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Abstract:
Millions of patients worldwide experience a coma every year due to trauma, stroke, and other severe brain injuries, but the mechanisms by which patients emerge from coma are incompletely understood. A major reason for this gap in knowledge is the absence of an animal model of coma, which would provide a means to study both the pathogenesis of coma and the mechanisms that enable reemergence of consciousness. Here, we develop a rat coma model to systematically study the progression of rat brain function and behavior after coma. Endothelin-1 (ET-1), a potent vasoconstrictor, was injected into the caudal brainstem to cause hypoxic-ischemic injury to brainstem nuclei that mediate arousal, as confirmed by T2-weighted MRI. Based on the human Glasgow Coma Scale and Full Outline of UnResponsiveness, a Tübingen-Boston Rat Coma Scale was developed to quantify the severity of neurological impairment and track behavioral recovery. Cortical function was simultaneously assessed using Local Field Potential (LFP) recordings and resting-state functional MRI (rs-fMRI) connectivity mapping. Animals that recovered spontaneous breathing and brainstem reflexes showed increasing global cortical activity on LFP (Fig.1) and increasing whole brain functional connectivity on rs-fMRI. This is, to our knowledge, the first report of a rat coma model that enables multimodality studies of the mechanisms underlying coma pathogenesis and recovery following brainstem injury. Ongoing studies using optogenetics and calcium imaging will investigate the role of specific brainstem-thalamo-cortical circuits in the comatose brain, which will help elucidate the mechanisms that underlie coma emergence.
