Protection of Thalamic Neurons Which Regulate Consciousness by Ethosuximide After Cardiac Arrest - A Randomized Pre-Clinical Trial

Disorders of consciousness such as coma occur often after cardiac arrest (CA). They complicate recovery and prognosis. Currently, they have no treatment. To improve recovery of consciousness and quality of life in CA survivors, we need new therapies. The proposed study focuses on CA-­ induced injury to a deep brain nucleus critical to consciousness – the thalamic reticular nucleus (TRN). We have discovered that a subset of TRN neurons dies early after resuscitation in a rodent model of pediatric asphyxial CA. TRN neuronal death increases in a front-­to-­back pattern which overlaps with increasing expression of a T-­type Ca2+ channel Cav3.3. Cav3.3 enables TRN neurons to fire rapid bursts of action potentials from a hyperpolarized state. TRN bursts occur in unconscious states during anesthesia, sleep, absence seizures. Importantly, they also occur in 50% of comatose CA survivors. Here for the 1st time, we will test the hypothesis that Cav3.3-­dependent bursts during post-­arrest coma contribute to degeneration of TRN neurons. We will use our clinically realistic model of severe brain injury in asphyxial CA to examine the effect of ethosuximide, an FDA-­approved T-­type Ca2+ channel inhibitor, on TRN neurons. In Aim 1, we will combine EEG and in vivo multichannel extracellular recordings of single TRN neurons to determine if post-­arrest ethosuximide prevents bursting on EEG and in TRN. In Aim 2, we will determine if post-­arrest ethosuximide prevents CA-­ induced degeneration of TRN neurons and associated microglial activation. Our preliminary data show biological plausibility and technical feasibility. The rigorous experimental approach employs randomization, blinding, inclusion of sex as a biological variable and appropriate controls. Our laboratory has extensive expertise with CA models and in vivo neurophysiology, ensuring successful execution of the proposed experiments. This study will examine a novel translational approach to protecting thalamic neurons which regulate consciousness from injury after CA. More broadly, it will advance a paradigm in which post-­arrest neuronal activity not only marks injury severity but indeed regulates evolving brain injury in CA survivors. Successful completion of this study will identify Cav3.3 in particular and neuronal activity in general as targets for new therapies to improve recovery of consciousness and neurologic outcomes after cardiac arrest.