that the rostral MnPN may facilitate sleep, particularly at elevated ambient temperatures.

Abstract Introduction The ventrolateral preoptic (VLPO) nucleus is a key area involved in the initiation and maintenance of sleep. During wakefulness, sleep-promoting galanin neurons in the VLPO are directly inhibited by arousal signals including noradrenaline and acetylcholine. We have found that while these neurotransmitters directly inhibit VLPO galanin neurons, they also activate GABAergic neurons in the VLPO that do not express galanin. We propose that when activated by monoaminergic and cholinergic inputs, these local VLPO GABAergic neurons provide an additional inhibition of the VLPO galanin sleep-promoting neurons. We tested this model in brain slices in mice. Methods We studied VLPO galanin neurons in mouse brain slices using patch-clamp recordings. We recorded from fluorescently labeled VLPO galanin neurons following the injection of a cre-dependent AAV encoding for mCherry, into the VLPO of Gal-cre mice. For the optogenetic studies we expressed channelrhodopsin-2 (ChR-2) in VLPO VGAT neurons and mCherry in galanin neurons by injecting a flp-dependent and a cre-dependent AAV encoding respectively for ChR2 and mCherry into the VLPO of VGAT-flp::Gal-cre mice. We photo-stimulated local GABAergic neurons and recorded from labeled VLPO galanin neurons. Noradrenaline, carbachol and receptor antagonists were bath-applied. Results Noradrenaline and carbachol inhibited VLPO galanin neurons by alpha-2 and muscarinic receptors and these effects were maintained in the presence of tetrodotoxin (TTX) indicating, as previously proposed, a direct inhibitory effect of noradrenaline and carbachol on VLPO galanin neurons. In addition, both noradrenaline and carbachol increased the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) of VLPO galanin neurons, suggesting an additional inhibitory action on VLPO galanin neurons. Finally, optogenetic stimulation of local VLPO GABAergic neurons produced short latency, TTX-resistant, opto-evoked IPSCs in VLPO galanin neurons. Both noradrenaline and carbachol increased the amplitude of these opto-evoked IPSCs by the activation of alpha-1 and muscarinic receptors. Conclusion Our results demonstrate that noradrenaline and acetylcholine inhibit VLPO galanin neurons directly and indirectly. Both noradrenaline and acetylcholine increase GABAergic afferent inputs to VLPO galanin neurons by activating local GABAergic neurons. We propose that during wakefulness this feedforward inhibition provides additional inhibition of VLPO galanin sleep-promoting neurons. Support (if any) NS091126 and HL149630

The median preoptic nucleus (MnPN) and the ventrolateral preoptic area (VLPO) are two hypothalamic regions that have been implicated in sleep regulation, and both nuclei contain sleep-active GABAergic neurons. Adenosine is an endogenous sleep regulatory substance, which promotes sleep via A1 and A2A receptors (A2AR). Infusion of A2AR agonist into the lateral ventricle or into the subarachnoid space underlying the rostral basal forebrain (SS-rBF), has been previously shown to increase sleep. We examined the effects of an A2AR agonist, CGS-21680, administered into the lateral ventricle and the SS-rBF on sleep and c-Fos protein immunoreactivity (Fos-IR) in GABAergic neurons in the MnPN and VLPO. Intracerebroventricular administration of CGS-21680 during the second half of lights-on phase increased sleep and increased the number of MnPN and VLPO GABAergic neurons expressing Fos-IR. Similar effects were found with CGS-21680 microinjection into the SS-rBF. The induction of Fos-IR in preoptic GABAergic neurons was not secondary to drug-induced sleep, since CGS-21680 delivered to the SS-rBF significantly increased Fos-IR in MnPN and VLPO neurons in animals that were not permitted to sleep. Intracerebroventricular infusion of ZM-241385, an A2AR antagonist, during the last 2 h of a 3-h period of sleep deprivation caused suppression of subsequent recovery sleep and reduced Fos-IR in MnPN and VLPO GABAergic neurons. Our findings support a hypothesis that A2AR-mediated activation of MnPN and VLPO GABAergic neurons contributes to adenosinergic regulation of sleep.

Corticotropin releasing factor (CRF) is implicated in sleep and arousal regulation. Exogenous CRF causes sleep suppression that is associated with activation of at least two important arousal systems: pontine noradrenergic and hypothalamic orexin/hypocretin neurons. It is not known whether CRF also impacts sleep-promoting neuronal systems. We hypothesized that CRF-mediated changes in wake and sleep involve decreased activity of hypothalamic sleep-regulatory neurons localized in the preoptic area. To test this hypothesis, we examined the effects of intracerebroventricular administration of CRF on sleep-wake measures and c-Fos expression in GABAergic neurons in the median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) in different experimental conditions. Administration of CRF (0.1 nmol) during baseline rest phase led to delayed sleep onset and decreases in total amount and mean duration of non-rapid eye movement (NREM) sleep. Administration of CRF during acute sleep deprivation (SD) resulted in suppression of recovery sleep and decreased c-Fos expression in MnPN/VLPO GABAergic neurons. Compared with vehicle controls, intracerebroventricular CRF potentiated disturbances of both NREM and REM sleep in rats exposed to a species-specific psychological stressor, the dirty cage of a male conspecific. The number of MnPN/VLPO GABAergic neurons expressing c-Fos was reduced in the CRF-treated group of dirty cage-exposed rats. These findings confirm the involvement of CRF in wake-sleep cycle regulation and suggest that increased CRF signaling in the brain 1) negatively affects homeostatic responses to sleep loss, 2) exacerbates stress-induced disturbances of sleep, and 3) suppresses the activity of sleep-regulatory neurons of the MnPN and VLPO.

Bien que beaucoup d'attention ait été consacrée à la dissection des circuits neuronaux qui sous-tendent l’architecture du sommeil de base, les mécanismes par lesquels les centres du sommeil s’adaptent de manière dynamique aux défis environnementaux demeurent mal connus. L'objectif de cette thèse était de déterminer comment et par quels mécanismes le sommeil est influencé par le stress chez la souris.La première partie de ma thèse a mis en évidence que le stress de défaite sociale (SDS) induit un état initial et transitoire d'insomnie, suivi d’un retour à des quantités de sommeil normales. Malgré cette récupération apparente, les souris ont montré une fragmentation du sommeil paradoxal qui a persisté plusieurs heures après le SDS. Grâce à l'inhibition chémogénétique, nous avons démontré que les projections du cortex préfrontal (PFC) vers le noyau préoptique ventrolatéral (VLPO) sont recrutées sélectivement dans des situations stressantes et sont nécessaires à la fragmentation du sommeil paradoxal induite par le SDS. De plus, nous avons montré que l’activation de la voie PFC-VLPO est suffisante pour imiter la fragmentation du sommeil paradoxal en l'absence d’un stress. Grâce à une approche optogénétique ex vivo, nous avons précisé le mécanisme cellulaire sous-jacent à cette voie en montrant que le PFC module directement les neurones promoteurs de sommeil du VLPO. En outre, l'activation in vivo de la voie PFC-VLPO interrompt le sommeil paradoxal au profit du sommeil lent, ce qui est en accord avec le rôle bien établi du VLPO. L'ensemble de ces résultats suggère un mécanisme limitant le temps passé en sommeil paradoxal, un état de forte vulnérabilité, qui permettrait à l'individu d'être plus réactif et prêt à affronter un danger ; sans toutefois supprimer la quantité totale de sommeil, indispensable à la survie.Dans la deuxième partie de mon travail, nous avons montré que les neurones du VLPO exprimant le CRH (VLPOCRH) étaient une cible privilégiée des projections excitatrices du PFC. Nos résultats mettent en évidence que l'activation chémogénétique des neurones VLPOCRH diminue fortement le sommeil paradoxal au profit d’un sommeil lent plus consolidé. Cependant, leur inhibition chémogénétique n'a eu aucun effet sur l'architecture du sommeil, suggérant que ces neurones ne seraient pas actifs de manière tonique en condition normale/ non stressante.La troisième et dernière partie de mon travail a consisté à développer une nouvelle méthode de classification précise et automatique du sommeil paradoxal. En effet, les parties précédentes de ma thèse ont mis en évidence que le stress peut entraîner des périodes de sommeil paradoxal particulièrement brèves qui peuvent être négligées par les méthodes de classification classiques. J’ai donc mis au point une approche permettant de capturer les fines modifications du sommeil et de quantifier les paramètres qui peuvent être subjectifs avec une classification manuelle. Ces résultats s’inscrivent donc dans une démarche de reproductibilité maximale
Although much attention has been dedicated to dissect the complex circuits underlying basic sleep architecture, how sleep centers dynamically adapt to environmental challenges remains to be fully understood. The objective of this thesis was to determine, in mice, how and by which mechanisms sleep is influenced by stress.The first part of my thesis demonstrates that the social defeat stress (SDS) induces an initial state of insomnia before sleep quantities return to normal. Beside this apparent recovery, mice showed a REM sleep fragmentation that persisted many hours after SDS. Using chemogenetic inhibition, we demonstrated that prefrontal cortex (PFC) projections to the VLPO are selectively recruited under stressful situations and necessary for the SDS-induced REM sleep fragmentation. We further demonstrate that the optogenetic activation of the PFC- VLPO pathway is sufficient to mimic the REM sleep fragmentation in the absence of an actual stressor. Finally, using ex vivo optogenetics, we precise the cellular mechanism underlying this pathway by showing that the PFC directly modulates VLPO sleep-promoting neurons. Consistent with that, we show that in vivo activation of the PFC-VLPO pathway interrupts REM sleep in favor of NREM sleep, which is in line with the well established role of the VLPO. Altogether these results provide a mechanism to shorten the time spent in REM sleep, a state of great vulnerability, allowing the individual to be more responsive and ready to face a danger, without suppressing the total amount of sleep, essential for survival.In the second part of my work, we showed that the CRH-expressing neurons (VLPOCRH) were a predilection target from the PFC excitatory projections. We then investigated the role of the VLPOCRH neurons in basal sleep regulation. Our results highlight that activation of the VLPOCRH neurons strongly suppress REM sleep, favoring a more consolidated NREM sleep. However, chemogenetic inhibition of the VLPOCRH neurons had no effect on the sleep architecture.The third, and last part, of my work sought to establish a novel method to accurately and automatically classify REM sleep. Indeed, previous parts of my thesis highlighted that stress can cause REM sleep bouts to be particularly short. These brief periods can be overlooked by classical scoring methods. We developed an approach capable of capturing these fine sleep modifications and tracking parameters that can be usually subjective with manual scoring, thus ensuring maximal reproducibility

Sleep disorders often respond to both pharmacologic agents and nonpharmacologic therapies. This chapter reviews the pharmacology of and indications for specific sleep agents. Most of the agents approved by the US Food and Drug Administration for insomnia, with the exception of antidepressants and ramelteon, modulate the function of the γ‎-aminobutyric acid (GABA)-A receptor complex. The ventrolateral preoptic nucleus (VLPO) has a critical role in sleep initiation and maintenance. GABA is the primary inhibitory neurotransmitter of the VLPO. Medications used for sleep promotion include benzodiazepines, chronobiotics, sedating antidepressants, histamine blockers, and γ‎-hydroxybutyric acid.

Stimulants are typically prescribed for their positive effects on mood, motivation, alertness, arousal, and energy. They are believed to exert their pharmacologic effects by increasing synaptic release of endogenous catecholamines (norepinephrine and dopamine) while simultaneously blocking catecholamine reuptake at the nerve terminals. Themost commonly used ‘‘traditional’’ agents are methylphenidate and dextroamphetamine. Methylphenidate reaches peak blood levels in 1 to 3 hours and has an elimination half-life of 2 to 3 hours. Dextroamphetamine reaches peak levels in 2 to 4 hours and has an elimination half-life of 3 to 6 hours. Controlled-release formulations are available, allowing for dosing once daily. Dextroamphetamine is excreted primarily in the urine in unchanged form, whereas methylphenidate is excreted mainly as ritalinic acid. The newer generation stimulant modafinil has been marketed in the United States since 1998. Initially used in the treatment of narcolepsy, it is now prescribed for a wider range of conditions because of its positive effects on wakefulness, vigilance, cognitive performance, and mood. Its pharmacologic effects are thought to result primarily from the stimulation of wakefulness-promoting orexinergic neurons in the anterior hypothalamus. Inhibition of norepinephrine reuptake in the ventrolateral preoptic nucleus and of dopamine reuptake (by binding to the transporter) may contribute to its action. Modafinil is administered orally, achieves peak plasma concentrations in 2 to 4 hours, and has an elimination half-life of 12 to 15 hours. It is 90% metabolized in the liver, and its metabolites are excreted in the urine. The ergot alkaloids bromocriptine and pergolide are familiar to most neurologists in their use in the treatment of Parkinson’s disease (PD) and migraine headache. These dopamine receptor agonists are also used in neuropsychiatry in the treatment of apathetic states in patients recovering from brain trauma, cerebral anoxia, and strokes. Amantadine is another familiar agent used in the treatment of PD and drug-induced parkinsonism. In addition to other effects in the central nervous system (CNS), amantadine facilitates dopamine release and inhibits its reuptake. It thus has modest ‘‘stimulant-like’’ effects useful in the treatment of executive dysfunction syndromes, particularly in patients with dementia. Bupropion is a dopamine and norepinephrine reuptake inhibitor. It usually is prescribed as a ‘‘nonsedating’’ antidepressant, but its potentiation of catecholamine neurotransmission results in modest stimulant-like clinical effects.