Exploring the connectome of the respiratory network

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Breathing requires the synchronization of a complex motor program to control gas exchange and adequately respond to various physiological and environmental conditions. The central pattern generator that orchestrates the respiratory rhythm lies in the medulla and is hypothesized to be composed by at least two coupled oscillators. The preBötzinger complex is essential for inspiratory rhythmogenesis through contraction of inspiratory muscles and the paraFacial Respiratory Group, silent in resting conditions, is recruited during periods of increased respiratory demand and generates active expiration through contraction of abdominal muscles. Recently, the existence of a third generator, the Post-Inspiratory Complex, has been proposed to regulate respiratory braking during post-inspiration. It is essential that these oscillatory networks interact with each other on a breath by breath basis when they are all active, and that they receive an appropriately timed balance of excitatory and inhibitory inputs that support their rhythmic activity and allow for the coordination of respiratory motor activity with more complex orofacial behaviours, such as swallowing or vocalization. Research conducted in my laboratory aims to gain an understanding of the neural mechanisms that control breathing and affect its function during sleep, with a particular interest to the dissection of rhythmogenic, pharmacological and state-dependent properties of respiratory networks in the paraFacial Respiratory group and in the preBötzinger Complex. In the next five years of my NSERC research program we will focus on investigating the role of excitatory, inhibitory and neuromodulatory inputs on the main inspiratory oscillator, the preBötzinger Complex. Using state-of the-art technologies and transgenic mice lines in which specific neuronal population can be identified and controlled we will illuminate not only the connectivity of the network, but more importantly, the functional dynamics, the state dependence of these connections and their effect on ongoing breathing. The program will provide an outstanding opportunity for trainees to get involved in a cutting edge research program that is at the intersection of neuroscience, respiratory physiology and molecular pharmacology. The results from this work will increase our mechanistic understanding of the indispensable motor behavior of breathing in mammals and will serve as an example and the foundation for future work addressing other state-dependent neuromodulatory processes occurring in the brain.