Our goal in this project is to determine the changes in sleep, temperature and activity that occur during the acute phase response and recovery phase after inoculation with Vesicular Stomatitis Virus (VSV), a well- established animal model of viral encephalitis, and to determine the relationship these changes have to viral- induced changes in profiles of chemokines and cytokines in the brain. To accomplish this goal, we will identify changes in sleep, temperature and activity that occur with wild-type VSV that infects throughout the brain, a recombinant VSV (rVSV) that infects only the olfactory bulb and a non-infectious rVSV that induces a chemokine/cytokine response without damaging neural tissues. We will first characterize the chemokine and pro-inflammatory cytokine response to infectious and non-infectious rVSV (Aim1A) and identify when changes in sleep and behaviors occur during the acute and recovery phases of this disease (Aim1B). We will also determine whether a single and transient episode of viral encephalitis results in persisting alterations in the responses of mice to future challenges using an uncontrollable stress model (inescapable footshock) that produces significant alterations in sleep (Aim 1C). Lastly, we will determine the relationship of chemokine and pro-inflammatory cytokine profiles in specific brain regions with changes in sleep, temperature and behavior in individual mice. Completing this work will assess VSV-induced encephalitis as a model for examining the role of chemokines and cytokines in modulating sleep, temperature and motor activity in response to infection. By comparing the effects of wild-type VSV, rVSV and non-infectious VSV, we will be able to delineate the effects on sleep and other physiological parameters of potential virus-induced damage to neurons in the brain relative to the induction of chemokines/cytokines without potential damage to neurons. By comparing these conditions across time, we will be able to determine chemokine/cytokine profiles associated with changes in sleep during the acute response phase and the recovery phase, and by assessing responses to a subsequent stressor, we will be able to determine whether a single transient episode of encephalitis produces persisting changes in the ability to cope with future challenges. This project will provide novel data regarding the effects of VSV-induced encephalitis and will provide the groundwork for future mechanistic studies examining the source of changes in chemokine/cytokine production and their roles in regulating sleep, temperature and other processes of host defense.

Public Health Relevance

The goal or this research is to evaluate a virus-induced encephalitis in mice as a model for examining the relationship between the induction of chemokines and cytokines and changes in sleep and other physiological variables, and to determine whether a single, transient episode of encephalitis produces alterations in the ability to respond to subsequent stressors. Infectious diseases are commonly accompanied by excessive sleepiness, fatigue and fever and it has been hypothesized that sleep functions in host defense. Chemokines and cytokines regulate host defense and they are also major mediators of the sleepiness and fatigue that occur during the acute phase response of infection. Cytokines may have detrimental short-term effects but beneficial effects in long-term repair and recovery though their precise role(s) are not fully understood. Determining the relationship between infection and sleep and the role chemokines and cytokines play in the host response should increase our understanding of how these immune modulators impact sleep/behavior over time, the role sleep may play in responses to infection and the mechanisms involved. Such understanding may provide insight that could lead to improved therapies and improved prognosis for infectious diseases.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Exploratory/Developmental Grants (R21)
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Biological Rhythms and Sleep Study Section (BRS)
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Hardy, Lynda R
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Eastern Virginia Medical School
Schools of Medicine
United States
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Ciavarra, Richard P; Machida, Mayumi; Lundberg, Patric S et al. (2018) Controllable and uncontrollable stress differentially impact pathogenicity and survival in a mouse model of viral encephalitis. J Neuroimmunol 319:130-141
Machida, Mayumi; Ambrozewicz, Marta A; Breving, Kimberly et al. (2014) Sleep and behavior during vesicular stomatitis virus induced encephalitis in BALB/cJ and C57BL/6J mice. Brain Behav Immun 35:125-34
Steel, Christina D; Breving, Kimberly; Tavakoli, Susan et al. (2014) Role of peripheral immune response in microglia activation and regulation of brain chemokine and proinflammatory cytokine responses induced during VSV encephalitis. J Neuroimmunol 267:50-60