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

战争条件会给平民带来长期的、有时是严重的压力。虽然许多研究已经描述了与长期应激状态相关的临床表现和发病率，但与应激相关疾病的生理和神经生物学机制尚不完全清楚。此外，到目前为止，既没有办法及早确定有特殊风险的个人，也没有实施预防战略来避免与应激有关的疾病的发展。这项三方合作研究建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方法的开发。我们将实施多模式方法，将在遗传、分子和生化内分泌措施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相结合。我们相信，这种多模式但深入的方法将导致对应激相关疾病的更好理解。此外，这种理解是开发新的方法来识别和评估高危个体以及预防和治疗在显著应激下或之后启动的神经行为变化的必要先决条件。这一建议建立在我们实验室先前进行的动物和临床前研究的基础上，这些研究指出胆碱能信号对哺乳动物应激反应的重要性。更具体地说，它侧重于那些关键的转录变化，这些变化发生在应激状态下的胆碱能系统中，并与实施应激相关的网络变化和大脑功能障碍密切相关。我们建议对长期处于战争条件下的弱势群体进行德国--巴勒斯坦--以色列的合作研究。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寻找新的替代标记物，从而能够预测大规模平民人口中与应激相关的大脑反应。具体地说，我们将研究暴露在频繁军事入侵中的巴勒斯坦和以色列青少年。测量将包括：(1)内分泌应激反应的标记物；(2)影响胆碱能相关蛋白表达的已知遗传多态；(3)有核血细胞中胆碱能相关基因的表达水平；以及(4)血清中乙酰胆碱酯酶(AChE)、丁基胆碱酯酶(BChE)和相关的氧化应激抑制物对氧磷酶(PON1)的酶活性。我们将寻找这些测量与压力诱发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。脑功能障碍的测量将使用：(1)关于急性应激反应、创伤后应激障碍、分离性健忘症和生活质量的有效问卷；(2)定量脑电(QEEG)，包括事件相关同步(ERS)和去同步(ERD)以及来源定位方法。最终，分子和功能数据将与使用已建立的临床评分系统的创伤后应激障碍和神经功能障碍的风险相关。拟议的研究将进一步收集暴露在长期战争条件下的年轻人的独特的大规模数据集。我们相信，收集的数据将导致新的发现，最终可能使预测和早期治疗处于危险中的个人成为可能。

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.