Injury-induced Alterations in Limbic Functional Circuity

描述（由申请人提供）：在美国，每年有超过50，000例死亡直接归因于创伤性脑损伤（TBI），而80，000名TBI幸存者表现出严重的神经学后遗症。即使是相对轻微的TBI也可能导致对功能表现的持续负面影响。更严重的认知功能障碍（例如，智力和记忆损伤、情绪不稳定和注意力下降）通常由TBI引起。在大脑中，海马体在记忆形成中起着关键作用，表现出对TBI的频繁脆弱性。有趣的是，这些损伤也可能发生在极轻微或不存在局灶性神经功能缺损的情况下。TBI在15-35岁年龄组中最常见，并且这些患者的短期和长期护理与显著的财务后果相关。使用小鼠模型，拟议的研究将调查脑外伤后边缘海马的电生理，解剖和分子改变。液压冲击损伤（FPI），通过诱导大脑皮层依赖的认知障碍，是一种临床相关的和高度可靠的模式，模仿TBI。 该项目的中心假设认为，TBI诱导的认知缺陷可以部分解释为GABA能功能的病理学改变，这种病理学改变导致兴奋性和抑制性突触传递之间的区域失衡，从而导致海马功能障碍。为了检验这一假设，我们将对FPI后一周和假手术动物海马中GABA A介导的突触功能的解剖学和生理学改变进行详细的时间和空间测定和表征。将使用膜片钳和胞外场记录技术评估突触传递的改变。神经元损失将通过基于设计的体视学方法确定，而介导GABA代谢的蛋白质的变化将使用免疫组织化学和生物化学程序进行检查。这种多方面的方法不仅可以增加识别特定损伤诱导的神经元功能改变的可能性，而且还可以阐明与创伤性脑损伤相关的潜在分子机制。了解这些变化的功能和分子性质是必要的，以加强创新疗法的发展，以减轻这种破坏性的条件。

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.