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ABSTRACT: Ghrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin-sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake-promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep-promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep-wake activity between ghrelin receptor KO and wild-type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin-receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep-promoting mechanisms.
European Journal of Neuroscience 12/2011; 35(2):233-43. · 3.63 Impact Factor
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ABSTRACT: Grizzly bears (Ursus arctos horribilis) are inactive for up to 6 months during hibernation. They undergo profound seasonal changes in food intake, body mass, and energy expenditure. The circa-annual regulation of metabolism is poorly understood. In this study, we measured plasma ghrelin, leptin, obestatin, and neuropeptide-Y (NPY) levels, hormones known to be involved in the regulation of energy homeostasis, in ten grizzly bears. Blood samples were collected during the active summer period, early hibernation and late hibernation. Plasma levels of leptin, obestatin, and NPY did not change between the active and the hibernation periods. Plasma total ghrelin and desacyl-ghrelin concentrations significantly decreased during the inactive winter period compared to summer levels. The elevated ghrelin levels may help enhance body mass during pre-hibernation, while the low plasma ghrelin concentrations during hibernation season may contribute to the maintenance of hypophagia, low energy utilization and behavioral inactivity. Our results suggest that ghrelin plays a potential role in the regulation of metabolic changes and energy homeostasis during hibernation in grizzly bears.
General and Comparative Endocrinology 12/2010; 172(1):181-3. · 3.27 Impact Factor
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ABSTRACT: Behavioral and physiological rhythms can be entrained by daily restricted feeding (RF), indicating the existence of a food-entrainable oscillator (FEO). One manifestation of the presence of FEO is anticipatory activity to regularly scheduled feeding. In the present study, we tested if intact ghrelin signaling is required for FEO function by studying food anticipatory activity (FAA) in preproghrelin knockout (KO) and wild-type (WT) mice. Sleep-wake activity, locomotor activity, body temperature, food intake, and body weight were measured for 12 days in mice on a RF paradigm with food available only for 4 h daily during the light phase. On RF days 1-3, increases in arousal occurred. This response was significantly attenuated in preproghrelin KO mice. There were progressive changes in sleep architecture and body temperature during the subsequent nine RF days. Sleep increased at night and decreased during the light periods while the total daily amount of sleep remained at baseline levels in both KO and WT mice. Body temperature fell during the dark but was elevated during and after feeding in the light. In the premeal hours, anticipatory increases in body temperature, locomotor activity, and wakefulness were present from RF day 6 in both groups. Results indicate that the preproghrelin gene is not required for the manifestation of FAA but suggest a role for ghrelinergic mechanisms in food deprivation-induced arousal in mice.
AJP Regulatory Integrative and Comparative Physiology 11/2009; 298(2):R467-77. · 3.34 Impact Factor
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ABSTRACT: Certain sickness behaviors occur consistently in influenza-infected humans and mice. These include body temperature changes, somnolence, and anorexia. Several cytokines serve as mediators of the influenza acute phase response (APR), including these sickness behaviors, and one likely inducer of these cytokines is dsRNA produced during viral replication. TLR3 is known to be one of the host cellular components capable of recognizing dsRNA and activating cytokine synthesis. To determine the role of TLR3-detected viral dsRNA in the causation of viral symptoms, TLR3-deficient mice (TLR3 knockouts, or KOs) were infected with a marginally-lethal dose of mouse-adapted X-31 influenza virus. TLR3 KOs and their wild-type (WT) controls were monitored for baseline body temperature, locomotor activity, and sleep profiles prior to infection. Both mouse strains were then infected and monitored for changes in these sickness behaviors plus body weight changes and mortality for up to 14days post-infection. Consistent with the observations that influenza pathology is reduced in TLR3 KOs, we showed that hypothermia after post-infection day 5 and the total loss of body weight were attenuated in the TLR3 KOs. Sleep changes characteristic of this infection model [particularly increased non-rapid-eye-movement sleep (NREMS)] were also attenuated in TLR3 KOs and returned to baseline values more rapidly. Locomotor activity suppression was similar in both strains. Therefore virus-associated dsRNA detected by TLR3 appears to play a substantial role in mediating several aspects of the influenza syndrome in mice.
Brain Behavior and Immunity 10/2009; 24(2):306-15. · 4.72 Impact Factor
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ABSTRACT: Peptidergic mechanisms controlling feeding, metabolism, thermoregulation, and sleep overlap in the hypothalamus. Low ambient temperatures and food restriction induce hypothermic (torpor) bouts and characteristic metabolic and sleep changes in mice. We report that mice lacking the preproghrelin gene, but not those lacking the ghrelin receptor, have impaired abilities to manifest and integrate normal sleep and thermoregulatory responses to metabolic challenges. In response to fasting at 17 degrees C (a subthermoneutral ambient temperature), preproghrelin knockout mice enter hypothermic bouts associated with reduced sleep, culminating in a marked drop in body temperature to near-ambient levels. Prior treatment with obestatin, another preproghrelin gene product, attenuates the hypothermic response of preproghrelin knockout mice. Results suggest that obestatin is a component in the coordinated regulation of metabolism and sleep during torpor.
Proceedings of the National Academy of Sciences 09/2009; 106(33):14069-74. · 9.68 Impact Factor
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ABSTRACT: Familial dysautonomia (FD) is an inherited, fatal, neurodegenerative disorder manifested by autonomic/hypertensive crises and cardiac instability. Patients produce little IKAP, the gene product of the affected mutated gene, and have low levels of monoamine oxidase A (MAO A), whose reduced presence appears to result in an increased accumulation of biogenic amines, which is a trigger for hypertensive crises. As ingestion of tocotrienols elevates IKAP and MAO A in FD patients, we examined their impact on the frequency of hypertensive crises and cardiac function. After 3 to 4 months of tocotrienol ingestion, approximately 80% of patients reported a significant (> or = 50%) decrease in the number of crises. In a smaller group of patients, a postexercise increase in heart rate and a decrease in the QT interval were observed in the majority of participants. Based on these findings, we hypothesize that tocotrienol therapy will improve the long-term clinical outlook and survival of individuals with FD.
Antioxidants and Redox Signaling 04/2008; 10(4):837-41. · 8.46 Impact Factor
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ABSTRACT: Ghrelin is well known for its feeding and growth hormone-releasing actions. It may also be involved in sleep regulation; intracerebroventricular administration and hypothalamic microinjections of ghrelin stimulate wakefulness in rats. Hypothalamic ghrelin, together with neuropeptide Y and orexin form a food intake-regulatory circuit. We hypothesized that this circuit also promotes arousal. To further investigate the role of ghrelin in the regulation of sleep-wakefulness, we characterized spontaneous and homeostatic sleep regulation in ghrelin knockout (KO) and wild-type (WT) mice. Both groups of mice exhibited similar diurnal rhythms with more sleep and less wakefulness during the light period. In ghrelin KO mice, spontaneous wakefulness and rapid-eye-movement sleep (REMS) were slightly elevated, and non-rapid-eye-movement sleep (NREMS) was reduced. KO mice had more fragmented NREMS than WT mice, as indicated by the shorter and greater number of NREMS episodes. Six hours of sleep deprivation induced rebound increases in NREMS and REMS and biphasic changes in electroencephalographic slow-wave activity (EEG SWA) in both genotypes. Ghrelin KO mice recovered from NREMS and REMS loss faster, and the delayed reduction in EEG SWA, occurring after sleep loss-enhanced increases in EEG SWA, was shorter-lasting compared with WT mice. These findings suggest that the basic sleep-wake regulatory mechanisms in ghrelin KO mice are not impaired and they are able to mount adequate rebound sleep in response to a homeostatic challenge. It is possible that redundancy in the arousal systems of the brain or activation of compensatory mechanisms during development allow for normal sleep-wake regulation in ghrelin KO mice.
AJP Regulatory Integrative and Comparative Physiology 08/2007; 293(1):R510-7. · 3.34 Impact Factor
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ABSTRACT: Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 mug (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.
AJP Regulatory Integrative and Comparative Physiology 02/2007; 292(1):R575-85. · 3.34 Impact Factor
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ABSTRACT: Previous studies suggest that nitric oxide (NO) may play a role in sleep regulation, particularly in the homeostatic process. The present studies were undertaken to compare the sleep effects of injecting a NO synthase (NOS) inhibitor when homeostatic sleep pressure is naturally highest (light onset) or when it is at its nadir (dark onset) in rats. Sleep, electroencephalogram delta-wave activity during nonrapid eye movement sleep (NREMS), also known as slow-wave activity (SWA), and brain temperature responses to three doses of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME ; 5, 50, and 100 mg/kg) injected intraperitoneally at light or dark onset were examined in rats (n = 6 to 8). The effects of 5 mg/kg L-NAME were determined in both normal and vagotomized (VX) rats. Light onset administration of 50 mg/kg L-NAME decreased NREMS amounts and suppressed SWA and increased rapid eye movement sleep (REMS) amounts. At dark onset, L-NAME injection also dose dependently suppressed SWA; however, unlike light onset injections, both NREMS and REMS amounts were increased after all three doses. Sleep responses to 5 mg/kg L-NAME were not different in control and VX rats, suggesting that the sleep effects of L-NAME are not mediated through the activation of sensory vagal mechanisms. The present findings suggest that timing of the injection is a major determinant of the sleep responses observed after systemic L-NAME injection in rats.
AJP Regulatory Integrative and Comparative Physiology 09/2005; 289(2):R521-R531. · 3.34 Impact Factor
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ABSTRACT: Cyclic GMP is the second messenger that mediates most of the neuronal effects of nitric oxide (NO). Several lines of evidence suggest that NO-ergic mechanisms play an integral role in the regulation of vigilance. In the present study, we tested the effects of the activation of cGMP-receptive mechanisms and the inhibitor of guanylyl cyclase (GC), LY-83,583, on sleep in rats. Rats were injected intracerebroventricularly (icv) with 0.16, 4, 100, and 500 microg or 2.5 mg 8-Br-cGMP, a membrane-permeable analogue of cGMP, or 1 and 100 microg LY-83,583. Administration of 4 microg-2.5 mg 8-Br-cGMP increased wakefulness and suppressed rapid-eye-movement sleep (REMS) and non-REMS (NREMS) in rats when given before dark onset but not when given before the light period. The GC inhibitor LY-83,583 strongly promoted NREMS and suppressed REMS during the light period of the day. Furthermore, LY-83,583 induced striking increases in the delta-wave activity of the electroencephalogram (EEG) during NREMS, whereas EEG activity above the 4.5 Hz wave range was suppressed in all vigilance states. Our finding that cGMP has an arousal-promoting activity is in line with the hypothesis that NO/cGMP signaling pathway is involved in the regulation of vigilance.
Brain Research 08/2005; 1049(1):25-33. · 2.73 Impact Factor
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ABSTRACT: The purpose of the present study was to determine the effects of restricting food and water intake to the light period on sleep and brain temperature (Tbr). Sprague–Dawley male rats were anesthetized and provided with electrodes and thermistors for electroencephalographic (EEG) and Tbr recordings. Baseline recordings were performed after a 3-week recovery period. After baseline recordings, access to food and water was restricted (FWR) to the light period for 29 days. During FWR, the diurnal distribution of rapid-eye-movement sleep (REMS) and Tbr were reversed, while the distribution of non-REMS (NREMS) between the dark and light periods was attenuated. Daily food and water intake, body weight, and the diurnal distribution of EEG slow-wave activity within NREMS remained unchanged. In a separate study, sham-operated and pinealectomized rats were studied in a similar manner. The sleep responses of pinealectomized and sham-operated rats to FWR were similar. Further, FWR did not affect melatonin levels in the sham-operated rats, thereby suggesting that the pineal gland does not mediate the effects of FWR on sleep.
Physiology & Behavior 12/1999; · 2.87 Impact Factor
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ABSTRACT: Previous findings indicate that nitric oxide (NO) may play a role in the regulation of sleep-wake activity. In rabbits, blocking the production of endogenous NO by a nitric oxide synthase inhibitor, Nω-nitro-l-arginine (l-NAME) suppresses spontaneous sleep and interferes the somnogenic actions of interleukin 1. In the present experiments we extended our earlier work by studying the long-term effects of l-NAME treatment on sleep-wake activity including power spectra analyses of the electroencephalogram (EEG) in rats. Rats implanted with EEG electrodes, brain thermistor, and intracerebroventricular (i.c.v.) guide cannula were injected i.c.v. with vehicle or 0.2, 1, or 5 mg l-NAME at light onset. In separate experiments, rats were injected intraperitoneally (i.p.) with l-NAME three times (50, 50, 100 mg/kg), 12-12 h apart. Both i.c.v. and i.p. injections of l-NAME elicited decreases in time spent in NREMS and REMS. After i.c.v. injection of 5 mg l-NAME the sleep responses were long-lasting; NREMS did not return to baseline even 72 h after injection. EEG delta-wave activity during NREMS (slow wave activity) was also suppressed after 0.2 and 5 mg l-NAME. Brain temperature was slightly increased after the two lower doses of l-NAME, whereas there was a transient decrease in Tbr after 5 mg l-NAME. Acute i.p. injection of 50 mg/kg l-NAME elicited an immediate decrease in NREMS which lasted for ∼ 2 h. The second injection of 50 mg/kg l-NAME and the following injection of 100 mg/kg l-NAME induced biphasic decreases in NREMS but not REMS. These results are in accordance with our earlier observations that inhibition of nitric oxide synthesis suppresses spontaneous sleep and are consistent with the hypothesis that NO is involved in the maintenance of normal sleep-wake activity.
Brain Research 12/1994; · 2.73 Impact Factor
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ABSTRACT: Hypothalamic growth hormone-releasing hormone (GHRH) is one of the key neurohumoral regulators of non-rapid eye movement sleep. The focus of the present paper is the role of GHRH in the regulation of sleep and body temperature in the context of a larger biochemical regulatory network. This network includes other members of the somatotopic axis such as growth hormone, insulin-like growth factor-1, somatostatin and ghrelin and members of the cytokine family such as interleukin-1.
Journal of Thermal Biology 31:30-39. · 1.37 Impact Factor
