Adaptation to chronic hypercapnia drives time- and region-dependent changes in brainstem cardiorespiratory nuclei.

Hypercapnia occurs in numerous clinical conditions, both acutely and chronically. We previously demonstrated in healthy goats that chronic hypercapnia (CH) produced by exposure to elevated inspired CO 2 leads to a sustained increase in minute ventilation, despite dynamic changes in acute CO 2 sensitivity across the first week of exposure. Specifically, steady-state ventilation increased during CH, whereas acute CO 2 sensitivity was transiently blunted at 24 hours and returned toward baseline after 7 days. These findings suggest that ventilatory acclimatization to CH is not solely explained by changes in acute CO 2 sensitivity or by traditional mechanisms of neuroplasticity within the respiratory network. To further explore the tissue-level responses to CH in the cardiorespiratory network, we performed bulk-tissue RNA sequencing on medullary brainstem regions involved in cardiorespiratory control. We hypothesized that CH would induce time- and region-dependent transcriptomic responses during the period when ventilatory acclimatization occurs. Differential expression analyses revealed dynamic, region-specific transcriptomic changes at 3 hours (h), 24h, and 7 days (d) of CH. At 3h, differentially expressed genes were enriched in vascular- and endothelial-associated gene ontology terms. By 24h, genes within the NTS/DMV and VRC were associated with mitochondrial function were broadly downregulated, particularly transcripts related to mitochondrial respiratory complexes and oxidative phosphorylation. At 7d, relatively few differentially expressed genes were detected. These findings suggest a time- and region-dependent tissue-level transcriptional response to CH. Data reported herein highlight vascular- and mitochondria-associated pathways as candidates for future studies mechanistic studies of physiological adaptation to chronic CO 2 exposure.