Neuroimmune activation is a common consequence of ischemia, but the behavioral ramifications are not well-described. The studies proposed in this grant application will provide a neurobiological foundation on which to study the effects of microglial activation on anxiety following cardiac arrest and cardiopulmonary resuscitation (CA/CPR). The interaction between exposure to stress and microglial activation also will be examined. It is well-established that stress can have long-term physiological and psychological consequences. Our overall hypothesis is that microglial activation following CA/CPR is exacerbated by prior exposure to stress and is directly responsible for increased anxiety. The specific hypotheses that we will test in mice are (1) that treatment with exogenous microglia will increase measures of microglial activation and anxiogenic-like behavior, while treatment with minocycline (an antibiotic) following CA/CPR will decrease microglial activation and anxiogenic-like behavior, 2) that chronic stress will be more effective than acute stress in activating microglia and increasing anxiogenic-like behavior following CA/CPR, and 3) that prior exposure to stress increases microglial activation and anxiogenic responses to CA/CPR via increased corticosterone concentrations acting through glucocorticoid receptors. Thus, we propose that altering the neuroimmune response to CA/CPR can affect behavior and potentially contribute to neuronal death. Because microglial activation is thought to contribute to neural degeneration in a variety of CMS disorders, including ischemic injury, head trauma, Alzheimer disease, and Parkinson disease, the data from the present proposal may have broad implications. ? ? ?
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