Defining the remote effects of cortical spreading depolarizations on hippocampus after traumatic brain injury

项目总结 美国每年有超过22.3万名创伤性脑损伤(TBI)患者住院，其中 每天有超过166人死亡。过去二十年的临床研究已经证明， 大脑皮层扩散去极化(CSD)，也被称为“脑海啸”，是一种电波活动， 发生在60%的创伤性脑损伤患者。CSD是大量神经元去极化的波，会导致周期性的 电性沉默和脑损伤患者6个月预后较差独立相关。它是 尚不清楚CSD是否会造成局部皮质以外的损害，也不知道CSD是如何造成损害的 导致颅脑损伤后预后不良。我们假设CSD对脑损伤后的海马区有远程影响。 这导致了糟糕的结果。我们将在TBI和CSD的实验模型中验证这一假设。我们 将定义CSD对电生理学、组织病理学和成人神经发生的远程影响。此外，它还 将测试CSD是否通过跨突触机制引起远程影响。了解远程 CSD的影响将提供一种范式转换，当临床观察CSD时，我们如何看待CSD， 并提供对脑外伤疗法的洞察。

PROJECT SUMMARY Over 223,000 patients with traumatic brain injury (TBI) are hospitalized in the United States annually, with more than 166 deaths each day. It has been demonstrated over the past two decades of clinical research that cortical spreading depolarizations (CSDs), also known as “brain tsunamis,” are waves of electrical activity that occur in 60% of patients with TBI. CSDs are waves of massive neuronal depolarization that cause periods of electrical silencing and are independently associated with worse 6-month outcomes in TBI patients. It is unknown whether CSDs cause damage beyond the area of local cortical spread, and it is unknown how CSDs cause poor outcomes after TBI. We hypothesize that CSDs cause remote effects in hippocampus of TBI brain that contribute to poor outcomes. We will test this hypothesis in an experimental model of TBI and CSDs. We will define CSDs remote effects on electrophysiology, histopathology, and adult neurogenesis. Additionally, it will be tested whether CSDs cause remote effects via a trans-synaptic mechanism. Understanding the remote effects of CSDs will provide a paradigm shift in how we think about CSDs when they are observed clinically, and provide insight into TBI therapeutics.