Miniscope in vivo imaging of cumulative traumatic brain injury

累积性脑外伤的微型活体成像

• 批准号: 10841846
• 负责人: JONATHAN LIFSHITZ
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10841846
• 关键词: Acceleration; Acute; Anesthesia procedures; Anxiety; Automobile Driving; Behavior; Behavioral; Blood flow; Blurred vision; Brain; Cephalic; Cerebrovascular Circulation; Clinical Management; Clinical Research; Closed head injuries; Cognitive; Data; Dextrans; Disinhibition; Dizziness; Drops; Drowsiness; Emotional; Extravasation; Female; Fluorescence; Functional disorder; Future; Head; Headache; Health Care Costs; Helmet; Hyperalgesia; Image; Impairment; Individual; Injury; Investigation; Location; Mechanics; Memory; Mental Depression; Microscope; Microscopy; Monitor; Mus; Nervous System Physiology; Neurologic; Neurologic Dysfunctions; Neurological outcome; Pain; Patients; Performance; Persons; Physiological; Post-Concussion Syndrome; Recovery; Reporting; Sleep; Sleep Disorders; Sleeplessness; Symptoms; Testing; Time; Traumatic Brain Injury; United States; Visualization; Weight; blood-brain barrier permeabilization; care costs; executive function; head impact; imaging modality; in vivo; in vivo imaging; insight; intraperitoneal; male; mild traumatic brain injury; miniaturize; neurobehavioral; neurophysiology; novel; response; restraint; societal costs; somatosensory; spatial memory

Project Summary/Abstract In the United States, millions of people sustain a traumatic brain injury (TBI) each year carrying individual, healthcare, and societal costs greater than $45 billion annually. Mild TBI (mTBI) accounts for more than 75% of all TBIs, with many individuals sustaining more than one. mTBI patients report post-concussion syndrome (PCS) symptoms that include sleep disorders (insomnia, daytime sleepiness), somatic symptoms (dizziness, headache, blurred vision), cognitive complaints (memory, executive function), and emotional problems (anxiety, depression, irritability, disinhibition). For many, PCS is transient, and still 10-25% report persistent PCS symptoms. The enigmatic PCS symptom presentation and persistence after mTBI urges investigation into dynamic responses in the brain that tie acute neurophysiology to behavioral function. The investigative team has refined in vivo imaging methods of miniaturized microscopes (miniscopes) to evaluate cerebral blood flow (CBF) and blood brain barrier (BBB) permeability in the unrestrained, behaving mouse. New preliminary data leverage the miniscope headcap to induce impact acceleration (weight drop) closed head injury. The data driving this proposal show immediate accumulation of fluorescent dextrans in the parenchyma within the field of view. The strength of this approach eliminates anesthesia during long-duration imaging, permits naturalistic behavior without head restraint, and locks into a baseplate for repeated imaging of single channel, wide-field, fluorescence. For the first time, the cumulative effects of TBI on neurophysiology (CBF, BBB permeability, sleep) can be regressed toward neurobehavioral impairments. The present proposal tests the hypothesis that the cumulative effects of mTBI on CBF and BBB permeability promote post-traumatic sleep and predict neurological impairments. Male and female mice are prepared for miniscope imaging through a cranial window and attached baseplate. The baseplate headcap substitutes for a helmet in closed-head impact acceleration TBI. With a 15 sec transition, miniscopes visualize CBF and BBB permeability with intraperitoneal dextrans (40-2000 kDa) in vasculature and parenchyma, respectively. The cumulative effects of mTBI are assessed with impacts delivered twice daily, daily, or every other day for a week. Aim 1 monitors the cumulative effects of mTBI with varying temporal spacing on CBF concurrent with post-traumatic sleep and subacute behavioral performance. Aim 2 quantifies the extent of dextran extravasation with post-traumatic sleep and subacute neurological performance. Neurological outcomes include anxiety (open field), spatial memory (novel object location), and somatosensory pain (mechanical hyperalgesia). Twice daily injuries likely show temporal summation of CBF, BBB permeability, and sleep effects, which are recovered with longer recovery times between injuries. The integration of miniscope imaging and closed head injury can propel future studies on physiological perturbations and clinical management of TBI.

项目摘要/摘要 在美国，每年载有个人脑损伤（TBI），数以百万计的人承载个人， 医疗保健和社会的成本超过450亿美元。轻度TBI（MTBI）占75％以上 所有TBI，许多人维持不止一个。 MTBI患者报告脑震荡后综合征（PC） 包括睡眠障碍（失眠，白天嗜睡），躯体症状（头晕，头痛， 视力模糊），认知投诉（记忆，执行功能）和情绪问题（焦虑，抑郁， 烦躁，抑制）。对于许多人来说，PC是短暂的，但仍有10-25％的PC报告持续的PC症状。这 MTBI敦促调查动态反应后，神秘的PC症状表现和持久性 在将急性神经生理学与行为功能联系起来的大脑中。调查团队在体内完善了 微型显微镜（Miniscopes）的成像方法评估脑血流（CBF）和血液 脑屏障（BBB）在不受约束的，行为的小鼠中的渗透性。新的初步数据利用 Miniscope头贴，以诱导冲击加速度（重量下降）闭合头部受伤。推动此提案的数据 在视野内显示荧光葡萄糖在实质中的立即积累。力量 这种方法消除了长期成像期间的麻醉，允许自然主义行为无头 约束，并锁定到底板中，以重复对单个通道，广阔的荧光进行成像。第一个 时间，TBI对神经生理学（CBF，BBB渗透性，睡眠）的累积影响可以回归到 神经行为障碍。本提案检验了以下假设 MTBI在CBF和BBB渗透性上促进创伤后睡眠并预测神经系统障碍。 雄性和雌性小鼠是通过颅窗和附着的底板制备的。 底板头顶替代闭合撞击加速度TBI的头盔。有15秒的过渡， Miniscopes用腹膜内葡萄糖（40-2000 kDa）可视化CBF和BBB渗透性 实质分别。 MTBI的累积效应每天，每天两次。 或每隔一天持续一个星期。 AIM 1通过不同的时间间距来监视MTBI的累积效应 CBF与创伤后睡眠和亚急性行为表现并发。目标2量化了 发作后睡眠和亚急性神经功能表现的巧克力渗出。神经学结果 包括焦虑（开放场），空间记忆（新对象位置）和体感疼痛（机械疼痛） Hypergansia）。每日两次受伤可能显示出CBF，BBB渗透性和睡眠效应的时间总和， 在受伤之间恢复时间更长的恢复时间。 Miniscope成像的整合 封闭的头部损伤可以推动未来关于TBI生理扰动和临床管理的研究。