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人的死亡直接归因于创伤性脑损伤（TBI），而80,000名TBI幸存者表现出明显的神经系统后遗症。即使是相对较小的创伤性脑损伤也可能对功能表现造成持续的负面影响。更严重的高级认知功能障碍（如智力和记忆障碍、情绪不稳定和注意力下降）通常由创伤性脑损伤引起。在大脑中，海马体在记忆形成中起着至关重要的作用，它经常表现出对创伤性脑损伤的脆弱性。有趣的是，这些损伤也可能发生在轻微或没有局灶性神经缺陷的情况下。TBI最常见于15-35岁年龄组，对这些患者的短期和长期护理会产生重大的经济后果。利用小鼠模型，研究脑外伤后边缘海马的电生理、解剖和分子变化。液体冲击损伤（FPI）通过诱导海马体依赖性认知损伤，是临床相关且高度可靠的模拟TBI模式。该项目的中心假设认为，脑损伤引起的认知缺陷部分可以通过gaba能功能的病理改变来解释，这种改变会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。为了验证这一假设，我们将对FPI后一周和假手术动物海马gabaa介导的突触功能的解剖和生理变化进行详细的时间和空间测定和表征。突触传递的改变将使用膜片钳和细胞外场记录技术进行评估。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通过免疫组织化学和生化程序进行检查。这种多方面的方法不仅将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对于促进创新疗法的发展以可能减轻这种破坏性疾病是必要的。

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.