Stress-induced neuroinflammatory priming: Glucocorticoids, inflammasomes, alarmins

 描述（由申请人提供）：神经炎症现在被认为是各种精神疾病病因学的一个促成因素，也是这些疾病之间存在的广泛共病的潜在介导因素。有人认为，当对诱发这些反应的刺激的“正常”神经炎症反应变得夸张时，可能会导致精神障碍。急性和慢性压力源的经历也与许多疾病的发展有关。人们很容易假设这两个过程是相关的，但无论是急性还是慢性应激都没有被证明会在应激源暴露之外产生持续的神经炎症。然而，我们最近发现，急性和慢性应激源，即使它们不产生大的或持久的神经炎症，有力地夸大了神经炎症反应的外周和中枢炎症刺激，后来管理。重要的是，这种致敏的神经炎症反应在应激源暴露后持续许多天。然而，导致应激源致敏随后的神经炎症的机制在很大程度上仍然未知。 在过去的十年中，在理解参与介导外周先天免疫/炎症的机制方面发生了革命。这些新的机制和过程几乎只在外周进行了研究，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鼓励这些存在于CNS先天免疫细胞（小胶质细胞）中的可能性，并且它们参与介导应激诱导的神经炎症反应对随后的炎症挑战的敏感性。所提出的研究的总体目标是a）牢固地确立这些过程在脑中的存在，迄今为止未在脑中研究，和B）探索这些过程在应激诱导的神经炎症致敏中的作用，以及通常由脑中先天免疫细胞的激活诱导的行为变化。

 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.