Victims of War: Contribution of the Cholinergic System to the Development of PTSD in Children and Adolescents in Palestine and Israel

战争条件给平民造成长期的、有时是严重的压力。虽然许多研究已经描述了与长期应激条件相关的临床表现和发病率，但应激相关疾病的生理和神经生物学机制尚未完全了解。此外，到目前为止，既没有办法及早发现有特别危险的个人，也没有办法执行预防战略，以避免患上与压力有关的疾病。这项三边合作研究提议通过探索特定人群在长期严重战争压力下的应激反应来启动这种手段的发展。我们将实施一种多模式的方法，将在遗传、分子和生化内分泌测量中观察到的外周变化与通过脑成像和电生理记录检测到的中枢神经系统变化结合起来。我们相信，这种多模式但深入的方法将有助于提高对压力相关疾病的理解。此外，这种理解是开发识别和评估高危个体的新方法以及在重大压力下或随之而来的神经行为变化的预防和治疗干预的必要前提。这一建议建立在先前在我们实验室进行的动物和临床前研究的基础上，这些研究指出了胆碱能信号传导对哺乳动物应激反应的重要性。更具体地说，它关注的是那些关键的转录变化，这些转录变化发生在压力下的胆碱能系统中，并且在实施与压力相关的网络变化和脑功能障碍中至关重要。我们建议对长期遭受战争条件压力的特定弱势群体进行一项德国-巴勒斯坦-以色列合作研究。通过挑战上述胆碱能假说，这项三方合作研究的主要目标是确定新的替代标记物，从而可以预测大规模平民人群中与压力相关的大脑反应。具体来说，我们将研究经常受到军事入侵的巴勒斯坦和以色列青少年。测量将包括：(1)内分泌应激反应标志物；(2)已知影响胆碱能相关蛋白表达的遗传多态性；(3)有核血细胞中胆碱能相关基因的表达水平；(4)血清乙酰胆碱酯酶（AChE）、丁基胆碱酯酶（BChE）及相关氧化应激抑制因子对氧磷酶（PON1）的活性。我们将寻找这些测量结果与压力诱导的脑功能障碍风险增加之间的联系，特别是创伤后应激障碍（PTSD）的发展。脑功能障碍测量采用：(1)急性应激反应、创伤后应激障碍、分离性遗忘和生活质量的有效问卷；(2)定量脑电图（qEEG），包括事件相关同步（ERS）和去同步（ERD）和源定位方法。最终，分子和功能数据将通过已建立的临床评分系统与PTSD和神经功能障碍的风险相关。拟议的研究将进一步允许从长期战争条件下的年轻人那里收集独特的大规模数据集。我们相信，收集到的数据将带来新的发现，最终可能使有风险的个体能够预测和早期治疗。

War conditions entail chronic and sometimes severe stress on civil populations. While numerous studies have described the clinical presentation and morbidity associated with prolonged stress conditions, the physiological and neurobiological mechanisms underlying stress-related illnesses are yet incompletely understood. Furthermore, to date there are neither means for early identification of individuals at particular risk nor for implementation of prevention strategies for avoiding the development of stress-related illnesses. This trilateral collaborative research proposes to initiate the development of such means by exploring the stress response in specific populations under prolonged, severe war stress. We will implement a multimodal approach, integrating peripheral changes observed in genetic, molecular and biochemical-endocrinological measures with central nervous system changes detected by brain imaging and electrophysiological recordings. We believe that this multi-modal yet in-depth approach will lead to improved understanding of stressrelated illnesses. Furthermore, such understanding is an essential pre-requisite to the development of novel methods for identification and assessment of at-risk individuals as well as preventive and therapeutic interventions with those neurobehavioral changes initiated under or following significant stresses.This proposal builds upon prior animal and pre-clinical studies performed in our laboratories that point to the importance of cholinergic signaling for mammalian stress responses. Yet more specifically, it is focused on those key transcriptional changes, which take place in the cholinergic system under stress and that are critically involved in implementing stress-related network changes and brain dysfunction. We propose to conduct a collaborative German-Palestinian-Israeli study on selected vulnerable populations, which are exposed to prolonged stress of war conditions. By challenging the above cholinergic hypothesis , the main objective of this trilateral cooperative study is to identify novel surrogate markers, which will allow the prediction of stress-related brain responses in large-scale civilian populations.Specifically, we will study Palestinian and Israeli adolescents exposed to frequent military incursions. Measurements will include: (1) Markers of endocrine stress response; (2) Known genetic polymorphisms affecting the expression of cholinergicrelated proteins; (3) Expression levels of cholinergic-associated genes in nucleated blood cells; and (4) Serum enzymatic activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and the related suppressor of oxidative stress, paraoxonase (PON1). We will search for an association between these measurements and increased risk of stress- inducible brain dysfunction, and specifically the development of post-traumatic stress disorder (PTSD). Brain dysfunction will be measured using: (1) validated questionnaires for acute stress reaction, PTSD, dissociate amnesia and quality of life; (2) quantitative electroencephalography (qEEG), including event-related synchronization (ERS) and desynchronization (ERD) and source localization methods. Eventually, the molecular and functional data will be related to the risk for PTSD and neuro-functional disturbances using established clinical scoring systems. The proposed study will further allow the collection of a unique large-scale data set from young individuals exposed to prolonged war conditions. We believe that the collected data will lead to new findings, which may eventually enable the prediction and early treatment of individuals at risk.