Impaired hippocampal function as a risk factor for Post-Traumatic Stress Disorder

描述（由申请人提供）： 据估计，20-30%的人暴露于创伤性事件发展创伤后应激障碍（PTSD），164万美军已被部署在游击式战斗（持久自由行动和伊拉克自由），具有高度不可预测和反复暴露于创伤性事件。因此，创伤后应激障碍造成成本上升并不奇怪 对退伍军人管理局和社会来说，由于生产力和质量的损失， 生活自1999年以来，与支付PTSD相关残疾相关的VA费用一直在稳步上升，2005年从战斗中返回的PTSD人员的治疗费用估计接近2.05亿美元。很明显，减少需要治疗创伤后应激障碍的退伍军人数量将减少与这种疾病相关的VA成本，更不用说提高许多退伍军人的生活质量了。重要的是，PTSD或其他焦虑症的既往史使一些人在随后的创伤事件后更容易患上PTSD。因此， 患有创伤后应激障碍或创伤后应激障碍易感性的退伍军人，当他们经历非战斗创伤时，如车祸，袭击和自然灾害，更有可能发展为创伤后应激障碍。 因此，识别易感性和预防方法可以降低PTSD相关的VA成本。 了解发展PTSD的风险因素可以帮助减少经历情感创伤后发生的可能性。这项资助的目的是调查海马功能的改变是否是导致PTSD样行为表型的创伤事件的风险因素或后果。如果它是一个危险因素，正如我们的初步数据所表明的那样，它可以作为易感性的神经功能标志物。在这些调查中，我们将应用两个不可或缺的工具。第一个是我们最近开发的一种新的行为模型，用于在大鼠经历情感创伤（恐惧条件反射）之前将其预先分类为易受或耐PTSD样表型（受损的消退，持续升高的惊吓反应）。第二种工具是PI共同开发的灵敏细胞成像方法，该方法可以评估由两种不同行为事件激活的神经元集合的大小和重叠。目的1将调查是否表达可塑性相关的立即早期基因，弧和荷马1a，在海马系统中的敏感性相比，耐药大鼠在经历创伤事件之前，将被预测，如果改变海马功能是一个危险因素，而不是PTSD的后果。将评估由两个探索事件中的每一个激活的集合的大小和重叠，沿着神经元密度。第二个实验将测试海马功能的改变是否可以通过减弱抗性大鼠中Arc/H1 a的表达来导致PTSD样行为，然后测试它们的恐惧消退和声音惊吓的持续升高。目的2将测试是否改变编码的创伤事件，在神经系统水平上，是一个PTSD样表型的病理生理学的一部分，通过评估Arc/H1 a的表达在易感和耐药大鼠经历情感创伤后。目的3将测试易感大鼠的PTSD样表型是否可以通过已知参与内侧前额叶皮层和海马的“认知运动”来逆转。结合起来，这项工作将对海马系统在PTSD病因学中的作用做出根本性的发现。这一发现将为未来的研究提供信息，即如何设计客观的、受试者内的易患性测试，这种测试不依赖于自我报告，并可用作诊断PTSD的补充工具。目标3的研究结果将建议研究治疗方法，以赋予具有高依从率的弹性，因为它们将是低压力的。

DESCRIPTION (provided by applicant): An estimated 20-30% of people exposed to traumatic events develop post-traumatic stress disorder (PTSD), and 1.64 million US troops have been deployed in guerilla-type combat (Operations Enduring Freedom and Iraqi Freedom) that have a high level of unpredictable and recurring exposures to traumatic events. Thus, it is not surprising that PTSD inflicts rising costs to the Veteran's Administration and society, in general, due to loss of productivity and quality of life. The VA costs associated with paying PTSD-related disability have been steadily rising since 1999, and the treatment costs for personnel with PTSD returning from combat in 2005 were estimated to be nearly $205 million. It is clear that decreasing the number of veterans requiring treatment for PTSD would decrease VA costs associated with this disorder, not to mention increasing the quality of life for many veterans. Importantly, a previous history of PTSD or other anxiety disorders renders some people more susceptible to developing PTSD after subsequent traumatic events. Therefore, the large number of veterans with PTSD or with PTSD susceptibility, are more likely to develop PTSD when they experience non-combat trauma, such as auto accidents, assault, and natural disasters. Therefore, identifying susceptibility and ways to prevent it could decrease PTSD-associated VA costs. Understanding the risk factors for developing PTSD can help reduce the probability of occurrence after experiencing emotional trauma. The goal of this grant is to investigate whether altered hippocampal function is a risk factor or a consequence of experiencing a traumatic event that leads to a PTSD-like behavioral phenotype. If it is a risk factor, as our preliminary data suggest, it can be used as a neurofunctional marker of susceptibility. In these investigations, we will apply two indispensable tools. The first is a novel behavioral model we recently developed to pre-classify rats as susceptible or resistant to developing a PTSD-like phenotype (impaired extinction, lasting elevated startle response) before they experience emotional trauma (fear conditioning). The second tool is the sensitive cellular imaging method, co-developed by the PI, which can assess both size and overlap of neuronal ensembles activated by two distinct behavioral events. Aim 1 will investigate whether expression of plasticity-associated immediate-early genes, Arc and Homer 1a, in the hippocampal system is altered in susceptible compared to resistant rats before experiencing a traumatic event, as will be predicted if altered hippocampal function is a risk factor and not a consequence of PTSD. Size and overlap of ensembles activated by each of two exploration events will be assessed, along with neuronal density. A second experiment will test whether altered hippocampal function can lead to PTSD-like behaviors by attenuating Arc/H1a expression in resistant rats and then testing their fear extinction and lasting elevation in acoustc startle. Aim 2 will test whether altered encoding of a traumatic event, at the neural systems level, is part of the pathophysiology of a PTSD-like phenotype by assessing Arc/H1a expression in susceptible and resistant rats after they experience emotional trauma. Aim 3 will test whether the PTSD-like phenotype of susceptible rats can be reversed with 'cognitive exercise' known to engage the medial prefrontal cortex and hippocampus. Combined, this work will make fundamental discoveries about the role of the hippocampal system in the etiology of PTSD. The finding will inform future studies of how to design objective, within-subject tests for susceptibilty that will not depend on self-reporting and may be used as a supplemental tool in diagnosing PTSD. Findings from Aim 3 will suggest investigating treatments to confer resilience that have a high compliance rate, as they will be low-stress.