Injury-induced Alterations in Limbic Functional Circuity

损伤引起的边缘功能回路的改变

• 批准号: 6872855
• 负责人: Akiva S Cohen
• 金额: $ 31.35万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872855
• 关键词: behavior test; brain electrical activity; brain injury; cognition; disease /disorder model; gamma aminobutyrate; hippocampus; immunocytochemistry; laboratory mouse; limbic system; long term potentiation; morphometry; neural plasticity; neural transmission; neurotransmitter metabolism; neurotransmitter transport; protein structure function; synapses; transport proteins; voltage /patch clamp

DESCRIPTION (provided by applicant): More than 50,000 deaths are directly attributable to traumatic brain injury (TBI) annually in the U.S., while 80,000 TBI survivors exhibit significant neurologic sequelae. Even relatively minor TBI may lead to persistent negative consequences on functional performance. More serious disorders of higher cognitive function (e.g., intellectual and memory impairment, emotional lability, and decreased concentration) commonly result from TBI. In the brain, the hippocampus, which plays a critical role in memory formation, demonstrates frequent vulnerability to TBI. Interestingly, these impairments may also occur with minimal or absence of focal neurological deficit. TBI is most common in the 15-35 year age group, and significant financial ramifications are associated with the short and long term care of these patients. Using a mouse model, the proposed research will investigate the electrophysiological, anatomical and molecular alterations of the limbic hippocampus following TBI. Fluid percussion injury (FPI), through induction of hippocampus-dependent cognitive impairment, is a clinically relevant and highly reliable modality for mimicking TBI. The central hypothesis of this project contends that TBI induced cognitive deficits are explicable, in part, by pathological alterations in GABAergic function that precipitate regional imbalances between excitatory and inhibitory synaptic transmission, thereby causing hippocampal dysfunction. To test this hypothesis, we will undertake a detailed temporal and spatial determination and characterization of the anatomical and physiological alterations in GABAA-mediated synaptic function in the hippocampus of one week post- FPI and sham animals. Alterations in synaptic transmission will be assessed using patch clamp and extracellular field recording techniques. Neuronal loss will be determined by design-based stereological methodology, while changes in proteins mediating GABA metabolism will be examined using immunohistochemical and biochemical procedures. Such a multifaceted approach will not only increase the probability of identifying the specific injury-induced alterations in neuronal function, but may also elucidate the underlying molecular mechanisms associated with the traumatically injured brain. Understanding both the functional and molecular nature of these changes is necessary to potentiate the development of innovative therapies to possibly alleviate this devastating condition.

描述（由申请人提供）：在美国，每年有50,000多例死亡直接归因于脑损伤（TBI），而80,000个TBI幸存者表现出明显的神经系统后遗症。即使是相对较小的TBI，也可能导致对功能性能的持续负面影响。 TBI通常会导致更严重的认知功能（例如智力和记忆障碍，情绪不稳定和浓度降低）的更严重的疾病。在大脑中，海马在记忆形成中起着至关重要的作用，表现出频繁的TBI脆弱性。有趣的是，这些障碍也可能导致最小或缺乏局灶性神经缺陷。 TBI在15-35岁年龄段中最常见，并且有重大的财务影响与这些患者的短期和长期护理有关。使用小鼠模型，提出的研究将研究TBI后边缘海马的电生理，解剖和分子改变。流体打击乐损伤（FPI）通过诱导海马依赖性认知障碍，是模仿TBI的临床相关且高度可靠的方式。 该项目的中心假设认为，TBI诱导的认知缺陷在某种程度上是通过GABA能功能的病理改变来阐明的，这会导致兴奋性和抑制性突触传播之间的区域失衡，从而导致肺泡功能障碍。为了检验这一假设，我们将在FPI和假动物后一周的海马中对GABAA介导的突触功能的解剖学和生理变化进行详细的时间和空间确定和表征。突触传播的改变将使用斑块夹和细胞外田间记录技术进行评估。神经元丧失将由基于设计的立体方法论确定，而介导GABA代谢的蛋白质的变化将使用免疫组织化学和生化程序检查。这种多方面方法不仅会增加识别特定损伤诱导的神经元功能改变的可能性，而且还可能阐明与创伤受伤的大脑相关的潜在分子机制。了解这些变化的功能和分子性质对于增强创新疗法的发展是必要的，以减轻这种毁灭性的状况。