Influenza virus-induced sleep responses in mice with targeted disruptions in neuronal or inducible nitric oxide synthases

Chen, Lichao; Duricka, Deborah; Nelson, Scott W.; Mukherjee, Sumitava; Bohnet, Stewart; Taishi, Ping; Majde, Jeannine A.; Krueger, James M.

doi:10.1152/japplphysiol.01355.2003

Cited by 28 publications

(19 citation statements)

References 72 publications

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“…However, SWS delta power, a measure of SWA, was significantly greater in nNOS KO mice than in their wild type controls during all phases of the circadian cycle (Chen et al, 2003). The same authors also found that influenza-induced elevation of time spent in SWS was attenuated in nNOS-deficient mice (Chen et al, 2004). Thus, while nNOS may in fact suppress sleep SWA under baseline conditions, it appears to facilitate sleep in the context of viral infection.…”

Section: Neuronal No As a Sleep-inducing Factor: Local Regulation Of mentioning

confidence: 89%

Sleep-Active Neuronal Nitric Oxide Synthase-Positive Cells of the Cerebral Cortex: A Local Regulator of Sleep?

Wisor

Gerashchenko²,

Kilduff³

2011

CTMC

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Our recent report demonstrated that a small subset of GABAergic interneurons in the cerebral cortex of rodents expresses Fos protein, a marker for neuronal activity, during slow wave sleep (Gerashchenko et al., 2008). The population of sleep-active neurons consists of strongly immunohistochemically-stained cells for the enzyme neuronal nitric oxide synthase. By virtue of their widespread localization within the cerebral cortex and their widespread projections to other cortical cell types, cortical neuronal nitric oxide synthase-positive neurons are positioned to play a central role in the local regulation of sleep waveforms within the cerebral cortex. Here, we review the possible functions of neuronal nitric oxide synthase and its diffusible gas product, nitric oxide, in regulating neuronal activity, synaptic plasticity and cerebral blood flow within the context of local sleep regulation in the cerebral cortex. We also summarize what is known, in addition to their expression of neuronal nitric oxide synthase, about the biochemical phenotype, synaptic connectivity and electrophysiological properties of this novel sleep-active population of cells. Finally, we raise some critical unanswered questions about the role of this population in local sleep regulation within the cerebral cortex and describe some experimental approaches that might be used to address those questions.

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Section: Neuronal No As a Sleep-inducing Factor: Local Regulation Of mentioning

confidence: 89%

Sleep-Active Neuronal Nitric Oxide Synthase-Positive Cells of the Cerebral Cortex: A Local Regulator of Sleep?

Wisor

Gerashchenko²,

Kilduff³

2011

CTMC

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“…A mouse-adapted strain of influenza, H1N1 A/Puerto Rico/8/34 H1N1 (PR8) (lot#3X010621) suspended in pyrogen-free allantoic fluid (Specific Pathogen-Free Avian Supply, North Franklin, CT) was purified by sucrose-gradient sedimentation by ultracentrifugation as previously described (18). The virus was diluted to a protein concentration of 200 µg/mL, aliquoted, frozen on dry ice, and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, the purified virus tested negative for mycoplasma and acholeplasma contamination by nested PCR (nPCR) (American Type Culture Collection, Manassas, VA) as previously described (19). In Madin-Darby canine kidney (MDCK) cells, viral titrations were assessed and expressed as median tissue culture infectious doses (TCID 50 ) as previously described (18) . The starting titer of purified PR8 virus was 5× 10 4 TCID 50 /µL.…”

Section: Methodsmentioning

confidence: 99%

Olfactory Bulb and Hypothalamic Acute-Phase Responses to Influenza Virus: Effects of Immunization

Zielinski

Souza

Taishi

et al. 2013

Neuroimmunomodulation

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Background: Within hours of intranasal challenge, mouse-adapted H1N1 A/Puerto Rico/8/34 (PR8) influenza genomic RNA is found in the olfactory bulb (OB) and OB pro-inflammatory cytokines are up-regulated. Severing the olfactory tract delays the acute-phase response (APR) and the APR is attenuated by immunization. Objectives: To determine if immunization affects OB localization of influenza or the molecular brain mechanisms regulating APR. Methods: Male mice were immunized with PR8 influenza, then OB viral RNA, APR, and influenza-related cytokine responses were determined after homologous viral challenge. Results: Immunization did not prevent influenza OB viral invasion within 24 h of viral challenge. However, it greatly attenuated OB viral RNA 6 days after viral challenge and the APR including hypothermia and body weight loss responses. Within the OB, 24 h after influenza challenge, prior immunization blocked virus-induced up-regulation of toll-like receptor 7 and interferon (IFN) γ mRNAs. At this time, hypothalamic (HT) growth hormone-releasing hormone receptor and tumor necrosis factor-α mRNAs were greatly enhanced in immunized but not in positive control mice. By 6 days after viral challenge, OB and HT mRNAs returned towards baseline values. In the lung, mRNA up-regulation was greater than that in the brain and maximized 6 days after challenge. Lung IFNγ mRNA decreased at 24 h but increased 6 days after challenge in the positive compared to negative controls. Immunization prevented the up-regulation of most of the flu-related mRNAs measured in lungs. Conclusion: Collectively, these data suggest a role for OB and HT involvement in immunization protection against influenza infection.

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“…About 10,000-fold more X-31 virus is required to kill mice in the same time-frame as PR8, largely due to the retention of glycosylated surface proteins on X-31 that are targeted by circulating host lectins (Reading et al, 1997). The X-31 virus grown in specific pathogen-free chick embryos was purified and tested for possible contaminants as previously described (Chen et al, 2004). Viral titrations were performed in Madin-Darby canine kidney cells as previously described (Chen et al, 2004) and expressed as median tissue culture infectious doses (TCID 50 ).…”

Section: Methodsmentioning

confidence: 99%

Attenuation of the influenza virus sickness behavior in mice deficient in Toll-like receptor 3

Majde

Kapás

Bohnet

et al. 2010

Brain, Behavior, and Immunity

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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 14 days 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.

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Influenza virus-induced sleep responses in mice with targeted disruptions in neuronal or inducible nitric oxide synthases

Cited by 28 publications

References 72 publications

Sleep-Active Neuronal Nitric Oxide Synthase-Positive Cells of the Cerebral Cortex: A Local Regulator of Sleep?

Sleep-Active Neuronal Nitric Oxide Synthase-Positive Cells of the Cerebral Cortex: A Local Regulator of Sleep?

Olfactory Bulb and Hypothalamic Acute-Phase Responses to Influenza Virus: Effects of Immunization

Attenuation of the influenza virus sickness behavior in mice deficient in Toll-like receptor 3

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