Mechanisms of neuronal dysfunction in mild traumatic brain injury

本申请中描述的职业发展计划是实现长期目标的重要一步， 申请人开发新的治疗退伍军人遭受创伤性脑损伤（TBI）介导的 视力丧失和认知功能障碍，并成为VA系统的独立调查员。 本提案的研究目标是鉴定治疗爆炸诱发的中枢神经系统损伤的化合物。 使用分子、电生理学和药理学工具的组合来治疗系统功能障碍。的 实验将使用爱荷华州市退伍军人部开发的小鼠模型进行 预防和治疗视力丧失事务中心（CPTVL），具有眼部表型（视网膜 神经节细胞损伤）和神经功能缺损（学习、记忆和协调问题）， 人类轻度TBI在小鼠模型中产生异常神经元活动。在分子水平上， 神经元功能可能是主要抑制性神经递质γ-受体变化的结果。 氨基丁酸（GABA）。第一个目的是确定表达、组成和功能的分子变化。 GABAA受体在暴露于爆炸的小鼠的视网膜和脑中的定位。 第二个目标是找到减轻视网膜神经节细胞异常放电活动的治疗剂 我们发现爆炸引起的轻度创伤性脑损伤后会出现这种情况。电生理和药理学工具 将用于测试GABAA受体靶向药理学试剂对神经元活性的影响， 确定他们是否能在轻度TBI后恢复正常功能。GABAA受体可以被广泛的靶向。 各种充分表征的治疗剂（苯二氮卓类、巴比妥类、神经类固醇和吸入性 麻醉剂）调节它们的功能。通过定义GABAA的分子和功能变化 受体诱导的爆炸介导的创伤性脑损伤，药物，可以补偿的变化，在GABA能 可以识别和测试系统。使神经元活动正常化并防止神经元死亡， 我们假设，最终发生在表现出异常放电模式的神经元中， 视觉和认知功能。 确保所进行研究的临床适用性，并确保申请人学习必要的工具 和技能，进行基础研究，对转化为临床实践有很强的影响， 导师是一个执业精神病学家。培训和指导计划还包括与CPTVL的互动 研究人员，包括一名神经眼科医生，我们中心的主任，以及科学家和医疗人员， 与永利视觉研究所和爱荷华州临床研究所和 翻译科学。

The career development plan described in this application is an essential step in fulfilling the long-term goals of the applicant of developing novel therapeutics for Veterans suffering from traumatic brain injury (TBI)-mediated visual loss and cognitive dysfunctions and becoming an independent investigator in the VA system. The research objective of this proposal is to identify compounds that treat blast-induced central nervous system dysfunctions using a combination of molecular, electrophysiologic and pharmacologic tools. The experiments will be performed using a mouse model developed at the Iowa City Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss (CPTVL) that has an ocular phenotype (retinal ganglion cell damage), and neurological deficits (learning, memory and coordination problems) present in humans. Mild TBI generates abnormal neuronal activity in the mouse model. At molecular level, the abnormal neuronal function could be the result of changes in the receptors of the main inhibitory neurotransmitter γ- aminobutyric acid (GABA). The first aim is to identify molecular changes in the expression, composition and localization of GABAA receptors in the retina and the brain of mice exposed to blast. The second aim is to find therapeutic agents that mitigate the abnormal firing activity of retinal ganglion cells that we have discovered to occur following blast-induced mild TBI. Electrophysiologic and pharmacologic tools will be used to test the effects of GABAA receptor targeting pharmacologic agents on neuronal activity to establish if they can restore proper function after mild TBI. The GABAA receptors can be targeted by a wide variety of well-characterized therapeutic agents (benzodiazepines, barbiturates, neurosteroids and inhaled anesthetics) that modulate their function. By defining the molecular and functional changes in the GABAA receptors induced by blast-mediated TBI, drugs that can compensate for the alterations in the GABAergic system can be identified and tested. Normalizing the neuronal activity and preventing the death of neurons, which we assume, ultimately, occurs in neurons exhibiting abnormal firing patterns, will result in preserved visual and cognitive functions. To ensure the clinical applicability of the research performed and that the applicant learns the necessary tools and skills to perform basic research with strong implications for translation into clinical practice, one of the mentors is a practicing psychiatrist. The training and mentoring plans also include interactions with the CPTVL Investigators, including a neuro-ophthalmologist, the Director of our Center, and the scientists and medical doctors associated with The Wynn Institute for Vision Research and the Iowa Institute for Clinical and Translational Science.