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 CO₂ leads to a sustained increase in minute ventilation, despite dynamic changes in acute CO₂ sensitivity across the first week of exposure. Specifically, steady-state ventilation increased during CH, whereas acute CO₂ sensitivity was transiently blunted at 24 h and returned toward baseline after 7 days. These findings suggest that ventilatory acclimatization to CH is not solely explained by changes in acute CO₂ 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), 24 h, and 7 days of CH. At 3 h, differentially expressed genes were enriched in vascular- and endothelial-associated gene ontology terms. By 24 h, genes within the nucleus tractus solitarius (NTS)/dorsal motor nucleus of the vagus (DMV) and ventral respiratory column (VRC) were associated with mitochondrial function were broadly downregulated, particularly transcripts related to mitochondrial respiratory complexes and oxidative phosphorylation. At 7 days, 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 mechanistic studies of physiological adaptation to chronic CO₂ exposure.NEW & NOTEWORTHY Chronic hypercapnia elicited time- and region-dependent tissue-level transcriptomic responses in brainstem regions involved in cardiorespiratory control. At 3 h, differentially expressed genes (DEGs) were enriched in vascular- and endothelial-associated GO terms. At 24 h, mitochondria-associated transcripts were downregulated within the NTS/DMV and VRC. By 7 days, few DEGs were detected. These findings reveal novel, temporally distinct transcriptional responses to CH and identify vascular- and mitochondria-related pathways for future studies of physiological acclimatization to chronic hypercapnia.