Injury-induced Alterations in Limbic Functional Circuity

描述（由申请人提供）：在美国，创伤性脑损伤（TBI）每21秒发生一次，每年折磨多达200万人，是年轻人和儿童死亡和残疾的主要原因。现在已知最初的TBI损伤传播长期的继发性异质性病理，这是长期发病的基础。海马体是一种对学习和记忆至关重要的大脑结构，也是癫痫发作的常见部位，在TBI期间经常受损。然而，损伤诱导的细胞代谢、神经递质功能和突触可塑性的变化如何导致局部海马兴奋性的改变，从而导致创伤后认知障碍和癫痫发作，仍然是未知的。我们的实验室已经阐明了受损海马中代谢和电生理变化之间的新联系。我们以前已经确定，抑制效果减弱会损害齿状回功能。此外，我们已经确定了海马功能中的几种分子和代谢适应，这些适应可能是传入输入的齿状回过滤效率降低和海马长时程增强抑制的基础，包括氯转运蛋白KCC2表达降低，NMDA受体介导的钙内流减少和必需氨基酸代谢中断。我们的长期目标是开发有效和耐受性良好的策略，以改善与TBI相关的病理学。本申请的目的是了解损伤引起的海马兴奋性和代谢改变的原因和后果。我们的初步数据导致了以下中枢假设的形成：TBI诱导的神经元氨基酸代谢的改变导致海马兴奋性的区域变化，这与氯离子转运和钙介导的信号传导的中断一起，导致癫痫发作和认知缺陷的易感性增加。为了验证这一假设，一个多学科的方法，侧重于阐明基本机制，将检查兴奋和抑制功能，以及海马子区域的神经元代谢。对这些机制的透彻理解将为指导开发潜在的治疗方法以改善TBI患者的认知功能障碍和癫痫发作提供见解。创伤性脑损伤（TBI）是一个重大的公共卫生问题，对我们的医疗保健系统有重大影响。对TBI相关残疾的年度成本进行的经济分析从45亿美元的直接支出（医疗保健和服务）到206亿美元的伤害相关工作损失和残疾。我们的长期目标是开发有效和耐受性良好的临床管理策略，以减少或改善TBI患者的认知功能障碍和癫痫发作。

DESCRIPTION (provided by applicant): In the United States, traumatic brain injury (TBI) occurs every 21 seconds, afflicts up to two million people annually, and is the primary cause of death and disability in young adults and children. The initial TBI lesion is now known to propagate long-lasting secondary heterogeneous pathologies, which underlie long term morbidities. The hippocampus, a brain structure crucial for learning and memory and also a frequent site of seizure initiation, is often damaged during TBI. It is still unknown however, how injury-induced changes in cellular metabolism, neurotransmitter function, and synaptic plasticity lead to the altered regional hippocampal excitability that contributes to post traumatic cognitive impairment and seizures. Our laboratory has elucidated novel connections between metabolic and electrophysiological alterations in the injured hippocampus. We have previously established that diminshed inhibitory efficacy compromises dentate gyrus function. Moreover, we have identified several molecular and metabolic adaptations in hippocampal function that may underlie reduced dentate gyrus filtering efficiency of afferent input and suppression of hippocampal long-term potentiation, including reduced expression of the chloride transporter KCC2, reduced NMDA receptor mediated calcium influx, and disruption of essential amino acid metabolism. Our long-range goal is to develop effective and well-tolerated strategies for ameliorating pathologies associated with TBI. The objective of this application is to understand the causes and consequences of injury-induced alterations in hippocampal excitability and metabolism. Our preliminary data led to the formulation of the following CENTRAL HYPOTHESIS: TBI-induced alteration in neuronal amino acid metabolism causes regional changes in hippocampal excitability, which together with disruptions in chloride transport and calcium mediated signaling, results in increased susceptibility to seizures and cognitive deficit. To test this hypothesis, a multi-disciplinary approach focused on elucidating basic mechanisms will examine excitatory and inhibitory function, as well as neuronal metabolism in hippocampal subregions. A thorough comprehension of these mechanisms will provide insight for directing the development of potential therapies to ameliorate cognitive dysfunction and seizures in TBI patients. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major public health issue, which has a significant impact upon our healthcare system. Economic analyses of the annual cost of TBI-related disabilities range from $4.5 billion in direct expenditure (medical care and services) to $20.6 billion in injury-related work loss and disability. Our long-range goal is to develop effective and well-tolerated clinical management strategies for reducing or ameliorating cognitive dysfunction and seizures in TBI patients.