Longitudinal Assessment of Cortical Hypoactivity in a Model of Comorbid TBI-PTSD

 描述(由申请人提供)： 在阿富汗和伊拉克的作战行动与退伍军人中创伤性脑损伤(TBI)和创伤后应激障碍(PTSD)的患病率增加有关。最近的数据表明，那些患有创伤后应激障碍的人，在延迟的部署后阶段，症状会恶化。创伤后应激障碍-创伤性脑损伤的综合影响使受影响的患者的诊断、管理、治疗和康复成为退伍军人管理局、军事和民用医疗机构面临的挑战。它已经变得越来越重要 在康复期，与单纯的创伤后应激障碍或创伤后应激障碍相关的症状相比，识别患有创伤后应激障碍的退伍军人的症状。最近成为焦点的一种机制解释了并发PTSD-TBI的复合效应是皮质激活受损，这是在TBI或PTSD单独发生后观察到的情况。脑外伤本身会导致皮质神经元活动不足，这在受ONL PTSD影响的患者中也是如此。令人惊讶的是，到目前为止，很少有临床前研究评估TBI和PTSD联合治疗对前额叶皮质神经元活动的影响，这增加了拟议项目的意义和概念创新。在目前的应用中，这一知识缺口将通过使用轻度、非挫伤性脑损伤和创伤后应激障碍的小鼠模型，通过检查并发PTSD-TBI的皮质低激活来解决。将在多个水平上评估皮质活性低下，包括兴奋性神经传递、树突结构、皮质体积、神经元激活和皮质介导的行为的标志物。这一应用的优势是对从受体表达和激活到行为测量的皮质功能进行全面分析，并使用新的成像方式来检查症状的纵向进展。此外，使用新型谷氨酸能化合物的康复干预措施，如美金刚，将被用作与翻译相关的疗法，用于治疗并发的PTSD-TBI。我们假设，与任何一种情况相比，PTSD-TBI的组合将加剧行为和分子终点、兴奋性神经递质水平的功能/结构评估、树突形态、皮质体积、神经元可塑性和皮质激活，这些缺陷将被神经治疗干预逆转。我们将使用以下具体目标来检验这一假设：1)(1.评估与单独情况相比，合并PTSD-TBI对认知行为、神经元结构和兴奋性神经传递标志物的影响。)与单独使用任何一种情况相比，使用新的磁共振(MR)成像技术在体内以纵向方式量化并发PTSD-TBI对皮质神经递质水平(神经化学)、体积(结构)和神经激活(功能)的长期影响，3)评估神经治疗改善/恢复与创伤后应激障碍相关的结构和神经递质相关缺陷的能力，从而改善认知行为和皮质功能。

 DESCRIPTION (provided by applicant): Combat operations in Afghanistan and Iraq have been associated with increased prevalence of both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) among veterans. Recent data demonstrate that those with TBI-related injuries concurrent with PTSD, experience worsening of symptoms in the delayed post- deployment period. The compounded effects of PTSD-TBI make the diagnosis, management, treatment, and rehabilitation of those affected a challenge in VA, military, and civilian medical facilities. It has become increasingly important to recognize symptoms in veterans with comorbid PTSD-TBI compared to those symptoms associated with TBI or PTSD alone, in the rehabilitation period. One mechanism to have recently come into focus to explain the compounded effects of comorbid PTSD-TBI is impaired cortical activation, a condition that has been observed following either TBI or PTSD alone. TBI itself results in hypoactivity of cortical neurons, which is mirrored in patients affected with onl PTSD. Surprisingly, to date, there have been few preclinical studies to evaluate the impact of combined TBI and PTSD on neuronal activity in the prefrontal cortex, adding to the significance and conceptual innovation of the proposed project. This knowledge gap will be addressed in the current application by examining cortical hypoactivation in comorbid PTSD-TBI, using mouse models of mild, non-contusive TBI and PTSD. Cortical hypoactivation will be evaluated at numerous levels, including markers of excitatory neurotransmission, dendritic structure, cortical volume, neuronal activation and cortically-mediated behaviors. The strength of this application is the comprehensive analysis of cortical function from receptor expression and activation to behavioral measures and use of novel imaging modalities to examine the longitudinal progression of symptoms. In addition, rehabilitative interventions using novel glutamatergic compounds, such as memantine, will be employed as translationally-relevant therapies for comorbid PTSD-TBI. We hypothesize that the combination of PTSD-TBI will exacerbate behavioral and molecular endpoints, functional/structural assessments of excitatory neurotransmitter levels, dendritic morphology, cortical volume, neuronal plasticity and cortical activation compared to either condition alone and that these deficits will be reversed by neurotherapeutic intervention. We will test this hypothesis using the following Specific Aims: 1.) Evaluate the influence of comorbid PTSD- TBI on cognitive behaviors, neuronal structure and markers of excitatory neurotransmission compared to either condition alone, 2.) Quantify the long-term impacts of comorbid PTSD-TBI on cortical neurotransmitter levels (neurochemical), volume (structural) and neuroactivation (functional) using novel magnetic resonance (MR) imaging techniques in a longitudinal manner in vivo compared to either condition alone, 3.) Evaluate the ability of neurotherapeutic treatment to improve/restore structural and neurotransmitter-related deficits associated with PTSD-TBI and thereby, to improve cognitive behaviors and cortical function.