Stress-induced neuroinflammatory priming: Glucocorticoids, inflammasomes, alarmins

 描述(由申请人提供)：神经炎现在被认为是一系列精神疾病的病因中的一个促成因素，也是这些疾病之间存在的广泛共病的潜在介导者。有人提出，当对刺激的“正常”神经炎性反应变得夸张时，可能会导致精神障碍。急性和慢性应激源的经历也与许多疾病的发展有关。人们很容易认为这两个过程是相关的，但除了应激源暴露之外，急性或慢性应激都没有证明会产生持续性的神经炎症。然而，我们最近发现，急性和慢性应激源，即使它们不会产生大规模或长期的神经炎症，也会潜在地夸大对稍后给予的外周和中枢炎性刺激的神经炎性反应。重要的是，这种敏感化的神经炎性反应在应激源暴露后会持续很多天。然而，导致应激源敏化随后的神经炎症的机制在很大程度上仍不清楚。在过去的十年里，人们在理解参与调节外周先天免疫/炎症的机制方面发生了一场革命。这些新的机制和过程几乎只在外围地区进行了研究，它们是否发生在中枢神经系统尚不清楚。我们的初步研究强烈支持这样一种可能性，即这些细胞存在于中枢神经系统固有免疫细胞(小胶质细胞)中，并参与介导应激诱导的神经炎性反应对后续炎症挑战的敏感化。这项拟议研究的总体目标是：a)确定这些迄今未在大脑中研究过的过程在大脑中的存在，以及b)探索这些过程在应激诱导的神经炎症敏化中的作用，以及通常由大脑中固有免疫细胞激活所引起的行为变化。

 DESCRIPTION (provided by applicant): Neuroinflammation is now regarded to be a contributing factor in the etiology of a wide range of psychiatric disorders and a potential mediator of the extensive co-morbidities that are present between these disorders. It has been suggested that psychiatric disorders may result when "normal" neuroinflammatory responses to stimuli that induce these responses become exaggerated. The experience of both acute and more chronic stressors also are associated with the development of a number of disorders. It has been tempting to suppose that these two processes are related, but neither acute nor chronic stress have proved to produce persistent neuroinflammation beyond the stressor exposure. However, we have recently found that both acute and chronic stressors, even though they do not produce either large or long-lasting neuroinflammation, potently exaggerate neuroinflammatory responses to both peripheral and central inflammatory stimuli that are administered later. Importantly, this sensitized neuroinflammatory reaction persists for many days after stressor exposure. However, the mechanisms that lead stressors to sensitize subsequent neuroinflammation remain largely unknown. Within the past decade there has been a revolution in understanding the mechanisms involved in mediating peripheral innate immunity/inflammation. These new mechanisms and processes have been studied almost exclusively in the periphery, and whether or not they occur in the CNS is unknown. Our Preliminary Studies strongly encourage the possibility that these are present in CNS innate immune cells (microglia) and that they are involved in mediating stress-induced sensitization of neuroinflammatory responses to subsequent inflammatory challenges. The global goals of the proposed research are to a) firmly establish the presence of these processes, heretofore unstudied in brain, in brain, and b) explore the role of these processes in stress- induced sensitization of neuroinflammation, as well as the behavioral changes that typically induced by the activation of innate immune cells in the brain.