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

定义创伤性脑损伤后皮质扩散去极化对海马的远程影响

• 批准号: 10566200
• 负责人: LAURA Benjamin NGWENYA
• 金额: $ 65.28万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566200
• 关键词: Adult; Animals; Area; Brain; Brain Injuries; Brain region; Caring; Cessation of life; Chemicals; Clinical; Clinical Research; Data; Development; Electrophysiology (science); Experimental Models; Generations; Genetic; Gliosis; Goals; Hippocampus; Histopathology; Hospitalization; Human; Injury; Interphase Cell; Intervention; Knowledge; Lateral; Learning; Mediator; Memory; Modeling; Morphology; Neurons; Outcome; Pathologic; Pathology; Patients; Pattern; Process; Proliferating; Property; Rattus; Seizures; Survivors; Synapses; TBI Patients; Testing; Therapeutic; Tissues; Traumatic Brain Injury; United States; adult neurogenesis; designer receptors exclusively activated by designer drugs; entorhinal cortex; experience; experimental study; fluid percussion injury; granule cell; improved outcome; injured; injury-related death; insight; neural circuit; neuron loss; optogenetics; prevent; remote assessment; therapy development

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.

项目摘要 美国每年有超过223，000名创伤性脑损伤（TBI）患者住院， 每天有超过166人死亡。过去二十年的临床研究已经证明， 皮层扩散去极化（CSD），也被称为“脑海啸”，是电活动的波， 发生在60%的TBI患者中。CSD是大量神经元去极化的波， 在TBI患者中，电沉默与6个月的不良结局独立相关。是 目前尚不清楚CSD是否会导致局部皮质扩散区域以外的损伤，也不清楚CSD是如何造成损伤的。 导致创伤性脑损伤后预后不佳。我们假设CSD在TBI脑的海马中引起远程效应 导致不良结果的因素。我们将在TBI和CSD的实验模型中测试这一假设。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。而且 将测试CSD是否通过跨突触机制引起远程效应。了解遥控器 CSD的影响将为我们在临床观察CSD时如何看待CSD提供一个范式转变， 并提供对创伤性脑损伤治疗的见解。