Imaging Synaptic Injury in TBI using SEQUIN

创伤性脑损伤（TBI）是45岁以下成年人死亡和残疾的主要原因， 20%的退伍军人来自最近的战争。曾经被认为是一种双相损伤，现在已知TBI会引发一种 惰性神经退行性过程，大大增加了阿尔茨海默氏症和其他形式的 老年痴呆症所有由TBI引起的残疾都源于其功能性神经损伤， 网络. TBI中断这些网络并建立进一步神经退行性变的机制 网络崩溃是不充分的定义，虽然损伤位点以外观察到的白色的问题， 越来越被认可。在人类和动物模型中，已经在TBI后确定了突触损伤， 导致突触的病理性分子、结构和功能变化，或它们的明显丧失。突触 丧失也是阿尔茨海默病（AD）中常见的早期发现，是最强的病理相关性 甚至比淀粉样斑块或tau蛋白缠结更强。神经炎症通路 在动物模型和人类中，TBI后以延长的方式被激活，并在以下方面发挥核心作用： 介导AD中的突触丧失。更好地理解TBI中的突触损伤及其神经炎症反应 因此，调解人可以提供一种缺失的、可能中断的结构-机制联系 在这些条件之间。然而，由于突触的尺寸非常小， 以及哺乳动物神经细胞异常复杂的亚细胞环境中的混合物。我们开发了一个 创新的、可广泛访问的超分辨率成像和图像分析平台SEQUIN（Synaptic 通过纳米结构成像的评估和定量），以使得能够常规监测突触健康。 动物模型和人类。我们的初步数据表明，突触丢失是一个突出的特点， 在军事相关小鼠模型中弥散性、闭合性头部TBI，并表明补体的抑制 TBI后，突触通路（先天免疫系统的一部分）可防止创伤性突触丢失并改善功能。 这些发现表明，神经炎性突触损伤导致急性神经功能障碍， 弥漫性TBI，使大脑对随后的神经退行性变化敏感， 痴呆我们建议首先（目标1）描述弥漫性TBI导致的区域性突触丢失， 确定其神经心理和行为相关的规模不可能达到前SEQUIN。我们 然后（目标2）确定补体途径在介导创伤性突触丢失中的作用， 确定该通路的遗传和/或药理学靶向是否可以挽救突触终点 并改善功能结果。最后，我们将（目标3）确定TBI是否以及如何增强突触 在以后的生活中，由于淀粉样蛋白和tau蛋白相关的神经变性而导致的损失，这是AD的典型特征。这些研究 有望揭示TBI后回路损伤的新的、可药物化的机制，这些机制与认知功能有关。 和情绪残疾返回现役军人，警卫，和预备役人员。他们将进一步 建立创新工具（SEQUIN），以了解对退伍军人具有独特意义的情况， 并确定AD与其最完善的表观遗传风险因子--大脑--之间的可干预机制联系 外伤

Traumatic brain injury (TBI) is the leading cause of death and disability in adults under the age of 45, affecting ∼20% of veterans from recent wars. Once thought to be a monophasic injury, TBI is now known to trigger an indolent neurodegenerative process that substantially increases the risk of Alzheimer’s and other forms of dementia for older veterans. All disability resulting from TBI stems from its disruption of functional neural networks. The mechanisms by which TBI interrupts these networks and sets up further neurodegenerative network breakdown are inadequately defined, though injury loci beyond those observed in white matter are increasingly recognized. Synaptic injury has been identified following TBI in humans and in animal models, resulting in pathological molecular, structural, and functional changes to synapses, or their frank loss. Synapse loss is also a common, early finding in Alzheimer’s disease (AD) where it is the strongest pathological correlate of AD-induced dementia—even stronger than amyloid plaques or tau tangles. Neuroinflammatory pathways are activated in a prolonged fashion after TBI in animal models and in humans, and play a central role in mediating synapse loss in AD. A better understanding of synaptic injury in TBI, and its neuroinflammatory mediators, therefore, could supply a missing and potentially interruptible structural-mechanistic connection between these conditions. Synapses, however, are very challenging to study due to their extremely small size and admixture within the extraordinarily complex subcellular milieu of mammalian neuropil. We developed an innovative, widely accessible super-resolution imaging and image analysis platform called SEQUIN (Synaptic Evaluation and QUantification by Imaging of Nanostructure) to enable routine monitoring of synaptic health in animal models and in humans. Our preliminary data demonstrate that synapse loss is a prominent feature of diffuse, closed head TBI in a militarily-relevant mouse model, and indicate that inhibition of the complement pathway (part of the innate immune system) prevents traumatic synapse loss and improves function after TBI. These findings suggest that neuroinflammatory synaptic injury leads to acute neurological disability following diffuse TBI and sensitizes the brain to subsequent neurodegenerative changes, hastening the onset of dementia. We propose to first (Aim 1) characterize regional synapse loss resulting from diffuse TBI and determine its neuropsychological and behavioral correlates at a scale impossible to achieve pre-SEQUIN. We will then (Aim 2) determine the role of the complement pathway in mediating traumatic synapse loss, and determine whether genetic and/or pharmacological targeting of this pathway can rescue synaptic endpoints and improve functional outcomes. Lastly, we will (Aim 3) determine whether and how TBI potentiates synapse loss later in life in response to the amyloid- and tau-related neurodegeneration that typifies AD. These studies are expected to reveal novel, druggable mechanisms of circuit injury after TBI that are connected to cognitive and emotional disability in returning active military, guard, and reserve personnel. They will furthermore establish innovative tools (SEQUIN) for the understanding of conditions with unique significance for veterans, and identify an intervenable mechanistic link between AD and its best-established epigenetic risk factor, brain trauma.