Behavioral effects of cardiac arrest in mice

描述（由申请人提供）：神经免疫激活是缺血的常见后果，但行为后果尚未得到很好的描述。本资助申请中提出的研究将为研究小胶质细胞激活对心脏骤停和心肺复苏（CA/CPR）后焦虑的影响提供神经生物学基础。暴露于压力和小胶质细胞激活之间的相互作用也将被检查。众所周知，压力会产生长期的生理和心理后果。我们的总体假设是，CA/CPR后的小胶质细胞激活因先前暴露于压力而加剧，并直接导致焦虑增加。我们将在小鼠中测试的具体假设是：（1)外源性小胶质细胞治疗将增加小胶质细胞激活和焦虑样行为的测量，而CA/CPR后使用二甲胺四环素（一种抗生素）治疗将减少小胶质细胞激活和焦虑样行为，2）慢性应激比急性应激在CA/CPR后激活小胶质细胞和增加焦虑样行为方面更有效。3)先前的应激暴露通过增加皮质酮浓度通过糖皮质激素受体作用而增加CA/CPR的小胶质细胞激活和焦虑性反应。因此，我们提出改变对CA/CPR的神经免疫反应可以影响行为并可能导致神经元死亡。由于小胶质细胞激活被认为有助于多种CMS疾病的神经退行性变，包括缺血性损伤、头部创伤、阿尔茨海默病和帕金森病，因此本研究的数据可能具有广泛的意义。

DESCRIPTION (provided by applicant): 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.