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

共病 TBI-PTSD 模型中皮质活动减退的纵向评估

• 批准号: 9046401
• 负责人: ALANA C. CONTI
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046401
• 关键词: AMPA Receptors; Address; Affect; Afghanistan; Attention; Behavior; Behavioral; Cognitive; Comorbidity; Conflict (Psychology); Creatine; Data; Diagnosis; Dose; Energy Metabolism; Functional Magnetic Resonance Imaging; Glutamate Transporter; Glutamates; Glutamine; Health; Human; Imaging Techniques; Impaired cognition; Impairment; In Vitro; Injury; Inositol; Intervention; Iraq; Knowledge; Long-Term Effects; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manganese; Measurement; Measures; Mediating; Medical; Memantine; Military Personnel; Mission; Modeling; Molecular; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-acetylaspartate; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevalence; Protons; Receptor Activation; Recovery; Rehabilitation therapy; Risk; Stress; Structure; Symptoms; Techniques; Testing; Tissues; Traumatic Brain Injury; Veterans; Weight; associated symptom; behavior measurement; behavioral outcome; combat; design; experience; functional outcomes; gray matter; imaging modality; improved; in vivo; innovation; mild traumatic brain injury; molecular marker; mouse model; nervous system disorder; neurochemistry; neurotransmission; novel; object recognition; operation; preclinical study; receptor expression; rehabilitation management; rehabilitation strategy; tool

 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.

 描述（由申请人提供）： 在退伍军人中，阿富汗和伊拉克的战斗行动与创伤性脑损伤（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，与PTSD同时发生的与TBI相关伤害的人，在部署后延迟时会担心症状。 PTSD-TBI的复杂作用使对弗吉尼亚州，军事和平民医疗设施的挑战的诊断，管理，治疗和康复造成了诊断，管理，治疗和康复。它变得越来越重要 与单独使用TBI或PTSD相关的症状相比，合并症PTSD-TBI的退伍军人的认可症状在康复期间。最近，一种重点是解释合并症PTSD-TBI的复合作用的一种机制是皮质激活受损，这种情况仅在TBI或PTSD后观察到了这种情况。 TBI本身会导致皮质神经元的不连续性，这反映在受ONL PTSD影响的患者中。令人惊讶的是，迄今为止，很少有临床前研究评估联合TBI和PTSD对前额叶皮层中神经元活动的影响，从而增加了所提出的项目的重要性和概念创新。通过使用轻度，非凸性TBI和PTSD的小鼠模型，将通过检查合并症PTSD-TBI中的皮质性低激活来解决该知识差距。皮质低激活将在许多级别上进行评估，包括兴奋，树突结构，皮质体积，神经元激活和皮质介导的行为。该应用的强度是对从受体表达和激活到行为测量以及使用新型成像方式的皮质功能的全面分析，以检查症状的纵向进展。此外，使用新型的谷氨酸能化合物（例如美容剂）进行的康复干预措施将被聘为合并症PTSD-TBI的翻译疗法。我们将检验这一假设，即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，与单独的条件以及这些缺陷的Neutione recretiention recretiention cretiention cretiention cretiention cretiention。我们将使用以下特定目的检验这一假设：1。）评估合并PTSD-TBI对单独情况的兴奋性神经传递的认知行为，神经元结构和标志物的影响。 (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 defines associated with PTSD-TBI and thereby, to improve cognitive behaviors and cortical function.