Neural control of rhythmic orofacial movements

Abstract Major efforts to understand how brain circuits activity gives rise to perception, mental experience, and behavior have broadly advanced our understanding of most of the central nervous system. In contrast, the brainstem circuit that connects the brain to patterned muscle outputs is arguably the least understood. The brainstem also

generates rhythms on its own. Networks of premotor neurons (central pattern generators) control and autonomously coordinate rhythmic movements such as breathing, chewing, drinking, swallowing, and vocalization. Understanding this neural coordination is fundamentally important for a host of survival-critical

conditions. For example, disorganization of breathing and swallowing leads to choking, which is a leading cause of death among children and elderly, and a common manifestation of neurodegeneration. Current understanding of brainstem central pattern generators, such as the breathing oscillator, are derived from neurophysiological

recordings, but these data are extremely limited. Central pattern generators for drinking and swallowing have not been definitely identified and there is no suitable model system for study neural coordination of multiple rhythmic movements. A challenge has been applying emerging technologies for large-scale neurophysiology

and mechanistic circuit dissection to the brainstem in behaving animals. I propose a transformative research program to map and dissect brainstem central pattern generators that coordinate orofacial rhythms. First, using approaches recently established in my lab for large-scale high-density electrophysiology mapping of multi-

regional neural circuits, we will map the premotor networks for licking, breathing, and swallowing in brainstem of behaving mice. Using circuit tracing tools, we will further delineate the organization of these premotor circuits in terms of their molecular cell types and connectivity. Using this roadmap, we will probe interactions between these

premotor circuits using simultaneous recordings of their activities in conjunction with controlled perturbation of individual circuits. Finally, we will dissect how brainstem intrinsic rhythms interact with descending volitional control (analogous to how we are able to adjust our breath when we vocalize) by simultaneously recording the

higher motor centers with the downstream brainstem circuits in mice performing volitional drinking. The outcome will shed light on why life-threatening symptoms occur in many forms neurological malfunctions that all trace their roots to the brainstem, paving the way for development of therapeutic interventions.