Injury-induced Alterations in Limbic Functional Circuity

损伤引起的边缘功能回路的改变

• 批准号: 7813996
• 负责人: Akiva S Cohen
• 金额: $ 32.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813996
• 关键词: Amino Acids; Area; Basic Science; Brain; Brain Injuries; Branched-Chain Amino Acids; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calculi; Caring; Cause of Death; Child; Chloride Ion; Chlorides; Clinical; Clinical Management; Cognitive deficits; Comprehension; Convulsions; Cytoplasmic Granules; Data; Depressed mood; Development; Direct Expenditure; Drug Formulations; Economics; Equilibrium; Essential Amino Acids; Functional disorder; Future; Glutamates; Goals; Healthcare Systems; Hippocampus (Brain); Human; Impaired cognition; Infusion procedures; Injury; Isoleucine; Laboratories; Lateral; Lead; Learning; Lesion; Leucine; Long-Term Potentiation; Mediating; Medical; Memory; Metabolic; Metabolism; Methodology; Modeling; Molecular; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; Neurons; Neurotransmitters; Pathology; Patients; Predisposition; Public Health; Research; Rodent; Seizures; Services; Signal Transduction; Site; Stress; Structure; Synapses; Synaptic plasticity; Testing; Traumatic Brain Injury; United States; Valine; Water; Work; calmodulin-dependent protein kinase II; cost; dentate gyrus; disability; fluid percussion injury; hippocampal subregions; improved; injured; insight; mouse model; neurotransmission; neurotransmitter metabolism; novel; postsynaptic; public health relevance; receptor function; young adult

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.

描述（由申请人提供）：在美国，每21秒发生创伤性脑损伤（TBI），每年遭受多达200万人的折磨，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病变可以传播长期持久的二次异质性病变，这是长期病毒的基础。海马是一种对学习和记忆至关重要的大脑结构，也是经常发生的癫痫发作部位，在TBI期间经常受到损害。然而，尚不清楚，损伤引起的细胞代谢，神经递质功能和突触可塑性的变化如何导致区域海马兴奋性改变，这有助于后创伤后认知障碍和癫痫发作。我们的实验室阐明了损伤海马的代谢和电生理改变之间的新联系。我们以前已经确定，抑制疗效降低会损害齿状回的功能。 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.我们的远程目标是制定有效且耐受性良好的策略，以改善与TBI相关的病理。该应用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心假设的制定：TBI诱导的神经氨基酸代谢改变会导致海马兴奋性的区域变化，这与氯化物传输和钙介导的信号的破坏一起导致对癫痫发作和认知缺陷的易感性增加。为了检验这一假设，以阐明基本机制为重点的多学科方法将检查兴奋性和抑制性功能，以及海马子区域中的神经元代谢。对这些机制的彻底理解将为指导潜在疗法的发展，以改善TBI患者的认知功能障碍和癫痫发作。公共卫生相关性：创伤性脑损伤（TBI）是一个主要的公共卫生问题，对我们的医疗保健系统产生了重大影响。与TBI相关残疾的年成本的经济分析范围从45亿美元的直接支出（医疗服务和服务）到与伤害有关的工作损失和残疾的206亿美元。我们的远程目标是制定有效且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。