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Acute Hypoxia Induces Long‐term Plasticity of the Motor Command for Lung Ventilation in Pre‐metamorphic Tadpole Brainstem Preparations

In terrestrial vertebrates, significant developmental changes in the connectivity and functionality of central neural networks are essential for the emergence of lung ventilation. Yet, the factors influencing early development within these critical, highly conserved networks remain unresolved. In pre‐metamorphic tadpoles of Lithobates catesbeianus (American bullfrog), gill ventilation is predominant, while lung ventilation is rarely observed until metamorphosis. However, hypoxic exposure stimulates acute increases in gill and lung ventilation in freely‐behaving pre‐metamorphic tadpoles. Since accelerated respiratory development constitutes an adaptive response to deterioration of the milieu, we hypothesized that central hypoxia would elicit long‐term expression of the motor command for lung ventilation in pre‐metamorphic tadpoles. Fictive respiratory activity was recorded from cranial nerves V, VII and X in isolated brainstems before, during, and up to 2h after exposure to 15 min of mild (PwO2 range: 114–152 Torr) or moderate (PwO2 range: 45–76 Torr) hypoxia. To test for stage‐dependent effects, data were compared between early (Taylor‐Kollros: VI‐IX,) and mid (X‐XIII) stage tadpoles (n=6 for each stage:hypoxia treatment). Early stages showed increased lung burst frequency during moderate hypoxia. In line with our predictions, early stage brainstems previously exposed to mild or moderate hypoxia had augmented lung frequencies during the re‐oxygenation period. Surprisingly, lung frequencies of mid stage brainstems did not differ from time‐matched normoxic controls during hypoxia or the re‐oxygenation period, indicating a stage‐dependent susceptibility to hypoxic exposure. Central hypoxia was not an important factor controlling fictive buccal burst frequency, which drives gill ventilation in tadpoles. Underlying the amphibian acute hypoxic response is a conserved chemosensitive region: the locus coeruleus (LC). To test the necessity of LC neurons for long‐term lung frequency augmentation, experiments were repeated following surgical ablation of pontine structures (n=5). In early stage brainstems, LC ablation depressed lung bursting during hypoxia and blocked long‐term augmentation of lung frequency, without affecting buccal motor activity. Collectively, these data demonstrate that during early tadpole neurodevelopment, central hypoxia induces plasticity within respiratory networks resulting in long‐term expression of lung motor activity. An intact LC was necessary for the long‐term frequency augmentation to manifest, suggesting that this chemoreceptive pathway plays an important role in the respiratory motor plasticity. In a broader sense, it is acknowledged that the suite of factors experienced during early neurodevelopmental periods can determine the developmental trajectory of neural networks. Our results suggest that hypoxia, a factor commonly encountered during development, can elicit significant long‐term plasticity within respiratory motor control networks, long before these networks become functionally mature.