Spreading depolarizations and brain dysfunction following traumatic brain injury

项目摘要 在美国，每年有280万人受到创伤性脑损伤的影响，但尽管 尽管人们对脑外伤的认识和社区兴趣不高，但对脑外伤相关疾病尚无有效的干预措施， 尤其是认知障碍。有趣的是，超过50%的脑损伤患者表现为皮质扩散。 住院期间进行去极化(SD)治疗。这些“脑海啸”是死亡率和 受伤后的发病率。尽管重型颅脑损伤后经常发生抑郁，但重型颅脑损伤和重型颅脑损伤的综合影响是 未知。本研究将确定十二烷基硫酸钠对颅脑损伤病理的影响，提供关键的 有针对性的治疗干预指导。我们的总体假设是，传播的发生 脑外伤后的去极化加剧了大脑的病理，尤其是对海马体功能的破坏。我们 我将通过在脑外伤大鼠模型中诱导抑郁来测试这一点，并解决三个特定的目标。在目标1中，我们将 研究TBI+十二烷基硫酸钠是否会导致更大的损伤病理和异常神经发生。在《目标2》中我们将 确定十二烷基硫酸钠是否导致海马区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。该提案将允许恩文亚博士学习新的 实验和分析技术将有助于她作为一名独立研究人员的发展和 让她在翻译神经科学中提出和回答最大可能的问题。

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.