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）： 阿富汗和伊拉克的战斗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 TBI 相关损伤并伴有 PTSD 的人，在部署后的延迟期间会经历症状恶化。 PTSD-TBI 的复合效应使受影响者的诊断、管理、治疗和康复成为退伍军人管理局、军队和民用医疗机构的挑战。这已变得越来越重要 与仅与 TBI 或 PTSD 相关的症状相比，在康复期间识别患有共病 PTSD-TBI 的退伍军人的症状。最近引起关注的解释共病 PTSD-TBI 复合效应的一个机制是皮质激活受损，这种情况在单独 TBI 或 PTSD 后观察到。 TBI 本身会导致皮质神经元活动减退，这在仅患有 PTSD 的患者中也有反映。令人惊讶的是，迄今为止，很少有临床前研究来评估 TBI 和 PTSD 联合对前额皮质神经元活动的影响，这增加了该项目的意义和概念创新。这一知识差距将在当前的应用中通过使用轻度、非挫伤性 TBI 和 PTSD 小鼠模型检查共病 PTSD-TBI 中的皮质功能低下来解决。皮质低活性将在多个层面进行评估，包括兴奋性神经传递标记、树突结构、皮质体积、神经元激活和皮质介导的行为。该应用的优势在于对皮质功能（从受体表达和激活到行为测量）的综合分析，并使用新型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（例如美金刚）的康复干预措施将被用作共病 PTSD-TBI 的翻译相关疗法。我们假设，与单独的任何一种情况相比，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，并且这些缺陷将通过神经治疗干预得到逆转。我们将使用以下具体目标来检验这一假设： 1.) 与单独的任何一种情况相比，评估共病 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，2.) 量化共病 PTSD-TBI 对皮质神经递质水平（神经化学）、体积（结构）和神经激活的长期影响 （功能）与单独使用任一条件相比，在体内以纵向方式使用新型磁共振（MR）成像技术，3.）评估神经治疗治疗改善/恢复与 PTSD-TBI 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。