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血管恢复的丘脑调节

• 批准号: 10274765
• 负责人: Xin Yu
• 金额: $ 62.36万
• 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/10274765
• 关键词: Acute; Animals; Arousal; Astrocytes; Behavior assessment; Behavioral; Blood Vessels; Brain; Brain Stem; Calcium; Cerebrum; 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; Imaging technology; Injury; Label; Lesion; Measures; Mediating; Modeling; Multimodal Imaging; Neurons; Outcome; Patients; Permanent Vegetative States; Pharmacological Treatment; Pharmacology; Photometry; Publishing; Rattus; Recovery; Regulation; Rest; Rodent; Rodent Model; Role; Signal Transduction; Specificity; System; Tail; Testing; Thalamic structure; Therapeutic; Time; Wakefulness; Work; base; blood oxygen level dependent; cingulate cortex; drug development; experience; experimental study; extracellular; hemodynamics; inhibitor/antagonist; insight; interest; multimodality; neuroregulation; neurovascular; noradrenergic; novel; novel therapeutic intervention; optogenetics; 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表现出较高的死亡率和较高的死亡率。 患者保持永久植物人状态的机会。对于那些恢复意识的人来说 患者处于昏迷状态的时间越长，其康复效果就越差。如何促进急性昏迷恢复 处于严重未满足的需求中。然而，尽管神经胶质血管（NGV）恢复对于急性昏迷恢复至关重要， 详细的 NGV 信号，例如星形胶质细胞功能和 NGV 恢复的基于电路的机制 由于固有的技术困难，尚未对昏迷患者进行彻底的研究。我们最近有 开发了脑干昏迷大鼠模型，为机制研究提供了前所未有的机会 昏迷在 12 小时的急性时间窗口内恢复，在此期间新的治疗干预措施是 脑干损伤患者的转化兴趣。我们的目标是阐明机械调节 NGV 恢复是急性昏迷恢复的基础。我们将用光遗传学瞄准丘脑皮质回路 阐明急性昏迷恢复期间 NGV 恢复的特定电路机制的工具。学习 NGV 修复，我们将功能性 MRI 与基于多通道光纤光度测定的钙 (Ca2+) 和 谷氨酸（Glu）记录。这个多模态功能磁共振成像平台揭示了中枢丘脑激活是耦合的 唤醒波动期间的内在星形细胞 Ca2+ (IAC) 瞬变。这个新颖的观察引导我们测试 一个中心假设是丘脑对 IAC 特异性 NGV 恢复的调节是急性昏迷的基础 覆盖。将评估三个具体目标：1）。检验以下假设：与觉醒相关的 NGV 信号传导是 与急性昏迷恢复有关。 2）。检验丘脑刺激促进急性昏迷的假设 通过 IAC 特定的 NGV 信令进行恢复。 3）。检验 Glu-星形胶质细胞信号传导是 急性昏迷恢复期间 IAC 特异性 NGV 恢复的丘脑调节。我们希望第一眼看到 IAC 特异性 NGV 恢复的研究将有助于完善针对星形胶质细胞功能的治疗范式，以促进 急性昏迷恢复。我们的建议是及时融合新型脑干昏迷大鼠模型、先进的多 模态成像技术以及对 NGV 信号的日益深入的了解，为我们打开了前所未有的窗口 研究急性昏迷恢复中 NGV 恢复的基于电路的机制。