Investigating the Thalamic Regulation of Neuro-Glio-Vascular Restoration Underlying Acute Coma Recovery with Multi-Modal fMRI in a Brainstem Coma Rodent Model

在脑干昏迷啮齿动物模型中利用多模态功能磁共振成像研究急性昏迷恢复过程中神经胶质细胞血管恢复的丘脑调节

• 批准号: 10636837
• 负责人: Xin Yu
• 金额: $ 65.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636837
• 关键词: Acute; Animals; Arousal; Astrocytes; Behavior assessment; Behavioral; Blood Vessels; Brain; Brain Stem; Calcium; Cerebral cortex; Coma; Conscious; Coupled; Coupling; Data; Death Rate; Deep Brain Stimulation; Electrophysiology (science); Ensure; Fiber; Frequencies; Functional Magnetic Resonance Imaging; Future; Glutamate Transporter; Glutamates; Goals; Homeostasis; Hour; Human; Imaging technology; Injury; Label; Lesion; Measures; Mediating; Modeling; Multimodal Imaging; Mus; Neurons; Outcome; Pathway interactions; Patients; Permanent Vegetative States; Persons; Pharmacological Treatment; Photometry; Protocols documentation; Publishing; Rattus; Recovery; Regulation; Rest; Rodent; Rodent Model; Role; Signal Transduction; Specificity; System; Testing; Thalamic structure; Therapeutic; Time; Wakefulness; Work; antagonist; blood oxygen level dependent; cingulate cortex; drug development; experience; experimental study; extracellular; hemodynamics; inhibitor; insight; interest; multimodality; neuroregulation; neurovascular; nonhuman primate; noradrenergic; novel; novel therapeutic intervention; optogenetics; pharmacologic; restoration; tool

Among millions of comatose cases per year, brainstem injury-induced coma shows a high death rate and a high chance for patients remaining in a permanent vegetative state. For those who recovered consciousness, the longer patients remain in a coma the poorer outcomes of their recovery. How to promote acute coma recovery in a serious unmet need. Yet, although neuro-glio-vascular (NGV) restoration is crucial for acute coma recovery, detailed NGV signaling, e.g. astrocytic function, and circuit-based mechanisms underlying NGV restoration have not been thoroughly investigated in comatose patients due to inherent technical difficulties. We have recently developed a brainstem coma rat model, providing an unprecedented opportunity to enable mechanistic studies of coma recovery within an acute 12 hour time window, during which novel therapeutic interventions are of translational interest to patients with brainstem injuries. Our goal here is to elucidate the mechanistic regulation of NGV restoration underlying acute coma recovery. We will target the thalamocortical circuit with optogenetic tools to elucidate circuit-specific mechanisms underlying NGV restoration during acute coma recovery. To study NGV restoration, we will combine functional MRI with multi-channel fiber photometry-based Calcium (Ca2+) and glutamate (Glu) recordings. This multi-modal fMRI platform reveals that central thalamic activation is coupled with Intrinsic Astrocytic Ca2+ (IAC) transients during arousal fluctuation. This novel observation leads us to test a central hypothesis that the thalamic regulation of IAC-specific NGV restoration underlies the acute coma re- covery. Three specific aims will be assessed: 1). To test the hypothesis that arousal-related NGV signaling is associated with acute coma recovery. 2). To test the hypothesis that thalamic stimulation promotes acute coma recovery via IAC-specific NGV signaling. 3). To test the hypothesis that Glu-astrocyte signaling underlies the thalamic regulation of IAC-specific NGV restoration during acute coma recovery. We hope that the first glimpse of IAC-specific NGV restoration will help refine the therapeutic paradigm to target astrocyte function to promote acute coma recovery. Our proposal is a timely convergence of novel brainstem coma rat model, advanced multi- modal imaging technologies, and growing insights of NGV signaling, opening an unprecedented window into investigating circuit-based mechanisms that underlie NGV restoration in acute coma recovery.

在每年数以百万计的昏迷病例中，脑干损伤引起的昏迷显示出高死亡率和高死亡率。 病人有可能永远处于植物人状态。对于那些恢复意识的人来说， 病人昏迷的时间越长，恢复的效果就越差。如何促进急性昏迷恢复 在一个严重的未满足的需求。然而，尽管神经胶质血管（NGV）的恢复对急性昏迷的恢复至关重要， 详细的NGV信号传导，例如星形胶质细胞功能，以及NGV恢复的基于回路的机制， 由于固有的技术困难，尚未在昏迷患者中进行彻底研究。我们最近 开发了脑干昏迷大鼠模型，为进行机制研究提供了前所未有的机会 在急性12小时时间窗内昏迷恢复，在此期间， 脑干损伤患者的翻译兴趣。我们的目标是阐明 急性昏迷恢复的基础上的NGV恢复。我们将用光遗传学瞄准丘脑皮层回路 工具，以阐明电路的具体机制，在急性昏迷恢复NGV恢复。研究 NGV恢复，我们将联合收割机功能MRI与多通道纤维光度计为基础的钙（Ca 2+）， 谷氨酸（Glu）记录。这个多模态功能磁共振成像平台揭示了中央丘脑激活是耦合的， 与唤醒波动期间的内在星形胶质细胞Ca 2+（IAC）瞬变。这一新的观察使我们能够测试 一个中心假设，即丘脑对IAC特异性NGV恢复的调节是急性昏迷再发的基础， 精心制作。将评估三个具体目标：1）。为了验证唤醒相关NGV信号是 与急性昏迷恢复有关2）。为了验证丘脑刺激促进急性昏迷的假设 通过IAC特异性NGV信号传导恢复。（3）第三章。为了验证Glu-星形胶质细胞信号转导是 急性昏迷恢复期间IAC特异性NGV恢复的丘脑调节我们希望第一次看到 IAC特异性NGV恢复将有助于完善治疗范式，以靶向星形胶质细胞功能， 急性昏迷恢复我们的建议是一种新颖的及时衔接脑干昏迷大鼠模型，先进的多功能脑脊髓电成像系统， 模态成像技术，以及对NGV信号的日益深入的了解，打开了一扇前所未有的窗口， 研究急性昏迷恢复中NGV恢复的基础机制。