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

RFA-AA-17 - 016指出，"在目前的创伤后应激障碍模型中研究酒精相关行为， 潜在地在PTSD的新型动物模型中寻找”。创伤后应激障碍的动物模型是 利用个体差异来理解弹性和易感性的潜在机制 精神病理学经验证的创伤后应激障碍模型概括了创伤后应激障碍在创伤暴露者中的患病率。 个体（约15 - 30%，取决于创伤）。我们将使用2个经过充分验证的PTSD动物模型，社会 击败压力和捕食者压力，以了解在什么生物背景下创伤和随后的持久 应激反应会引发饮酒行为。捕食者压力模型的持久影响，严重的单一 创伤性事件，而社会失败压力模型的慢性身体和情绪压力的影响。两 模型在对创伤暴露的持久反应率方面产生差异，（30 - 50%的动物表现出 延长的行为和神经生物学变化），为PTSD提供病因学有效性。我们建议 检查是否有两个高度可翻译的创伤症状发展标志，睡眠障碍和增加 外周免疫信号传导，预测啮齿动物应激后饮酒的发展和/或维持。这 一种方法解决了RFA的任务，即"识别预测PTSD向共病转变的生物标志物 PTSD酒精滥用目标是（1）开发长期创伤影响的强大跨物种生物标志物 与增加的酒精消耗量相关，以及（2）确定预测治疗的生物标志物 反应我们将检验这一假设，即创伤后睡眠和炎症异常预测创伤后睡眠和炎症增加。 饮酒和治疗反应。为了检验这一假设，我们将使用一个大型（N = 200/模型）前瞻性， 基于临床研究方法的纵向设计。这种策略使我们能够使用复杂的 统计模型，以确定饮酒行为的生物预测。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， 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， 酒精依赖，睡眠和周围炎症，在战斗部署之前和之后。一旦 在我们的动物模型中鉴定并在人类中验证的睡眠和免疫生物标志物， 筛选新型药物治疗的预防和治疗效果。

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.