Research 3- Morton

研究3-莫顿

• 批准号: 10026519
• 负责人: Russell Morton
• 金额: $ 25.02万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10026519
• 关键词: Acute; Address; Adolescent; Anatomy; Animal Behavior; Animals; Astrocytes; Attention; Behavior; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Brain Concussion; Brain Injuries; Brain Pathology; Centers of Research Excellence; Cerebrovascular Circulation; Clinical; Cognition; Cognitive deficits; Conscious; Core Facility; Cortical Contusions; Detection; Diagnosis; Disorientation; Early Diagnosis; Electrophysiology (science); Event; Extramural Activities; Functional disorder; Funding; Goals; Guidelines; Headache; Hour; Individual; Injury; Intervention; Knowledge; Laser Speckle Imaging; Lesion; Link; Measurement; Measures; Mentors; Metabolic dysfunction; Modeling; Monitor; Motion; Mus; Nausea; Neurologic; Neurologic Dysfunctions; Neuronal Injury; Neurons; New Mexico; Patients; Phase; Predisposition; Property; Publications; Recording of previous events; Recovery; Research; Role; Speed; Stroke; Symptoms; Synapses; Task Performances; Testing; Tissues; Traumatic Brain Injury; Unconscious State; Universities; Vertigo; Work; acute symptom; base; chronic traumatic encephalopathy; collaborative environment; concussive symptom; cranium; critical period; effective therapy; improved; insight; mild traumatic brain injury; minimally invasive; multimodality; multiphoton microscopy; neuron loss; novel strategies; pre-clinical; repaired; response; success; synaptic depression; time use; touchscreen

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.

项目概要 该项目探讨了可能导致脑震荡和急性脑震荡症状的基本机制。 相关的轻度创伤性脑损伤。我们的长期目标是增进对潜在机制的理解 急性神经功能障碍，从而可以显着改善诊断和/或治疗。这部作品是 预计对大量遭受脑震荡的人来说意义重大，包括 相当多的人在单次或重复击中后无法完全恢复。该项目的重点是 传播去极化 (SD) 现象是最近才出现的一个关键因素 ICU 中患有严重创伤性脑损伤或中风的患者的病变进展。数量非常有限 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，另一个小组提供了第一份间接出版物 类似模型中的 SD 测量。现在的挑战是提供额外的直接电生理学 SD 记录结合模拟行为测量，以确定是否由脑震荡引起 SD 是造成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，然后针对 SD 的干预措施对于这些患者可能非常有价值，并且 这一发现可能为早期诊断提供新的机会。此外，神经元的巨大破坏 SD 引起的血管功能可能会导致第二次打击的脆弱性——一种可能性 以前没有被调查过。因此，该项目解决了以下方面的关键知识空白： 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 电生理学和行为记录的结合，以及高通量解剖学 分析以评估神经元损伤的迹象。具体目标 1 测试短期抑郁是否 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 后的血流和/或突触活动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使可持续发展成为一个重要的目标 造成脑震荡的症状和后果，并为检测和治疗打开新的大门 这种非常常见且常常使人严重衰弱的脑损伤。该项目非常适合 COBRE 中心的跨学科环境。临床前和临床导师的广泛投入 和同事以及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 出版物和独立外部资助成功的进展。