Miniscope in vivo imaging of cumulative traumatic brain injury

累积性脑外伤的微型活体成像

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要在美国，每年有数百万人遭受创伤性脑损伤 (TBI)，其中包括个人、医疗保健和社会成本每年超过 450 亿美元。轻度 TBI (mTBI) 占 75% 以上所有 TBI，其中许多人承受不止一种创伤性脑损伤。 mTBI 患者报告脑震荡后综合征 (PCS) 症状包括睡眠障碍（失眠、白天嗜睡）、躯体症状（头晕、头痛、视力模糊）、认知问题（记忆力、执行功能）和情绪问题（焦虑、抑郁、烦躁、抑制解除）。对于许多人来说，PCS 是短暂的，但仍有 10-25% 的人报告持续存在 PCS 症状。这 mTBI 后神秘的 PCS 症状表现和持续性敦促对动态反应进行调查在大脑中将急性神经生理学与行为功能联系起来。调查组已在体内细化微型显微镜（微型显微镜）的成像方法评估脑血流量（CBF）和血液不受约束、表现良好的小鼠的脑屏障（BBB）通透性。新的初步数据利用微型显微镜头帽可引起冲击加速度（重量下降）闭合性头部损伤。推动该提案的数据显示视野内实质内荧光右旋糖酐的立即积累。实力这种方法消除了长时间成像过程中的麻醉，允许无头自然行为约束，并锁定在基板上，用于单通道、宽视野、荧光的重复成像。对于第一个随着时间的推移，TBI 对神经生理学（CBF、BBB 通透性、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 对 CBF 和 BBB 通透性的影响可促进创伤后睡眠并预测神经损伤。雄性和雌性小鼠准备通过颅窗和附加底板进行微型显微镜成像。在闭头冲击加速 TBI 中，底板头盖可替代头盔。通过 15 秒的过渡，微型显微镜通过腹膜内葡聚糖 (40-2000 kDa) 可视化脉管系统中的 CBF 和 BBB 通透性，薄壁组织，分别。 mTBI 的累积效应通过每天两次、每天、或一周内每隔一天。目标 1 监测不同时间间隔的 mTBI 的累积影响 CBF 与创伤后睡眠和亚急性行为表现同时发生。目标 2 量化了右旋糖酐外渗与创伤后睡眠和亚急性神经功能的关系。神经系统结果包括焦虑（开放视野）、空间记忆（新物体位置）和体感疼痛（机械性疼痛）痛觉过敏）。每天两次受伤可能会显示 CBF、BBB 通透性和睡眠影响的时间总和，两次受伤之间的恢复时间较长。微型显微镜成像与集成闭合性颅脑损伤可以推动未来对 TBI 生理扰动和临床治疗的研究。