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

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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.