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

海马功能受损是创伤后应激障碍的危险因素

• 批准号: 8803351
• 负责人: Almira Vazdarjanova
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803351
• 关键词: Accidents; Address; Affect; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Attenuated; Behavior; Behavior Therapy; Behavioral; Behavioral Model; Brain; Cognitive; Data; Development; Diagnosis; Disease; Elements; Etiology; Event; Exercise; Exposure to; Extinction (Psychology); Freedom; Fright; Functional disorder; Future; Goals; Grant; Health; Hippocampus (Brain); Homer 1a; Human Resources; Imaging Techniques; Immediate-Early Genes; Individual; Investigation; Lateral; Lead; Medial; Memory; Methods; Modeling; Natural Disasters; Neurons; Patient Self-Report; Pattern; Pharmacological Treatment; Phenotype; Physiological; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Prevalence; Probability; Process; Prosencephalon; Quality of life; Rattus; Recording of previous events; Recovery; Research; Resistance; Rewards; Risk Factors; Role; Series; Silicon Dioxide; Societies; Stimulus; Stream; Stress; System; Techniques; Testing; Training; Trauma; Treatment Cost; United States Department of Veterans Affairs; Veterans; Work; anxiety-related disorders; assault; cellular imaging; combat; conditioned fear; cost; density; design; disability; emotional trauma; entorhinal cortex; experience; imaging modality; memory process; novel; operation; payment; prevent; productivity loss; relating to nervous system; research study; resilience; response; tool; traumatic event

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.

描述(由申请人提供)： 据估计，暴露在创伤事件中的人中有20%-30%会患上创伤后应激障碍(PTSD)，164万名美国士兵被部署在游击式战斗(持久自由行动和伊拉克自由行动)中，这种战斗具有高度不可预测和反复暴露于创伤事件的风险。因此，创伤后应激障碍导致成本上升也就不足为奇了 对于退伍军人管理局和社会来说，由于失去了生产力和质量， 生活。自1999年以来，支付与创伤后应激障碍相关的伤残费用一直在稳步上升，2005年从战斗中返回的创伤后应激障碍患者的治疗费用估计接近2.05亿美元。显然，减少需要治疗创伤后应激障碍的退伍军人人数将减少与这种疾病相关的退伍军人费用，更不用说提高许多退伍军人的生活质量了。重要的是，以前有创伤后应激障碍或其他焦虑症的病史使一些人在随后的创伤事件后更容易患上创伤后应激障碍。因此，大量患有创伤后应激障碍或患有创伤后应激障碍易感性的退伍军人，在经历车祸、袭击和自然灾害等非战斗创伤时，更有可能患上创伤后应激障碍。因此，确定易感性和预防方法可以降低与创伤后应激障碍相关的VA成本。了解发生创伤后应激障碍的风险因素有助于降低经历情感创伤后发生创伤后的可能性。这项资助的目的是调查海马体功能改变是否是经历导致创伤后应激障碍样行为表型的创伤性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，它可以被用作易感性的神经功能标志。在这些调查中，我们将使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，在经历情感创伤(恐惧条件反射)之前，将大鼠预先分类为易患或抵抗形成类似创伤后应激障碍的表型(灭绝受损，持续升高的惊吓反应)。第二个工具是由PI共同开发的敏感细胞成像方法，它可以评估由两个不同的行为事件激活的神经元集合的大小和重叠。目的1研究易感大鼠与耐受大鼠相比，在经历创伤事件之前，海马区可塑性相关即刻早期基因Arc和Hmer 1a的表达是否发生改变，如果海马区功能改变是创伤后应激障碍的危险因素而不是后果，将会被预测。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，以及神经元密度。第二个实验将通过减弱耐药大鼠Arc/H1a的表达，然后测试它们在声音惊吓中的恐惧消退和持续升高，来测试海马体功能改变是否会导致类似创伤后应激障碍的行为。目的2将通过评估易感和抵抗大鼠在经历情绪创伤后Arc/H1a的表达，在神经系统水平上测试创伤事件编码的改变是否是创伤后应激障碍样表型的病理生理学的一部分。目的3将测试易感大鼠的类似创伤后应激障碍的表型是否可以通过已知的参与内侧前额叶皮质和海马区的“认知练习”来逆转。总而言之，这项工作将对海马体系统在创伤后应激障碍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，说明如何设计客观的、受试者内的易感性测试，而不依赖于自我报告，并可能被用作诊断创伤后应激障碍的补充工具。来自AIM 3的研究结果将建议研究具有高依从性的弹性治疗方法，因为它们将是低压力的。