Injury-induced Alterations in Limbic Functional Circuity

描述(由申请人提供)：在美国，每年有50,000多人直接死于创伤性脑损伤(TBI)，而80,000名TBI幸存者表现出严重的神经后遗症。即使是相对较小的颅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)通常是由脑外伤引起的。在大脑中，在记忆形成中起关键作用的海马体经常表现出对脑外伤的脆弱性。有趣的是，这些损害也可能发生在有轻微或无局灶性神经缺陷的情况下。创伤性脑损伤在15-35岁年龄组中最常见，对这些患者的短期和长期护理具有显著的经济影响。利用小鼠模型，这项拟议的研究将研究脑外伤后边缘海马区的电生理、解剖学和分子变化。流体冲击损伤(FPI)通过诱导海马体依赖的认知功能障碍，是一种临床上相关且高度可靠的模拟脑损伤的方法。该项目的中心假说认为，颅脑损伤引起的认知障碍是可以解释的，部分原因是GABA能功能的病理改变，导致兴奋性和抑制性突触传递之间的区域性失衡，从而导致海马区功能障碍。为了验证这一假设，我们将对FPI后一周和假手术组动物海马区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胞外场记录技术进行评估。神经元的丢失将通过基于设计的体视学方法来确定，而介导GABA新陈代谢的蛋白质的变化将使用免疫组织化学和生化程序来检测。这种多方面的方法不仅将增加识别特定的损伤诱导的神经元功能变化的可能性，而且还可能阐明与创伤损伤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促进创新疗法的发展可能缓解这种毁灭性的疾病是必要的。

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.