Neuronal basis of cardiorespiratory control in vertebrates

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Cardiorespiratory control is essential for survival of all vertebrates, yet our understanding of the neuronal circuits involved is rudimentary, in part because there is little data beyond mammals to guide us. My NSERC-funded research program addresses this important knowledge gap by investigating cardiorespiratory rhythm generation in lower vertebrates. Most of our efforts have focused on respiratory rhythm generation in the bullfrog by using an isolated brainstem preparation. This preparation produces breathing motor patterns resembling those of intact animals for at least 24 hours. This resilience and the developmental accessibility of tadpoles makes frogs ideal for teaching neuroscience and for studying neuronal development and function in vertebrates. We discovered striking similarities in the neuronal circuits controlling breathing between bullfrogs and mammals, despite fundamental differences in their breathing mechanics. We found three discrete sites essential for rhythmogenesis (i.e., oscillators); one is for buccal ventilation, the other two are for lung inflation. Interactions between these oscillators (i.e.., their coupling) is required for the normal breathing motor patterns. Three coupled respiratory oscillators in mammals have also been identified, two for inspiration, the other for expiration. Moreover, the oscillators in the mammal and bullfrog brainstems are bilaterally iterated, occupy similar hindbrain rhombomere locations, and appear to share several functional properties. Recently, my graduate students discovered (a) that a mild increase in network excitation causes the buccal oscillator to transform into a distributed rhythm generating network (i.e. neuronal activity at the site of the buccal oscillator is no longer critical for rhythm generation) and (b) a fourth bilaterally-iterated oscillator in the frog nervous system at the level of Spinal Nerve (SN) III that is likely part of the sympathetic nervous system. The overall objective of the proposed research is to increase our understanding of cardiorespiratory circuits by critically evaluating the hypothesis that network excitation transforms discrete respiratory and sympathetic oscillators into distributed networks. In the next 5 years, my trainees and I will (a) pinpoint sympathetic oscillators to specific neuronal populations in the spinal cord; (b) test if network excitation transforms lung and sympathetic oscillators into distributed networks, as it does the buccal; and (c) test which architecture oscillator vs distributed is most likely in more intact preparations. This research will (a) provide excellent training opportunities in cellular and comparative neuroscience; (b) shed new light on cardiorespiratory rhythm generating networks in frogs; and (c) have the potential to determine the identity of the sympathetic oscillator in mammals important new knowledge for a deeper mechanistic understanding of how we breathe and regulate tissue perfusion.