Biomedical subjects

James M Krueger

Publications and source records attributed to James M Krueger.

16 recordsLinked to original sources

PubMed2003

Intracerebroventricular injection of erythropoietin enhances sleep in the rat.

Systemic injection of erythropoietin (EPO) over several days reduces sleep fragmentation in patients with periodic limb movements in sleep (PLMS). However, there are no studies concerning the effects of EPO on spontaneous sleep. In this study, we determined the effects of intracerebroventricular (i.c.v.) administration of EPO on spontaneous rat sleep. Three doses of EPO (25, 75, and 125 ng) were injected i.c.v. at the onset of the dark period. All doses of EPO increased non-rapid eye movement sleep (NREMS). In addition, high and low doses of EPO (125 and 25 ng) increased rapid eye movement sleep (REMS), but the medium dose of EPO (75 ng) inhibited REMS. Electroencephalogram slow-wave activity during NREMS also increased following the two higher doses of EPO. In contrast, EPO injection during the light period failed to affect sleep. Brain temperature (Tbr) was not affected by any dose of EPO. These results suggest that EPO could be part of the cytokine network involved in sleep regulation.

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PubMed2003

Tumor necrosis factor alpha increases cytosolic calcium responses to AMPA and KCl in primary cultures of rat hippocampal neurons.

Acute behavioral effects of tumor necrosis factor alpha (TNFalpha) have been previously reported, however the cellular basis for these actions are unknown. To address this issue we examined the effects of TNFalpha on AMPA- and depolarization-induced changes in cytosolic Ca(2+) in cultured hippocampal neurons. Single cell Ca(2+) levels were determined with the fluorescent calcium indicator fura-2. TNFalpha caused an up-regulation of AMPA (10 microM)- and depolarization (55 mM KCl)-induced Ca(2+) responses. This effect occurred within a window of concentrations (1 and 10 ng/ml but not 0.1 or 100 ng/ml) and times (3 and 6 h but not 1 and 24 h). The effect was dependent upon protein synthesis (blocked by cycloheximide) and was prevented by the soluble TNF receptor and by a soluble TNF receptor fragment. Treatment with the soluble TNF receptor fragment also caused a decrease in the basal response. The TNFalpha treatment protocols did not appear to produce any toxicity to the neurons. Results are consistent with the hypothesis that TNFalpha regulates proteins known to be involved in neuronal communication (AMPA receptors) and cell regulation (voltage-dependent calcium channels) in a relatively rapid period of time (a few hours). These actions may be related to the behavioral effects produced by TNFalpha that occur within this time frame.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Neurotrophins 3 and 4 enhance non-rapid eye movement sleep in rabbits.

We determined if neurotrophins 3 and 4 (NT-3, NT-4) would promote sleep in rabbits. Two doses of NT-3 (50 and 500 ng) and three doses of NT-4 (50, 500 and 2000 ng) were intracerebroventricularly injected at dark onset. Additionally, 500 ng of each NT were injected during the light period. The electroencephalogram (EEG), brain temperature, and motor activity were recorded for 23 h following NT injection. NT-3 (500 ng dose) and NT-4 (500 and 2000 ng doses) injected at dark onset increased the time spent in non-rapid eye movement sleep. After the 2000 ng dose of NT-4, EEG power was reduced.

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PubMed2003

Spontaneous sleep in mice with targeted disruptions of neuronal or inducible nitric oxide synthase genes.

Nitric oxide (NO) affects almost every physiological process, including the regulation of sleep. There is strong evidence that NO plays an important role in rapid eye movement sleep (REMS) regulation. To further investigate the role of NO in sleep, we characterized spontaneous sleep in mice with targeted disruptions (knockout; KO) in the neuronal nitric oxide synthase (nNOS) or inducible (i)NOS genes. REMS in nNOS KO mice was substantially lower than that of their control mice. In contrast, the iNOS KO mice had significantly more REMS than their controls. Inducible NOS KO mice also had less non-REMS (NREMS) during the dark period. Results suggest that nNOS and iNOS play opposite roles in REMS regulation.

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PubMed2003

Sleep function.

A theory of sleep function and brain organization positing that sleep serves a neuronal connectivity function and is a fundamental property of highly interconnected groups of neurons (neuronal groups) is presented. Cellular electrical activity within neuronal groups leads to the production of sleep-promoting substances which are also cytokine growth factors. The somnogenic cytokine growth factors (SCGF) in turn, induce molecules necessary for synaptic connectivity. The SCGFs change the synaptic activation patterns within neuronal groups. SCGFs thus induce changes in the input-output relationships of neuronal groups and thereby, cause a neuronal group state shift. Altered input-output relations result in increased efficacy of some synapses. Sleep is thus, targeted to active neuronal groups and serves to incorporate novel stimulus patterns into a synaptic contextual network and also to preserve that network. Coordination of neuronal group state is brought about by sleep regulatory networks. Organism sleep is an emergent property of a population of neuronal groups in the sleep state. After the neuronal group state shift, environmental input is divorced from output. Sleep is thus, useful to keep the animal stationary at a time when its brain is most dysfunctional. Thus, not only is unconsciousness needed because output activity would be out of phase with environmental events, but it is the consequence of the process itself.

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PubMed2003

Biochemical regulation of non-rapid-eye-movement sleep.

The concept, that sleep regulatory substances (sleep factors) exist, stems from classical endocrinology and is supported by positive transfer experiments in which tissue fluids obtained from sleepy or sleeping animals elicited sleep when injected into recipient animals. The transfer experiments concluded with the identification of four sleep factors: delta sleep-inducing peptide (DSIP), uridine, oxidized glutathione, and a muramyl peptide. A physiological sleep regulatory role, however, has not been determined for these substances. In contrast, transfer experiments did not play a part in the development of the strong experimental evidence that implicated the currently known sleep factors in sleep regulation. These substances include adenosine, prostaglandin D2 (PGD2), growth hormone-releasing hormone (GHRH), interleukin-1 (IL1) and tumor necrosis factor (TNF). They promote non-REMS in various species, inhibition of their action or endogenous production results in loss of spontaneous sleep, and their synthesis and/or release display variations correlating with sleep-wake activity. Although the source of these substances vary they all enhance sleep by acting in the basal forebrain/anterior hypothalamus--preoptic region. It is also characteristic of these substances that they interact in multiple ways often resulting in mutual stimulation or potentiation of each other. Finally, there is a third group of substances whose significance in sleep regulation is less clear but for which there are two or more lines of evidence suggesting that they may have a role in modulating non-REM sleep (NREMS). This group includes oleamide, cortistatin, cholecystokinin (CCK), insulin, and nitric oxide (NO). More sleep regulatory substances are likely to be discovered in the future although it is a long and difficult process requiring multiple laboratories to generate sufficient convincing data to implicate any one of them in sleep regulation.

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PubMed2003

A cyclooxygenase-2 inhibitor attenuates spontaneous and TNF-alpha-induced non-rapid eye movement sleep in rabbits.

Sleep is regulated in part by the brain cytokine network, including tumor necrosis factor-alpha (TNF-alpha). TNF-alpha activates the transcription factor nuclear factor-kappaB, which in turn promotes transcription of many genes, including cyclooxygenase-2 (COX-2). COX-2 is in the brain and is an enzyme responsible for production of prostaglandin D2. The hypothesis that central COX-2 plays a role in the regulation of spontaneous and TNF-alpha-induced sleep was investigated. Three doses (0.5, 5, and 50 microg) of NS-398, a highly selective COX-2 inhibitor, were injected intracerebroventricularly. The highest dose decreased non-rapid eye movement sleep. The intermediate and highest doses decreased electroencephalographic slow-wave activity; the greatest reduction occurred after 50 microg of NS-398 during the first 3-h postinjection period. Rapid eye movement sleep and brain temperature were not altered by any dose of NS-398. Pretreatment of rabbits with 5 or 50 microg of NS-398 blocked the TNF-alpha-induced increases in non-rapid eye movement sleep, electroencephalographic slow-wave activity, and brain temperature. These data suggest that COX-2 is involved in the regulation of spontaneous and TNF-alpha-induced sleep.

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PubMed2003

Alterations in EEG activity and sleep after influenza viral infection in GHRH receptor-deficient mice.

Viral infections induce excess non-rapid eye movement sleep (NREMS) in mice. Growth hormone-releasing hormone receptor (GHRH receptor) was previously identified as a candidate gene responsible for NREMS responses to influenza challenge in mice. The dwarf lit/lit mouse with a nonfunctional GHRH receptor was used to assess the role of the GHRH receptor in viral-induced NREMS. After influenza A virus infection the duration and intensity [electroencephalogram (EEG) delta power] of NREMS increased in heterozygous mice with the normal phenotype, whereas NREMS and EEG delta power decreased in homozygous lit/lit mice. Lit/lit mice developed a pathological state with EEG slow waves and enhanced muscle tone. Other influenza-induced responses (decreases in rapid eye movement sleep, changes in the EEG high-frequency bands during the various stages of vigilance, hypothermia, and decreased motor activity) did not differ between the heterozygous and lit/lit mice. GH replacement failed to normalize the NREMS responses in the lit/lit mice after influenza inoculation. Decreases in NREMS paralleled hypothermia in the lit/lit mice. Lung virus levels were similar in the two mouse strains. Lit/lit mice had a higher death rate after influenza challenge than the heterozygotes. In conclusion, GHRH signaling is involved in the NREMS response to influenza infection.

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PubMed2003

Sleep in host defense.

Sleep remains an important enigma in neurobiology; it has a robust adaptive value yet its function remains elusive. Changes in sleep are hallmarks of the acute phase response to infectious challenge. The molecular regulation of these responses involves a cytokine cascade within brain, including interleukin-1 and tumor necrosis factor, and several other substances such as growth hormone releasing hormone, prolactin, nitric oxide and nuclear factor kappaB. These substances are also involved in the regulation of normal spontaneous sleep. Fatigue and sleep disturbances are common in cancer patients and in those receiving cytokine therapy. Regardless, the role of sleep in cancer is relatively uninvestigated.

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PubMed2003

Humoral links between sleep and the immune system: research issues.

In the last twenty years we have realized that the immune system synthesizes a class of peptides, termed cytokines, that play a central role in alerting the brain to ongoing inflammation in peripheral tissues. Among the brain's responses to proinflammatory cytokines, or agents that induce these cytokines, are certain alterations in sleep profiles. Characteristically there is an increase in non-rapid eye movement sleep (NREMS), and NREMS intensity is often accompanied by a decrease in rapid eye movement sleep (REMS). Cytokines appear to play a role in normal sleep regulation; during pathology, higher levels of cytokines amplify the physiological cytokine sleep mechanisms. In this review we summarize the extensive literature on the roles of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in sleep regulation, and their interactions with the neuropeptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). We reach the tentative conclusion that the sleep-promoting actions of IL-1 and GHRH are mediated via anterior hypothalamic neurons that are receptive to these substances. It also seems likely that TNF-alpha and CRH also influence these neurons. In addition, we discuss an array of research issues raised by these studies that remain to be resolved.

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PubMed2002

Sleep in mice with nonfunctional growth hormone-releasing hormone receptors.

The role of the somatotropic axis in sleep regulation was studied by using the lit/lit mouse with nonfunctional growth hormone (GH)-releasing hormone (GHRH) receptors (GHRH-Rs) and control heterozygous C57BL/6J mice, which have a normal phenotype. During the light period, the lit/lit mice displayed significantly less spontaneous rapid eye movement sleep (REMS) and non-REMS (NREMS) than the controls. Intraperitoneal injection of GHRH (50 microg/kg) failed to promote sleep in the lit/lit mice, whereas it enhanced NREMS in the heterozygous mice. Subcutaneous infusion of GH replacement stimulated weight gain, increased the concentration of plasma insulin-like growth factor-1 (IGF-1), and normalized REMS, but failed to restore normal NREMS in the lit/lit mice. The NREMS response to a 4-h sleep deprivation was attenuated in the lit/lit mice. In control mice, intraperitoneal injection of ghrelin (400 microg/kg) elicited GH secretion and promoted NREMS, and intraperitoneal administration of the somatostatin analog octretotide (Oct, 200 microg/kg) inhibited sleep. In contrast, these responses were missing in the lit/lit mice. The results suggest that GH promotes REMS whereas GHRH stimulates NREMS via central GHRH-Rs and that GHRH is involved in the mediation of the sleep effects of ghrelin and somatostatin.

Animals↗

PubMed2002

GHRH and IL1beta increase cytoplasmic Ca(2+) levels in cultured hypothalamic GABAergic neurons.

GHRH and IL1beta regulate sleep via the hypothalamus. However, actions of these substances on neurons are poorly understood. In this study, we found both GHRH (100 nM) and IL1beta (1.2 pM) acutely increased cytosolic Ca(2+) in 7.6 and 4.0% of cultured hypothalamic neurons tested, respectively, and 1.2% of neurons responded to both. The neurons that responded were mostly GABAergic (96, 81, and 100% for GHRH, IL1beta, and dual-responsive neurons, respectively).

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PubMed2002

Intrapreoptic microinjection of TNF-alpha enhances non-REM sleep in rats.

Tumor necrosis factor-alpha (TNFalpha) is involved in sleep regulation. Peripheral or central administration of TNFalpha induces non-rapid eye movement sleep (NREMS) in many species. However, the brain site responsible for TNF-enhanced NREMS remains unclear. Thus, we tested the hypothesis that the preoptic area (POA) of the anterior hypothalamus, a crucial site for sleep regulation, is involved in TNF-induced sleep responses in rats. Unilateral microinjection of TNFalpha (2, 20 and 100 ng) or a TNF receptor fragment (TNFRF; 1.25, 5.0 and 12.5 microg) into the POA was performed at dark onset and light onset, respectively. The two higher doses of TNFalpha increased NREMS and brain temperature with little effect on REMS and EEG slow wave activity. These effects were lost after the heat-treatment of TNFalpha. The two higher doses of the TNFRF decreased NREMS without affecting the other parameters measured. Combined with previous results showing diurnal variations of TNFalpha in the hypothalamus, the present data suggest that POA TNFalpha is involved, in part, in the regulation of physiological sleep.

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PubMed2002

Alterations in GHRH binding and GHRH receptor mRNA in the pituitary of adult dw/dw rats.

Lewis dwarf (dw/dw) rats exhibit growth hormone (GH) deficiency and growth retardation linked to a malfunction of GHRH signaling. In this study, GHRH-receptor (GHRH-R) binding and mRNA in the pituitary of adult male dw/dw and age-matched normal Lewis rats was measured by radioligand binding assay and real-time PCR. Only one of nine pools of dw/dw pituitary membranes revealed detectable binding of [His(1), 125I-Tyr(10), Nle(27)]hGHRH(1-32) amide (B(max); 4.3 fmol/mg protein). In contrast, GHRH-R binding was 22.4 +/- 2.60 fmol/mg protein in normal Lewis rats. mRNA for GHRH-R was detectable in all dw/dw rat pituitaries examined, averaging 21% that of Lewis rats. Low expression of GHRH-R reflects reduced GHRH-R mRNA as well as a possible reduction in translation of the receptor protein.

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PubMed2002

Diurnal effects of acute and chronic administration of ethanol on sleep in rats.

BACKGROUND: Disturbances in sleep patterns are a complicating factor in recovery from alcoholism. The effects of acute and chronic alcohol treatments on sleep in rats were determined. METHODS: Adult male Sprague-Dawley rats were acclimated to a temperature-controlled chamber, and electromyograms and electroencephalograms (EEGs) were obtained during 23-hr recording sessions. Time spent in rapid eye movement sleep (REMS) and non-REM sleep (NREMS), EEG slow-wave activity (SWA) during NREMS, a spectral analysis of the EEG by fast Fourier transform, and brain temperatures were determined. RESULTS: Acute exposure to alcohol (2.3 and 3.0 g/kg) by gastric intubation at the beginning of dark onset produced an increase in NREMS and a suppression of SWA. Spectral analysis revealed that during the first 4 hr there was a small increase in very-low-frequency bands (0.5-2 Hz), with a suppression of higher-frequency bands. This was followed by a suppression of low-frequency bands. A dose of 3.0 g/kg at light onset caused an increase in NREMS and a suppression of SWA. Spectral analysis revealed a suppression of low-frequency bands throughout the first 12 hr of recording but no change on high-frequency bands with light-onset alcohol. Chronic treatment with alcohol (6% alcohol in a liquid diet with pair-fed isocaloric controls) for 3 weeks produced an increase in NREMS and a decrease in EEG power density in frequency bands above 2 Hz. Chronic alcohol also reduced the circadian variation of REMS, an effect that showed a rebound 1 week after the alcohol treatment was terminated. Two weeks after the alcohol treatment was stopped, NREMS and REMS values returned to baseline. CONCLUSIONS: These results demonstrate differences in the effect of acute alcohol on sleep depending on the time of administration and demonstrate that distinct alterations in sleep patterns are induced by chronic treatments in as little as 3 weeks.

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PubMed1998

Sleep. A physiologic role for IL-1 beta and TNF-alpha.

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in physiologic sleep regulation. Administration of exogenous IL-1 beta or TNF-alpha induces increased non-rapid eye movement sleep (NREMS). Inhibition of IL-1 or TNF reduces spontaneous sleep. There is a diurnal rhythm of TNF-alpha mRNA and IL-1 beta mRNA in brain with highest levels occurring during peak sleep periods. Mice lacking either the TNF 55-kD receptor or the IL-1 type I receptor sleep less than do strain controls. IL-1 beta and TNF-alpha are part of a larger biochemical cascade involved in sleep regulation; other somnogenic substances in this cascade include growth hormone-releasing hormone and nitric oxide. Several additional substances are involved in inhibitory feedback mechanisms, some of which inhibit IL-1 and TNF. A major challenge to sleep research is to define how and where these molecular steps produce sleep.

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