Mechanisms and Functions of Cortical Activity to Restore Behavior

Project Summary Monitoring the transition to wakefulness is critical during restoration to consciousness after brain injury, anesthesia, and in those COVID-19 survivors that have altered consciousness. However, we have an imprecise understanding of neural dynamics linked to behavioral changes as subjects awaken. Our previous work discovered that stimulating the anterior nucleus gigantocellularis (aNGC) promotes arousal from a coma-like state. We proposed recruiting multiple arousal pathways through aNGC as an avenue to triggering widespread activation resulting in wakefulness. Notably, aNGC activation increased frontal-motor cortical activity and restored full mobility through modulation of an aNGC-to-frontal-motor-cortex pathway despite high anesthetic concentration exposure. We also showed that animals emerging from diverse coma-like states share a common dynamic process of cortical and motor arousal that can be consistently sequenced from deep to high arousal levels. We identified five cortical periods that tracked restored motor behavior in a hypoglycemic coma and a range of anesthetics, whether inhaled or injected, alongside conventional righting reflex assays. Based on these findings, we postulate that restoring waking is a common progressive process in which cortical patterns contain metrics of consciousness that distinguish reflexive from purposeful movements. We hypothesize that cortical measurements that link neural responsiveness to defined behaviors are an applicable method that can extend the analysis of the recovery of consciousness beyond monitoring reflexive movements. Our proposal deepens our understanding of the contribution of cortical neural subtypes, the neuronal pathways underlying aNGC-induced changes in frontal-motor cortical activity, and the temporal dynamics that distinguish reflexive from the initiation of voluntary behaviors in our rodent-low arousal models. In addition, we will establish the cortical patterns that unpack these behavioral transitions. Since pathological states of unconsciousness are vastly heterogeneous, having a clear understanding of ordinary recovery serves to better appreciate the variability imposed by the injury to cortical activity and behavior. Thus, we will identify how damaged neural circuits affect established cortical activity pathways and dynamics that underlie behavior recovery. The proposed studies are thus significant because they will establish the mechanistic correspondence, examining activation of neural pathways and their dynamics linked to habitual and intentional behaviors that reveal novel, medically relevant biomarkers that promote a robust inference of arousal states during emergence from anesthesia and after brain injury.