Gigantocellular Neurons Awaken the Brain from Deep Pharmacologically-Induced Coma

Abstract

Attempts at neuromodulation using deep brain stimulation (DBS) have targeted a number of loci in brain arousal pathways such as the thalamus, mesencephalon and cervical cord. However, recovery following single location stimulation remains modest, especially in comatose patients. Although some of these pathways can trigger awakening from sleep or light planes of anesthesia upon activation are insufficient to promote arousal from a deeper arousal state like coma. Interpretation of these results suggests that to fully emerge from a deep arousal state, coordination of multiple pathways is required. The mechanism through which this coordination is achieved by the brain is poorly understood. Considering that medullary reticular neurons project to arousal- modulating areas throughout the brain, integrate a broad range of sensory and autonomic inputs, and fire in response to salient stimuli in close association with the initiation of behaviors, we modulated their activity during a pharmacologic induced coma (PIC). Our results showed that pharmacologic or optogenetic activation of an area located at the nucleus gigantocellularis (NGC)- elicited robust cortical, autonomic and motor arousal during a state of PIC. To understand how this small subpopulation of neurons exerts such widespread activational effects on arousal, we analyzed immunolabeling of c-Fos-a well-established marker of neuronal activation-following pharmacologic activation of NGC neurons. C-Fos labeling was sparse and largely limited to structures known to participate in arousal including rhombenchephalon (locus coeruleus and parabrachial nucleus); mesencephalon (periaqueductal gray and ventral tegmental area); diencephalon (intralaminar thalamic nuclei as well as posterior and anterior hypothalamus). These findings suggest that NGC is able to recruit these pathways to trigger arousal from a dense PIC. Results of this study will uncover novel mechanisms leading to new approaches for emerging treatments for patients under coma state.