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

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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.