Developing rodent models of PTSD/AUD: leveraging clinic-based strategies

RFA-AA-17-016规定：“对当前创伤后应激障碍模型中与酒精相关的行为的研究 可能在新的动物模型中寻找创伤后应激障碍“。创伤后应激障碍的动物模型处于 利用个体差异来了解潜在的复原力和易感性机制 精神变态学。创伤后应激障碍的有效模型概括了创伤暴露后创伤后应激障碍的患病率 个人(约15-30%，视创伤而定)。我们将使用两个经过充分验证的创伤后应激障碍动物模型，社会 战胜压力和捕食者压力，以了解在什么生物背景下创伤和随后的持久 压力反应会刺激饮酒行为。捕食者应激模拟严重单次 创伤事件，而社会失败压力模型慢性身体和情感压力的影响。两者都有 模型对创伤暴露的持久反应率存在差异(30%-50%的动物表现出 长期的行为和神经生物学改变)，为创伤后应激障碍提供了病因学上的有效性。我们建议 检查创伤的两个高度可翻译的标志--症状发展、睡眠障碍和增加 外周免疫信号，预测啮齿动物应激后饮酒的发展和/或维持。这 方法解决了RFA的任务，即确定将预测创伤后应激障碍向合并症转变的生物标记物 创伤后应激障碍--酒精滥用。我们的目标是(1)开发长期创伤效应的强大的跨物种生物标记物 与酒精摄入量增加有关，以及(2)确定可预测治疗的生物标记物 回应。我们将检验这一假设，即创伤后睡眠和炎症异常预示着增加 饮酒和治疗反应。为了检验这一假设，我们将使用一个大的(N=200/模型)预期， 基于临床研究方法的纵向设计。此策略允许使用复杂的 确定饮酒行为生物学预测因素的统计模型。我们将通过以下方式评估临床相关性 通过利用我们的前瞻性纵向研究的临床数据库，将这些发现与人类进行比较 现役军人创伤(N=2600)。这个数据库包括创伤、创伤后应激障碍症状、 在战斗部署前后都会出现酒精依赖、睡眠和外周炎症。一次 在我们的动物模型中识别并在人类中验证的验证、睡眠和免疫生物标记物可以使用 筛选新的药物疗法的预防和治疗效果。

RFA-AA-17-016 states that “Studies examining alcohol related behaviors in current models of PTSD and potentially in novel animal models of PTSD are sought”. Animal models of PTSD are on the cutting edge of exploiting individual differences to understand mechanisms underlying resilience and susceptibility to psychopathology. Validated models of PTSD recapitulate the prevalence of PTSD in trauma-exposed individuals (~15-30% depending on trauma). We will use 2 well-validated animal models of PTSD, social defeat stress and predator stress, to understand in what biological contexts trauma and subsequent enduring stress response provokes drinking behavior. Predator stress models the enduring effects of a severe single traumatic event while social defeat stress models effects of chronic physical and emotional stress. Both models produce variance in enduring response rates to trauma exposure, (30-50% of animals exhibit prolonged behavioral and neurobiological change), providing etiological validity for PTSD. We propose to examine if two highly translatable markers of trauma-symptom development, sleep disturbance and increased peripheral immune signaling, predict development and/or maintenance of drinking after stress in rodents. This approach addresses the RFA mandate to “identify biomarkers that will predict transition of PTSD to comorbid PTSD-alcohol misuse.” The goal is to (1) develop robust cross-species biomarkers of long term-trauma effects associated with increased alcohol consumption and (2) identify biomarkers that are predictive for treatment response. We will test the hypothesis that sleep and inflammation abnormalities after trauma predict increased drinking and treatment response. To test this hypothesis we will use a large (N=200/model) prospective, longitudinal design based on clinical research approaches. This strategy enables use of sophisticated statistical models to identify biological predictors of drinking behavior. We will assess clinical relevance by comparing these findings to humans by leveraging our clinical database of a prospective, longitudinal study of trauma in active duty service members (N=2600). This database includes data on trauma, PTSD symptoms, alcohol dependence, sleep and peripheral inflammation both before and after a combat deployment. Once validated, sleep and immune biomarkers identified in our animal models and validated in humans can be used to screen for prophylactic and therapeutic treatment effects of novel pharmacotherapies.