Research 3- Morton

项目摘要 该项目探讨了可能导致脑震荡急性症状的基本机制和 相关的轻微创伤性脑损伤。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，从而大大提高诊断和/或治疗水平。这项工作是 预计将对包括脑震荡在内的大量脑震荡患者产生重大影响 相当多的人在单次或重复击打后没有完全恢复。该项目的重点是 传播去极化(SD)现象，这是最近出现的一个关键因素 ICU中有严重创伤性脑损伤或中风患者的病变进展。有非常有限的 了解抑郁症是否发生在其他神经疾病中。2018年，我们提出了第一个证据 在小鼠脑震荡模型中发生了十二烷基硫酸钠，另一个小组首次发表了间接的 在类似的模型中测量SD。现在的挑战是提供更多的直接电生理 SD的记录，结合模拟的行为测量，以确定脑震荡是否导致 SDS是众所周知的脑震荡急性症状的罪魁祸首。如果SD是必要的且充分的 解释症状，然后针对SD的干预可能对这些患者非常有价值，并且 这一发现可能为早期诊断提供新的机会。此外，神经元的大规模破坏 SD引起的血管功能可能导致二次打击的脆弱性窗口--一种可能性 这之前还没有被调查过。因此，该项目解决了以下方面的主要知识差距 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 电生理和行为记录与高通量解剖记录的组合 分析以评估神经元损伤的迹象。特定目标1测试是否存在短期抑郁 SD之后的突触活动是脑震荡后行为的基础。《特定目标2》测试的是 SD后血液流动和/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。这些目标的成功完成预计将使可持续发展成为一项重要的 导致脑震荡症状和后果的因素，并为检测和治疗打开新的大门 这种非常常见且往往严重削弱的脑损伤类型。这个项目非常适合 科布雷中心的跨学科环境。来自临床前和临床导师的广泛意见 和同仁，以及优良的核心设施将为多个高影响力的企业提供卓越的平台 出版物和独立外部资金的进展取得成功。

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.