Spreading Depolarizations and Brain Dysfunction Following Traumatic Brain Injury

项目摘要 创伤性脑损伤（TBI）每年影响美国280万人，但尽管 TBI的认识和社区兴趣，没有有效的干预TBI相关的发病率， 尤其是认知障碍有趣的是，超过50%的TBI患者显示皮质扩散， 去极化（SD）在他们住院期间。这些“脑海啸”是死亡率的预测因子， 伤后发病率。尽管SD经常发生在TBI之后，但SD和TBI的综合影响是 未知本研究将确定SD对TBI诱导的病理学的影响， 指导有针对性的治疗干预。我们的总体假设是， TBI后的去极化加剧了脑病理学，尤其是破坏了海马功能。我们 将通过在TBI大鼠模型中诱导SD来测试这一点，并解决三个具体目标。在目标1中， 研究TBI+ SD是否引起更大的损伤病理学和异常神经发生。在目标2中， 确定SD是否导致海马依赖行为和癫痫的缺陷。在我们的探索中， 目的3对海马齿状回细胞进行单细胞RNA测序，以确定细胞类型 特定的分子干扰，以指导未来的研究。该提案将使Ngwenya博士了解新的 实验和分析技术，这将有助于她作为一个独立的研究人员的发展， 使她能够提出和回答转化神经科学中最大可能的问题。

Project Summary Traumatic brain injury (TBI) affects 2.8 million people in the US annually, but despite the heightened awareness and community interest in TBI, there are no effective interventions for TBI associated morbidities, especially cognitive impairment. Interestingly, more than 50% of patients with TBI show cortical spreading depolarizations (SDs) during their hospitalization. These “brain tsunamis” are a predictor of mortality and morbidity after injury. Despite the fact that SDs occur often after TBI, the combined impact of SDs and TBI is unknown. The present study will determine the impact of SDs on TBI-induced pathology, providing critical guidance for targeted therapeutic intervention. Our overall hypothesis is that the occurrence of spreading depolarizations after TBI exacerbates brain pathology and is especially disruptive of hippocampal function. We will test this by inducing SDs in a rat model of TBI and addressing three specific aims. In Aim 1 we will investigate whether TBI+SDs causes greater injury pathology and aberrant neurogenesis. In Aim 2 we will determine whether SDs lead to deficits in hippocampal dependent behaviors and epilepsy. In our exploratory Aim 3 we will conduct single cell RNA sequencing on hippocampal dentate gyrus cells to identify cell-type specific molecular disturbances to guide future studies. The proposal will allow Dr. Ngwenya to learn new experimental and analytic techniques that will aid in her development as an independent researcher and position her to ask and answer the largest possible questions in translational neuroscience.