Research 3- Morton

项目摘要 该项目涉及可能导致脑震荡急性症状的基本机制， 与轻度脑外伤有关我们的长期目标是增加对潜在机制的理解， 急性神经功能障碍，从而可以大大改善诊断和/或治疗。这项工作是 预计对大量患有脑震荡的人来说意义重大，包括 有相当多的人在单次或多次击中后不能完全恢复。该项目的重点是 扩散去极化（SD）现象，其相对最近已经出现，作为 重症监护病房中严重创伤性脑损伤或卒中患者的病变进展。非常有限 了解SD是否发生在其他神经系统疾病中。2018年，我们提出了第一个证据， SD发生在小鼠脑震荡模型中，另一组提供了第一篇间接的 在类似的模型中测量SD。现在的挑战是提供额外的直接电生理 SD的记录，结合行为的同时测量，以确定是否脑震荡诱导 SDs是众所周知的脑震荡急性症状的原因。如果SD是必要且充分的， 解释症状，那么针对SD的干预措施对这些患者可能非常有价值， 这一发现可能为早期诊断提供新的机会。此外，神经元的大破坏 由SD引起的血管功能可能导致对第二次打击的脆弱性窗口-一种可能性 这是以前没有调查过的。因此，该项目解决了以下知识方面的主要差距： 将SD与脑震荡症状和脆弱性联系起来的机制。我们将使用小鼠脑震荡模型， 电生理和行为记录的组合，以及高通量的解剖 分析以评估神经元损伤的迹象。具体目标1测试是否短期抑郁症 SD后的突触活动是脑震荡后行为的基础。具体目标2测试是否大规模 SD后血流和/或突触活动的中断使大脑更容易受到第二次打击 在这个急性期。成功完成这些目标，预计将确定可持续发展是一个重要的 有助于脑震荡的症状和后果，并打开新的大门，检测和治疗 这种非常常见且通常会严重削弱的脑损伤。该项目非常适合 COBRE中心的跨学科环境。来自临床前和临床导师的广泛意见 优秀的核心设施将为多个高影响力的项目提供卓越的平台， 出版物和发展到独立的校外资助成功。

Project Summary This project addresses fundamental mechanisms that may contribute to the acute symptoms of concussion and related mild traumatic brain injuries. Our long-term goal is to increase understanding of mechanisms underlying acute neurological dysfunction, so that diagnosis and/or treatment can be substantially improved. This work is expected to be significant for the large number of individuals who suffer from concussions, including the substantial number who do not recover fully after single or repetitive hits. The project focuses on the phenomenon of Spreading Depolarization (SD), which has emerged relatively recently as a key contributor to lesion progression in patients in the ICU with severe traumatic brain injury or stroke. There is very limited knowledge about whether SDs occur in other neurological conditions. In 2018 we presented the first evidence that SDs occur in a murine concussion model, and another group provided a first publication with indirect measurements of SD in a similar model. The challenge now is to provide additional direct electrophysiological recordings of SD, combined with simulatenous measures of behavior, to determine whether concussion-induced SDs are responsible for the well-known acute symptoms of concussion. If SDs are necessary and sufficient to explain the symptoms, then interventions targeting SD could be very valuable for these patients, and the discovery could suggest new opportunities for early diagnosis. Furthermore, the large disruptions in neuronal and vascular function caused by SD could contribute to a window of vulnerability to second hits – a possibility that has not previously been investigated. This project therefore addresses key gaps in knowledge about mechanisms linking SD to concussion symptoms and vulnerability. We will use a mouse concussion model and combinations of electrophysiological and behavioral recordings, together with high-throughput anatomical analyses to assess for signs of neuronal injury. Specific Aim 1 tests whether the short term depression of synaptic activity that follows SD underlies post-concussion behaviors. Specific Aim 2 tests whether the massive disruptions in blood flow and/or synaptic activity that follow SD render the brain more vulnerable to a second hit during this acute phase. Successful completion of these aims is expected to identify SD as a significant contributor to the symptoms and consequences of concussion, and open new doors to detection and treatment of this very common and often severely debilitating type of brain injury. The project is very well suited to the interdisciplinary environment of the COBRE Center. Extensive input from both preclinical and clinical mentors and colleagues, and excellent core facilities will provide an outstanding platform for multiple high-impact publications and progression to independent extramural funding success.