Prefrontal Cortex Stress Peptides in Traumatic Stress-Induced Escalation of Alcohol Drinking

 描述(申请人提供)：酒精使用障碍(AUD)影响约12%的世界人口，仅在美国每年就导致超过250万人死亡，每年给美国造成2200亿美元的损失。创伤后应激障碍(例如，创伤后应激障碍；PTSD)是一种衰弱性疾病，目前影响着770万美国人，约30%的美国退伍军人被观察到，每年给美国造成数十亿美元的损失。AUD和PTSD都会增加人类的死亡率和寿命，从而增加慢性病的发病率。创伤后应激障碍是受创伤后应激障碍影响的人类中最常见的精神健康障碍，22-43%的创伤后应激障碍患者符合创伤后应激障碍的标准(相比之下，总人口的这一比例为8%)。PTSD和AUD之间的高发病率提示PTSD和AUD之间存在重叠的神经生物学机制，但PTSD和AUD之间高发病率的生物学基础尚不清楚。这一建议的一个重要方面是对应激反应(脆弱性与恢复力)的个体差异的先验识别，该模型仅对暴露在应激中的一小部分人的创伤性应激障碍的发展进行建模。在这里，我们建议使用啮齿动物模型来研究PTSD和AUD共病的神经生物学基础。我们实验室的初步和已发表的数据表明，创伤应激通过影响促肾上腺皮质激素释放因子(CRF；一种应激肽)信号转导，使饮酒加剧并产生痛觉过敏，还改变了腹内侧额前皮质(VmPFC)的细胞外信号相关激酶磷酸化(PERK)，vmPFC是大脑中通过自上而下控制皮质下结构协调对环境反应的重要区域。这项拟议的工作试图通过探索vmPFC中CRF-ERK相互作用在调节创伤应激诱导的酒精饮酒和痛觉过敏升级中的作用来扩展这些发现。这一建议的主要假设是，vmPFC、CRF-CRF1R信号通过ERK通路介导了表现出高应激反应的大鼠不断升级的饮酒和痛敏。这项建议将为有前途的医学博士/博士学生提供重要的研究培训，通过研究使用综合方法来检验以下预测：1)创伤应激上调vmPFC中的CRF-CRF1-ERK信号通路，以及2)这一通路介导高应激反应动物的酒精饮酒升级。这些实验将在精神障碍的动物模型方面培训未来的内科科学家，这些研究的结果将为开发有效的治疗共病PTSD和AUD的策略提供信息，导致受影响个人的生活质量和健康状况的改善，降低与这些疾病相关的发病率，并潜在地为美国节省数百万美元的医疗保健 成本。

 DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) affects ~12% of the world population, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $220 billion annually. Traumatic stress disorders (e.g., post-traumatic stress disorder; PTSD) are debilitating disorders currently affecting 7.7 million Americans, are observed in ~30% of U.S. combat veterans, and cost the U.S. billions of dollars annually. AUD and PTSD both increase mortality rates and shorten life spans in humans, increasing the incidence of chronic disease states. AUD is the most commonly occurring mental health disorder in humans affected by PTSD, with 22-43% of individuals with PTSD meeting criteria for AUD (compared to 8% of the general population). The high rate of co-morbidity suggests an overlapping neurobiological mechanism between PTSD and AUD, but the biological basis for the high rate of co-morbidity between PTSD and AUD is not known. An important aspect of this proposal is the a priori identification of individual differences in stres reactivity (vulnerability vs. resilience), which models the development of traumatic stress disorders in only a subpopulation of stress- exposed humans. Here, we propose to use a rodent model to examine the neurobiological basis for co-morbid PTSD and AUD. Preliminary and published data from our lab suggest that traumatic stress escalates alcohol drinking and produces hyperalgesia in rats via effects on corticotropin-releasing factor (CRF; a pro-stress peptide) signaling, and also alters extracellular signal-related kinase phosphorylation (pERK) in the ventromedial prefrontal cortex (vmPFC), a brain region important for coordinating responses to the environment via top-down control of sub-cortical structures. The proposed work seeks to extend these findings by exploring the role of CRF-ERK interactions in the vmPFC in mediating traumatic stress-induced escalation of alcohol drinking and hyperalgesia. The overarching hypothesis of this proposal is that vmPFC CRF-CRF1R signaling via ERK pathways mediates escalated alcohol drinking and hyperalgesia in rats that exhibit high stress reactivity. This proposal will provide a promising M.D./Ph.D. student with vital research training through studies that use an integrative approach to test the predictions that: 1) traumatic stress upregulates CRF- CRF1-ERK signaling pathways in the vmPFC, and 2) this pathway mediates escalation of alcohol drinking in high-stress reactive animals. These experiments will train a future physician-scientist in animal models of psychiatric disorders, and the results of these studies will inform the development of effective treatment strategies for co-morbid PTSD and AUD, leading to improvements in quality of life and health of affected individuals, decreasing morbidity associated with these disorders, and potentially saving the U.S. millions of dollars in health care costs.