Wakefulness

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Robert W Mccarley - One of the best experts on this subject based on the ideXlab platform.

  • the menagerie of the basal forebrain how many neural species are there what do they look like how do they behave and who talks to whom
    Current Opinion in Neurobiology, 2017
    Co-Authors: Chun Yang, Robert W Mccarley, Stephen Thankachan, Ritchie E Brown
    Abstract:

    The diverse cell-types of the basal forebrain control sleep-wake states, cortical activity and reward processing. Large, slow-firing, cholinergic neurons suppress cortical delta activity and promote cortical plasticity in response to reinforcers. Large, fast-firing, cortically-projecting GABAergic neurons promote Wakefulness and fast cortical activity. In particular, parvalbumin/GABAergic neurons promote neocortical gamma band activity. Conversely, excitation of slower-firing somatostatin/GABAergic neurons promotes sleep through inhibition of cortically-projecting neurons. Activation of glutamatergic neurons promotes Wakefulness, likely by exciting other cortically-projecting neurons. Similarly, cholinergic neurons indirectly promote Wakefulness by excitation of wake-promoting, cortically-projecting GABAergic neurons and/or inhibition of sleep-promoting somatostatin/GABAergic neurons. Both glia and neurons increase the levels of adenosine during prolonged Wakefulness. Adenosine presynaptically inhibits glutamatergic inputs to wake-promoting cholinergic and GABAergic/parvalbumin neurons, promoting sleep.

  • a1 receptor and adenosinergic homeostatic regulation of sleep Wakefulness effects of antisense to the a1 receptor in the cholinergic basal forebrain
    The Journal of Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, Stuart Winston, Robert W Mccarley
    Abstract:

    We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged Wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of Wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A1 receptor antisense in the basal forebrain, spontaneous levels of sleep-Wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in Wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2–5 showing a reduction of ∼50–60%. There was an even greater postdeprivation reduction in delta power (60–75%) and a concomitant increase in Wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.

  • a1 receptor and adenosinergic homeostatic regulation of sleep Wakefulness effects of antisense to the a1 receptor in the cholinergic basal forebrain
    The Journal of Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, Stuart Winston, Robert W Mccarley
    Abstract:

    We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged Wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of Wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A1 receptor antisense in the basal forebrain, spontaneous levels of sleep-Wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in Wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2-5 showing a reduction of approximately 50-60%. There was an even greater postdeprivation reduction in delta power (60-75%) and a concomitant increase in Wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.

  • adenosinergic inhibition of basal forebrain Wakefulness active neurons a simultaneous unit recording and microdialysis study in freely behaving cats
    Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, R A Delgiacco, Robert E Strecker, Robert W Mccarley
    Abstract:

    Abstract The majority of neurons in the magnocellular basal forebrain are Wakefulness–active with highest discharge activity during Wakefulness and a marked reduction in activity just before and during the entry to non-rapid eye movement (REM) sleep. We have hypothesized that the reduction of discharge activity of Wakefulness-active neurons and a consequent facilitation of the transition from Wakefulness to sleep is due to an increase in the extracellular concentration of adenosine during Wakefulness. To test the hypothesis, the present study employed microdialysis perfusion of adenosinergic pharmacological agents combined with single unit recording in freely moving cats, so as to determine: 1) if there were dose-dependent effects on behaviorally identified Wakefulness-active neurons; 2) whether effects were mediated by the A1 receptor, as contrasted to the A2a receptor; and 3) if effects were specific to Wakefulness-active neurons, and not present in sleep-active neurons, those preferentially discharging in nonREM sleep. Both adenosine and the A1 receptor-specific agonist N 6-cyclo-hexyl-adenosine reduced the discharge activity of Wakefulness-active neurons ( n =16) in a dose-dependent manner but had no effect on sleep-active neurons ( n =4). The A1 receptor antagonist 8-cyclopentyl-1-3-dimethylxanthine increased the discharge of Wakefulness-active neurons ( n =5), but the A2a receptor agonist, CGS-16284, had no effect ( n =3). Recording sites were histologically localized to the cholinergic basal forebrain. These data support our hypothesis that adenosine acts via the A1 receptor to reduce the activity of Wakefulness-promoting neurons, thus providing a cellular mechanism explaining why the increased adenosine concentrations observed in the basal forebrain following prolonged Wakefulness act to induce sleep.

  • extracellular histamine levels in the feline preoptic anterior hypothalamic area during natural sleep Wakefulness and prolonged Wakefulness an in vivo microdialysis study
    Neuroscience, 2002
    Co-Authors: Robert E Strecker, Mahesh M Thakkar, Julia W Nalwalk, L J Dauphin, Y Chen, Vijaya Ramesh, Lindsay B Hough, Robert W Mccarley
    Abstract:

    Abstract Increased activity of the histaminergic neurons of the posterior hypothalamus has been implicated in the facilitation of behavioral Wakefulness. Recent evidence of reciprocal projections between the sleep-active neurons of the preoptic/anterior hypothalamus and the histaminergic neurons of the tuberomammillary nucleus suggests that histaminergic innervation of the preoptic/anterior hypothalamic area may be of particular importance in the Wakefulness-promoting properties of histamine. To test this possibility, we used microdialysis sample collection in the preoptic/anterior hypothalamic area of cats during natural sleep–Wakefulness cycles, 6 h of sleep deprivation induced by gentle handling/playing, and recovery sleep. Samples were analyzed by a sensitive radioenzymatic assay. Mean basal levels of histamine in microdialysate during periods of Wakefulness (1.155±0.225 pg/μl) did not vary during the 6 h of sleep deprivation. However, during the different sleep states, dramatic changes were observed in the extracellular histamine levels of preoptic/anterior hypothalamic area: Wakefulness>non-rapid eye movement sleep>rapid eye movement sleep. Levels of histamine during rapid eye movement sleep were lowest (0.245±0.032 pg/μl), being significantly lower than levels during non-rapid eye movement sleep (0.395±0.081 pg/μl) and being only 21% of Wakefulness levels. This pattern of preoptic/anterior hypothalamic area extracellular histamine levels across the sleep–Wakefulness cycle closely resembles the reported single unit activity of histaminergic neurons. However, the invariance of histamine levels during sleep deprivation suggests that changes in histamine level do not relay information about sleep drive to the sleep-promoting neurons of the preoptic/anterior hypothalamic area.

Takeshi Sakurai - One of the best experts on this subject based on the ideXlab platform.

  • sleep and Wakefulness are controlled by ventral medial midbrain pons gabaergic neurons in mice
    The Journal of Neuroscience, 2018
    Co-Authors: Yohko Takata, Emi Hasegawa, Takeshi Sakurai, Yoan Cherasse, Yo Oishi, Xuzhao Zhou, Koji Takahashi, Michael Lazarus
    Abstract:

    Sleep/wake behavior is controlled by a wide range of neuronal populations in the mammalian brain. Although the ventral midbrain/pons area is suggested to participate in sleep--wake regulation, the neuronal mechanisms have remained unclear. Here we found that non-specific cell ablation or selective ablation of GABAergic neurons by expressing diphtheria toxin fragment A in the ventral medial midbrain/pons area (VMP) in male mice induced a large increase in Wakefulness that lasted at least 4 weeks. In contrast, selective ablation of dopaminergic neurons in the VMP had little effect on Wakefulness. Chemogenetic inhibition of VMP GABAergic neurons also markedly increased Wakefulness. The wake-promoting effect of the VMP GABAergic neuron ablation or inhibition was attenuated to varying degrees by the administration of dopamine D 1 or D 2/3 receptor antagonists, and abolished by the administration of both antagonists together. In contrast, chemogenetic activation of VMP GABAergic neurons very strongly increased slow-wave sleep and reduced Wakefulness. These findings suggest that VMP GABAergic neurons regulate dopaminergic actions in the sleep/wake behavior of mice. SIGNIFICANCE STATEMENT Current understanding of the neuronal mechanisms and populations that regulate sleep/wake behavior is incomplete. In this paper, we identified a GABAergic ventral midbrain/pons area that is necessary for controlling the daily amount of sleep and Wakefulness in mice. We also found that these inhibitory neurons control Wakefulness by suppressing dopaminergic systems. Surprisingly, activation of these neurons strongly induced slow-wave sleep while suppressing Wakefulness. Our study reveals a new brain mechanism critical for sleep/wake regulation.

  • excitation of gabaergic neurons in the bed nucleus of the stria terminalis triggers immediate transition from non rapid eye movement sleep to Wakefulness in mice
    The Journal of Neuroscience, 2017
    Co-Authors: Shota Kodani, Shingo Soya, Takeshi Sakurai
    Abstract:

    Emotionally salient situations usually trigger arousal along with autonomic and neuroendocrine reactions. To determine whether the extended amygdala plays a role in sleep-Wakefulness regulation, we examined the effects of optogenetic and pharmacogenetic excitation of GABAergic neurons in the bed nucleus of the stria terminalis (GABABNST neurons). Acute optogenetic excitation of these cells during nonrapid eye movement (NREM) sleep resulted in an immediate state transition to Wakefulness, whereas stimulation during REM sleep showed no effect on sleep-Wakefulness states in male mice. An anterograde tracing study suggested GABABNST neurons send axonal projections to several brain regions implicated in arousal, including the preoptic area, lateral hypothalamus, periaqueductal gray, deep mesencephalic nucleus, and parabrachial nucleus. A dual orexin receptor antagonist, DORA-22, did not affect the optogenetic transition from NREM sleep to Wakefulness. Chemogenetic excitation of GABABNST neurons evoked a sustained Wakefulness state, but this arousal effect was markedly attenuated by DORA-22. These observations suggest that GABABNST neurons play an important role in transition from NREM sleep to Wakefulness without the function of orexin neurons, but prolonged excitation of these cells mobilizes the orexin system to sustain Wakefulness.SIGNIFICANCE STATEMENT We examined the role of the bed nucleus of the stria terminalis (BNST) in the regulation of Wakefulness. Optogenetic excitation of GABAergic neurons in the BNST (GABABNST neurons) during nonrapid eye movement (NREM) sleep in mice resulted in immediate transition to a Wakefulness state without function of orexins. Prolonged excitation of GABABNST neurons by a chemogenetic method evoked a longer-lasting, sustained Wakefulness state, which was abolished by preadministration of a dual orexin receptor antagonist, DORA-22. This study revealed a role of the BNST GABAergic system in sleep-Wakefulness control, especially in shifting animals' behavioral states from NREM sleep to Wakefulness, and provides an important insight into the pathophysiology of insomnia and the role of orexin in arousal regulation.

  • orexin neurons suppress narcolepsy via 2 distinct efferent pathways
    Journal of Clinical Investigation, 2014
    Co-Authors: Emi Hasegawa, Takeshi Sakurai, Masashi Yanagisawa, Michihiro Mieda
    Abstract:

    The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of Wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of Wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented Wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/Wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

  • effects of a newly developed potent orexin 2 receptor selective antagonist compound 1 m on sleep Wakefulness states in mice
    Frontiers in Neuroscience, 2014
    Co-Authors: Keishi Etori, Natsuko Tsujino, Yuki Saito, Takeshi Sakurai
    Abstract:

    Orexins (also known as hypocretins), which are hypothalamic neuropeptides, play critical roles in the regulation of sleep/Wakefulness states by activating two G-protein coupled receptors (GPCRs), orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to know the difference between effects of OX2R-selective antagonists (2-SORA) and dual orexin receptor antagonists (DORA), and to understand the mechanisms underlying orexin-mediated regulation of sleep/Wakefulness states, we examined the effects of a newly developed 2-SORA, Compound 1m (C1m), and a DORA, suvorexant, on sleep/Wakefulness states in C57BL/6J mice. After oral administration in the dark period, both C1m and suvorexant exhibited potent sleep-promoting properties with similar efficacy in a dose-dependent manner. While C1m did not increase NREM and REM sleep episode durations, suvorexant induced longer episode durations of NREM and REM sleep as compared with both the vehicle- and C1m-administered groups. When compounds were injected during light period, C1m did not show a significant change in sleep/Wakefulness states in the light period, whereas suvorexant slightly but significantly increased the sleep time. We also found that C1m did not affect the time of REM sleep, while suvorexant markedly increased it. This suggests that although OX1R-mediated pathway plays a pivotal role in promoting Wakefulness, OX1R-mediated pathway also plays an additional role. OX1R-mediated pathway also plays a role in suppression of REM sleep. Fos-immunostaining showed that both compounds affected the activity of arousal-related neurons with different patterns. These results suggest partly overlapping and partly distinct roles of orexin receptors in the regulation of sleep/Wakefulness states.

  • orexin hypocretin receptor agonists and antagonists for treatment of sleep disorders rationale for development and current status
    CNS Drugs, 2013
    Co-Authors: Michihiro Mieda, Takeshi Sakurai
    Abstract:

    Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). They play critical roles in the maintenance of Wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in the regulation of Wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in the maintenance of the Wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, phase III clinical trials were completed last year of suvorexant, a non-selective (dual) antagonist for orexin receptors, for the treatment of primary insomnia, and demonstrate promising results. The New Drug Application (NDA) for suvorexant has been submitted to the US FDA. Thus, the discovery of a critical role played by the orexin system in the regulation of sleep/Wakefulness has opened the door of a new era for sleep medicine.

Helen A Baghdoyan - One of the best experts on this subject based on the ideXlab platform.

  • extrasynaptic gabaa receptors in rat pontine reticular formation increase Wakefulness
    Sleep, 2013
    Co-Authors: Giancarlo Vanini, Helen A Baghdoyan
    Abstract:

    STUDY OBJECTIVES: Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the extracellular space regulate arousal state and cognition by volume transmission via extrasynaptic GABAA receptors. GABAergic transmission in the pontine reticular formation promotes Wakefulness. No previous studies have determined whether an agonist at extrasynaptic GABAA receptors administered into the pontine reticular formation alters sleep and Wakefulness. Therefore, this study used gaboxadol (THIP; agonist at extrasynaptic GABAA receptors that contain a δ subunit) to test the hypothesis that extrasynaptic GABAA receptors within the pontine reticular formation modulate sleep and Wakefulness. DESIGN: Within/between subjects. SETTING: University of Michigan. PATIENTS OR PARTICIPANTS: Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 10). INTERVENTIONS: Microinjection of gaboxadol, the nonsubtype selective GABAA receptor agonist muscimol (positive control), and saline (negative control) into the rostral pontine reticular formation. MEASUREMENTS AND RESULTS: Gaboxadol significantly increased Wakefulness and decreased both nonrapid eye movement sleep and rapid eye movement sleep in a concentration-dependent manner. Relative to saline, gaboxadol did not alter electroencephalogram power. Microinjection of muscimol into the pontine reticular formation of the same rats that received gaboxadol increased Wakefulness and decreased sleep. CONCLUSION: Tonic inhibition via extrasynaptic GABAA receptors that contain a δ subunit may be one mechanism by which the extracellular pool of endogenous GABA in the rostral pontine reticular formation promotes Wakefulness. CITATION: Vanini G; Baghdoyan HA. Extrasynaptic GABAA receptors in rat pontine reticular formation increase Wakefulness. SLEEP 2013;36(3):337-343.

  • sleep duration varies as a function of glutamate and gaba in rat pontine reticular formation
    Journal of Neurochemistry, 2011
    Co-Authors: Chris J Watson, Ralph Lydic, Helen A Baghdoyan
    Abstract:

    Glutamatergic signaling contributes to the regulation of sleep and Wakefulness. In numerous brain regions, levels of glutamate are highest during Wakefulness or rapid eye movement (REM) sleep (Azuma et al. 1996, Dash et al. 2009, John et al. 2008, Kodama & Honda 1999, Kodama et al. 1998, Lena et al. 2005, Lopez-Rodriguez et al. 2007). One exception is the thalamus, where levels of glutamate are highest during non-REM (NREM) sleep (Kekesi et al. 1997). The effects of glutamate receptor agonists on traits of sleep and Wakefulness are dependent on glutamate receptor subtype (Datta et al. 2002, Lai & Siegel 1991), agonist concentration (Datta et al. 2001a, Datta et al. 2001b), and brain region (Boissard et al. 2002, Cape & Jones 2000, Pal & Mallick 2009, Wigren et al. 2007, Alam & Mallick 1994). The oral part of the pontine reticular formation (PnO) is a component of the ascending reticular activating system and plays a role in sleep cycle control (Brown et al. 2010). The PnO receives glutamatergic projections from the amygdala (Fung et al. 2011), the laterodorsal tegmental and pedunculopontine tegmental nuclei (Lai et al. 1993), and data from immunohistochemical studies suggest that the PnO contains glutamatergic neurons (Kaneko et al. 1989). Administration of glutamate receptor agonists into the PnO excites PnO neurons in cat (Greene & Carpenter 1985) and rat (Stevens et al. 1992), indicating that functional glutamatergic signaling occurs within the PnO. GABAergic signaling also regulates sleep and Wakefulness. Dependent upon brain region, levels of endogenous GABA are highest during REM sleep (Nitz & Siegel 1997a, Nitz & Siegel 1997b), NREM sleep (Kekesi et al. 1997, Nitz & Siegel 1996), or Wakefulness (Kekesi et al. 1997, Vanini et al. 2011). GABAergic signaling also causes an increase in Wakefulness (Mallick et al. 2001) or REM sleep (Mallick et al. 2001, Nitz & Siegel 1997a, Pal & Mallick 2009, Vanini et al. 2007) in a brain-region dependent manner. Within the PnO, GABA promotes Wakefulness and inhibits REM sleep (Camacho-Arroyo et al. 1991, Flint et al. 2010, Xi et al. 1999, Watson et al. 2008, Marks et al. 2008, Sanford et al. 2003). GABAergic projection neurons from the thalamus, hypothalamus, basal forebrain, and ventral lateral periaqueductal gray terminate in the PnO (Rodrigo-Angulo et al. 2008, Boissard et al. 2003, Sapin et al. 2009). Each of these brain regions regulates sleep and Wakefulness. The rostral brainstem also contains a column of GABAergic neurons that connects both sides of the PnO, and these neurons may modulate sleep and Wakefulness (Liang & Marks 2009). Measuring levels of glutamate and GABA across states of sleep and Wakefulness presents an analytical challenge due to the short duration of rodent sleep episodes and analytical methods that require relatively large sample volumes (3 – 10 μL). To overcome these limitations, the present experiments took advantage of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF), which has the capacity to rapidly measure analytes from small sample volumes. With the use of in vivo microdialysis coupled on-line to CE-LIF, the present study measured concentrations of glutamate, GABA, aspartate, taurine, serine, and glycine. These measures were used to test the hypothesis that concentrations of glutamate and GABA in rat PnO vary significantly across states of Wakefulness, NREM sleep, and REM sleep. Concentrations of aspartate, taurine, serine, and glycine were not predicted to show state specific changes, as there is no existing evidence that any of these amino acids functions in the pontine reticular formation to modulate sleep and Wakefulness.

  • endogenous gaba levels in the pontine reticular formation are greater during Wakefulness than during rapid eye movement sleep
    The Journal of Neuroscience, 2011
    Co-Authors: Giancarlo Vanini, Ralph Lydic, Bradley L Wathen, Helen A Baghdoyan
    Abstract:

    Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes Wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during Wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and Wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during Wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during Wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REMNeo) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and Wakefulness, and decreased significantly below waking levels during REM sleep (−42%) and REMNeo (−63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared with NREM sleep, GABA levels decreased significantly during REM sleep (−27%) and REMNeo (−52%). Comparisons of REM sleep and REMNeo revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep.

  • hypocretin and gaba interact in the pontine reticular formation to increase Wakefulness
    Sleep, 2010
    Co-Authors: Holly Brevig, Chris J Watson, Ralph Lydic, Helen A Baghdoyan
    Abstract:

    THE NEUROPEPTIDES HYPOCRETIN-1 AND HYPOCRETIN-2 (OREXIN A AND OREXIN B) ARE SYNTHESIZED EXCLUSIVELY BY NEURONS IN THE LATERAL hypothalamic area.1–3 Hypocretin deficiency in humans underlies the pathophysiology of narcolepsy,4,5 and disruption of hypocretin signaling in mouse,6 rat,7,8 and dog9 leads to narcolepsy-cataplexy. Hypocretinergic neurons project to multiple areas of the brain, including those important for regulating sleep and Wakefulness.1 One such area is the pontine reticular nucleus, oral part (PnO).1,10 The PnO is the rostral portion of the rodent pontine reticular formation11 and contributes to the generation of Wakefulness and rapid eye movement (REM) sleep.12 Microinjection of hypocretin-1 into rat PnO causes an increase in Wakefulness,13 and microinjection of hypocretin-1 into cat pontine reticular formation increases the cortically activated states of REM sleep14 or Wakefulness.15,16 Administering hypocretin-1 into the PnO may increase Wakefulness by modulating the release of arousal-promoting neurotransmitters within the PnO. Direct administration of hypocretin-1 to the PnO of isoflurane-anesthetized rat causes a concentration-dependent increase in both acetylcholine (ACh) release17 and GABA levels13 within the PnO. Extracellular recording studies of PnO neurons in urethane-anesthetized rat show that iontophoretic application of hypocretin-1 causes a hyperpolarization that is blocked by prior application of bicuculline.10 This finding indicates that the hypocretin-1–induced inhibition of PnO neurons is mediated by GABAA receptors. Identified GABAergic neurons in brainstem slices of mouse PnO have been shown to be excited by hypocretin-1,18 and intracellular recording studies in halothane-anesthetized cat show that hypocretin-1 can also cause direct depolarization of PnO neurons and an increase in PnO neuronal firing rate.14 Numerous studies have demonstrated that GABAergic transmission in the PnO increases Wakefulness and inhibits REM sleep.13,19–25 The present study provides the first test of the hypothesis that the Wakefulness-promoting effects of delivering hypocretin-1 into the PnO are mediated by GABAA receptors as well as by hypocretin receptors. This hypothesis was evaluated by determining whether (1) microinjection of hypocretin-1 into the PnO causes a concentration-dependent increase in Wakefulness, (2) this increase in Wakefulness is blocked by coadministration of the hypocretin receptor-1 (hcrt-r1) antagonist SB-334867, and (3) coadministration of the GABAA receptor antagonist bicuculline also blocks the Wakefulness response to hypocretin-1. Portions of these data have been presented as abstracts.26,27

  • gabaa receptors in the pontine reticular formation of c57bl 6j mouse modulate neurochemical electrographic and behavioral phenotypes of Wakefulness
    The Journal of Neuroscience, 2010
    Co-Authors: Rashonda R Flint, Ralph Lydic, Theresa Chang, Helen A Baghdoyan
    Abstract:

    Drugs that potentiate transmission at GABA A receptors are widely used to enhance sleep and to cause general anesthesia. The mechanisms underlying these effects are unknown. This study tested the hypothesis that GABA A receptors in the pontine reticular nucleus, oral part (PnO) of mouse modulate five phenotypes of arousal: sleep and Wakefulness, cortical electroencephalogram (EEG) activity, acetylcholine (ACh) release in the PnO, breathing, and recovery time from general anesthesia. Microinjections into the PnO of saline (vehicle control), the GABA A receptor agonist muscimol, muscimol with the GABA A receptor antagonist bicuculline, and bicuculline alone were performed in male C57BL/6J mice ( n = 33) implanted with EEG recording electrodes. Muscimol caused a significant increase in Wakefulness and decrease in rapid eye movement (REM) and non-REM (NREM) sleep. These effects were reversed by coadministration of bicuculline. Bicuculline administered alone caused a significant decrease in Wakefulness and increase in NREM sleep and REM sleep. Muscimol significantly increased EEG power in the delta range (0.5–4 Hz) during Wakefulness and in the theta range (4–9 Hz) during REM sleep. Dialysis delivery of bicuculline to the PnO of male mice ( n = 18) anesthetized with isoflurane significantly increased ACh release in the PnO, decreased breathing rate, and increased anesthesia recovery time. All drug effects were concentration dependent. The effects on phenotypes of arousal support the conclusion that GABA A receptors in the PnO promote Wakefulness and suggest that increasing GABAergic transmission in the PnO may be one mechanism underlying the phenomenon of paradoxical behavioral activation by some benzodiazepines.

Mahesh M Thakkar - One of the best experts on this subject based on the ideXlab platform.

  • histamine in the regulation of Wakefulness
    Sleep Medicine Reviews, 2011
    Co-Authors: Mahesh M Thakkar
    Abstract:

    The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H1 and/or H3 receptor has a pivotal role in the regulation of sleep-Wakefulness. Administration of histamine or H1 receptor agonists induced Wakefulness, whereas administration of H1 receptor antagonists promoted sleep. The H3 receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H3 receptor decreased histamine release and promoted sleep. Conversely, blockade of H3 receptor promoted Wakefulness. Histamine release in the hypothalamus and other target regions was highest during Wakefulness. The histaminergic neurons displayed maximal activity during the state of vigilance, and cease their activity during NREM and REM sleep. The cerebrospinal levels of histamine were reduced in diseased states where hypersomnolence was a major symptom. The histamine deficient HDC KO mice displayed sleep fragmentation and increased REM sleep during the light period along with profound Wakefulness deficit at dark onset, and in novel environment. Similar results were obtained when histamine neurons were lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during Wakefulness.

  • adenosine and the homeostatic control of sleep effects of a1 receptor blockade in the perifornical lateral hypothalamus on sleep Wakefulness
    Neuroscience, 2008
    Co-Authors: Mahesh M Thakkar, Samuel C Engemann, K M Walsh, Pradeep Sahota
    Abstract:

    Abstract The orexinergic neurons of the lateral hypothalamus (LH) are critical for Wakefulness [McCarley RW (2007) Neurobiology of REM and NREM sleep. Sleep Med 8:302–330]. Recent evidence suggests that adenosine (AD), a homeostatic sleep factor, may act via A1 receptor (A1R) to control orexinergic activity and regulate sleep–Wakefulness [Thakkar MM, Winston S, McCarley RW (2002) Orexin neurons of the hypothalamus express adenosine A1 receptors. Brain Res 944:190–194; Liu ZW, Gao XB (2006) Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol]. To evaluate the role of AD in the orexinergic LH and its influences on sleep–Wakefulness, we designed two experiments in freely behaving rats: First, we bilaterally microinjected 1,3-dipropyl-8-phenylxanthine (DPX) (1.5 pmol and 15 pmol), a selective A1R antagonist into the LH during the light cycle and examined its effect on spontaneous sleep–Wakefulness. Second, we performed 6 h of sleep deprivation. Thirty minutes before the animals were allowed to enter recovery sleep, 15 pmol of DPX was bilaterally microinjected into the LH and its effects on recovery sleep were monitored. Microinjection of DPX into the orexinergic LH produced a significant increase in Wakefulness with a concomitant reduction in sleep, both during spontaneous bouts of sleep–Wakefulness and during recovery sleep. Local administration of DPX into the LH produced a significant increase in the latency to non-REM sleep during recovery sleep. However, total slow wave (delta) activity during non-REM sleep phase of recovery sleep remained unaffected after DPX treatment. This is the first study that implicates endogenous adenosine to have a functional role in controlling orexinergic tone and influencing the homeostatic regulation of sleep–Wakefulness.

  • a1 receptor and adenosinergic homeostatic regulation of sleep Wakefulness effects of antisense to the a1 receptor in the cholinergic basal forebrain
    The Journal of Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, Stuart Winston, Robert W Mccarley
    Abstract:

    We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged Wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of Wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A1 receptor antisense in the basal forebrain, spontaneous levels of sleep-Wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in Wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2–5 showing a reduction of ∼50–60%. There was an even greater postdeprivation reduction in delta power (60–75%) and a concomitant increase in Wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.

  • a1 receptor and adenosinergic homeostatic regulation of sleep Wakefulness effects of antisense to the a1 receptor in the cholinergic basal forebrain
    The Journal of Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, Stuart Winston, Robert W Mccarley
    Abstract:

    We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged Wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of Wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. After microdialysis perfusion of A1 receptor antisense in the basal forebrain, spontaneous levels of sleep-Wakefulness showed a significant reduction in non-rapid eye movement (REM) sleep with an increase in Wakefulness. After 6 hr of sleep deprivation, the antisense-treated animals spent a significantly reduced amount of time in non-REM sleep, with postdeprivation recovery sleep hours 2-5 showing a reduction of approximately 50-60%. There was an even greater postdeprivation reduction in delta power (60-75%) and a concomitant increase in Wakefulness. All behavioral state changes returned to control (baseline) values after the cessation of antisense administration. Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.

  • adenosinergic inhibition of basal forebrain Wakefulness active neurons a simultaneous unit recording and microdialysis study in freely behaving cats
    Neuroscience, 2003
    Co-Authors: Mahesh M Thakkar, R A Delgiacco, Robert E Strecker, Robert W Mccarley
    Abstract:

    Abstract The majority of neurons in the magnocellular basal forebrain are Wakefulness–active with highest discharge activity during Wakefulness and a marked reduction in activity just before and during the entry to non-rapid eye movement (REM) sleep. We have hypothesized that the reduction of discharge activity of Wakefulness-active neurons and a consequent facilitation of the transition from Wakefulness to sleep is due to an increase in the extracellular concentration of adenosine during Wakefulness. To test the hypothesis, the present study employed microdialysis perfusion of adenosinergic pharmacological agents combined with single unit recording in freely moving cats, so as to determine: 1) if there were dose-dependent effects on behaviorally identified Wakefulness-active neurons; 2) whether effects were mediated by the A1 receptor, as contrasted to the A2a receptor; and 3) if effects were specific to Wakefulness-active neurons, and not present in sleep-active neurons, those preferentially discharging in nonREM sleep. Both adenosine and the A1 receptor-specific agonist N 6-cyclo-hexyl-adenosine reduced the discharge activity of Wakefulness-active neurons ( n =16) in a dose-dependent manner but had no effect on sleep-active neurons ( n =4). The A1 receptor antagonist 8-cyclopentyl-1-3-dimethylxanthine increased the discharge of Wakefulness-active neurons ( n =5), but the A2a receptor agonist, CGS-16284, had no effect ( n =3). Recording sites were histologically localized to the cholinergic basal forebrain. These data support our hypothesis that adenosine acts via the A1 receptor to reduce the activity of Wakefulness-promoting neurons, thus providing a cellular mechanism explaining why the increased adenosine concentrations observed in the basal forebrain following prolonged Wakefulness act to induce sleep.

Zhili Huang - One of the best experts on this subject based on the ideXlab platform.

  • Medial Parabrachial Nucleus Is Essential in Controlling Wakefulness in Rats
    Frontiers in Neuroscience, 2021
    Co-Authors: Dian-ru Wang, Hui Dong, Li Chen, Michael Lazarus, Yoan Cherasse, Gui-hai Chen, Zhili Huang
    Abstract:

    Activation of the parabrachial nucleus (PB) in the brainstem induced Wakefulness in rats, suggesting which is an important nucleus that controls arousal. However, the sub-regions of PB in regulating sleep-wake cycle is still unclear. Here, we employ chemogenetics and optogenetics strategies and find that activation of the medial part of PB (MPB), but not the lateral part, induces continuous Wakefulness for 10 h without sleep rebound in neither sleep amount nor the power spectra. Optogenetic activation of glutamatergic MPB neurons in sleeping rats immediately wake rats mediated by the basal forebrain (BF) and lateral hypothalamus (LH), but not the ventral medial thalamus. Most importantly, chemogenetic inhibition of PB neurons decreases Wakefulness for 10 h. Conclusively, these findings indicate that the glutamatergic MPB neurons are essential in controlling Wakefulness, and that MPB-BF and MPB-LH pathways are the major neuronal circuits.

  • nucleus accumbens controls Wakefulness by a subpopulation of neurons expressing dopamine d 1 receptors
    Nature Communications, 2018
    Co-Authors: Yanjia Luo, Michael Lazarus, Yoan Cherasse, Jiangfan Chen, Lu Wang, Surong Yang, Xiangshan Yuan, Juan Wang, Zhili Huang
    Abstract:

    Nucleus accumbens (NAc) is involved in behaviors that depend on heightened Wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D1 receptor (D1R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D1R neurons. Optogenetic activation of NAc D1R neurons induces immediate transitions from non-rapid eye movement sleep to Wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D1R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce Wakefulness. Silencing of NAc D1R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D1R neuron circuits are essential for the induction and maintenance of Wakefulness.

  • role of the basal ganglia in the control of sleep and Wakefulness
    Current Opinion in Neurobiology, 2013
    Co-Authors: Michael Lazarus, Yoshihiro Urade, Zhili Huang, Jiangfan Chen
    Abstract:

    The basal ganglia (BG) act as a cohesive functional unit that regulates motor function, habit formation, and reward/addictive behaviors, but the debate has only recently started on how the BG maintain Wakefulness and suppress sleep to achieve all these fundamental functions of the BG. Neurotoxic lesioning, pharmacological approaches, and the behavioral analyses of genetically modified animals revealed that the striatum and globus pallidus are important for the control of sleep and Wakefulness. Here, we discuss anatomical and molecular mechanisms for sleep–wake regulation in the BG and propose a plausible model in which the nucleus accumbens integrates behavioral processes with Wakefulness through adenosine and dopamine receptors.

  • dopaminergic d1 and d2 receptors are essential for the arousal effect of modafinil
    The Journal of Neuroscience, 2008
    Co-Authors: Weimin Qu, Xinhong Xu, Naomi Matsumoto, Zhili Huang, Yoshihiro Urade
    Abstract:

    Modafinil is a wake-promoting compound with low abuse potential used in the treatment of narcolepsy. Although the compound is reported to affect multiple neurotransmitter systems such as catecholamines, serotonin, glutamate, GABA, orexin, and histamine, however, the molecular mechanism by which modafinil increases Wakefulness is debated. Herein we used dopamine (DA) D 2 receptor (D 2 R)-deficient mice combined with D 1 R- and D 2 R-specific antagonists to clarify the role of DA receptors in the arousal effects of modafinil. In wild-type mice, intraperitoneal modafinil induced Wakefulness in a dose-dependent manner. Pretreatment with either D 1 R antagonist SCH23390 [ R -(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine] at 30 μg/kg or D 2 R antagonist raclopride at 2 mg/kg blocked the arousal effects of low-dose modafinil at 22.5 and 45 mg/kg. When modafinil was given at 90 and 180 mg/kg, pretreatment of D 1 R antagonist did not affect the Wakefulness at all, whereas D 2 R antagonist significantly attenuated the Wakefulness to the half level compared with vehicle control. Similarly, D 2 R knock-out (KO) mice exhibited attenuated modafinil-induced Wakefulness. However, pretreatment of D 2 R KO mice with D 1 R antagonist completely abolished arousal effects of modafinil. These findings strongly indicate that dopaminergic D 1 R and D 2 R are essential for the Wakefulness induced by modafinil.

  • altered sleep wake characteristics and lack of arousal response to h3 receptor antagonist in histamine h1 receptor knockout mice
    Proceedings of the National Academy of Sciences of the United States of America, 2006
    Co-Authors: Zhili Huang, Zongyuan Hong, Takatoshi Mochizuki, Yoshihiro Urade, Weimin Qu, Takeshi Watanabe, Osamu Hayaishi
    Abstract:

    Abstract Histaminergic neurons play an important role in the regulation of sleep–wake behavior through histamine H1 receptors (H1R). Blockade of the histamine H3 receptor (H3R) is proposed to induce Wakefulness by regulating the release of various wake-related transmitters, not only histamine. In the present study, we characterized sleep–wake cycles of H1R knockout (KO) mice and their arousal responses to an H3R antagonist. Under baseline conditions, H1R KO mice showed sleep–wake cycles essentially identical to those of WT mice but with fewer incidents of brief awakening (<16-sec epoch), prolonged durations of non-rapid eye movement (NREM) sleep episodes, a decreased number of state transitions between NREM sleep and Wakefulness, and a shorter latency for initiating NREM sleep after an i.p. injection of saline. The H1R antagonist pyrilamine mimicked these effects in WT mice. When an H3R antagonist, ciproxifan, was administered i.p., Wakefulness increased in WT mice in a dose-dependent manner but did not increase at all in H1R KO mice. In vivo microdialysis revealed that the i.p. application of ciproxifan increased histamine release from the frontal cortex in both genotypes of mice. These results indicate that H1R is involved in the regulation of behavioral state transitions from NREM sleep to Wakefulness and that the arousal effect of the H3R antagonist completely depends on the activation of histaminergic systems through H1R. brief awakening ciproxifan microdialysis pyrilamine Wakefulness

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