Investigating the thalamic regulation of neuro-glio-vascular restoration underlying acute coma recovery with multi-modal fMRI in a brainstem coma rodent model

在每年数以百万计的昏迷病例中，脑干损伤所致昏迷表现出高死亡率和高死亡率。 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， 患者昏迷时间越长，他们的康复结果就越差。如何促进急性昏迷的恢复 在严重的未得到满足的需求中。然而，尽管神经胶质血管(NGV)的恢复对于急性昏迷的恢复至关重要， 详细的NGV信号，例如星形细胞功能，以及基于电路的NGV恢复机制 由于固有的技术困难，在昏迷患者中没有得到彻底的调查。我们最近做了 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 在急性12小时时间窗口内昏迷恢复，在此期间，新的治疗干预措施 对脑干损伤患者的翻译兴趣。我们在这里的目标是阐明机械性调节 NGV恢复在急性昏迷恢复的基础上。我们将用光遗传技术瞄准丘脑皮质环路 工具，以阐明在急性昏迷恢复期间潜在的NGV恢复的电路特定机制。学习 NGV修复，我们将结合功能磁共振和基于多通道纤维光度学的钙(Ca~(2+))和 谷氨酸(Glu)记录。这个多模式功能磁共振成像平台显示，中央丘脑的激活是耦合的 在觉醒波动期间有固有的星形细胞钙(IAC)瞬变。这一新颖的观察结果让我们得以验证 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复发的基础。 找回。将评估三个具体目标：1)。为了检验与觉醒相关的NGV信号是 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信号进行恢复。3)。为了验证谷氨酸-星形胶质细胞信号是 急性昏迷恢复期IAC特异性NGV恢复的丘脑调节。我们希望第一眼就能看到 IAC特异性NGV修复将有助于完善治疗范式，以靶向星形胶质细胞功能促进 急性昏迷恢复。我们的建议是及时收敛新的脑干昏迷大鼠模型，先进的多 模式成像技术，以及对NGV信号的日益深入的洞察，打开了一扇前所未有的窗口 研究急性昏迷恢复中NGV恢复的基于电路的机制。

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.