Abstract
Long-term hypercapnia is associated with respiratory conditions including obstructive sleep apnea, chronic obstructive pulmonary disease and obesity hypoventilation syndrome. Animal studies have demonstrated an initial (within hours) increase in ventilatory drive followed by a decrease in this response over the long-term (days–weeks) in response hypercapnia. Little is known about whether changes in the central respiratory chemoreflex are involved. Here we investigated whether central respiratory chemoreceptor neurons of the retrotrapezoid nucleus (RTN), which project to the respiratory pattern generator within the ventral respiratory column (VRC) have a role in the mechanism of neuroplasticity associated with long-term hypercapnia. Adult male C57BL/6 mice (n = 5/group) were used. Our aims were (1) to determine if galanin, neuromedin B and gastrin-releasing peptide gene expression is altered in the RTN after long-term hypercapnia. This was achieved using qPCR to measure mRNA expression changes of neuropeptides in the RTN after short-term hypercapnia (6 or 8 h, 5 or 8% CO2) or long-term hypercapnia exposure (10 day, 5 or 8% CO2), (2) in the mouse brainstem, to determine the distribution of preprogalanin in chemoreceptors, and the co-occurrence of the galanin receptor 1 (GalR1:Gi-coupled receptor) with inhibitory GlyT2 ventral respiratory column neurons using in situ hybridization (ISH) to better characterize galaninergic RTN-VRC circuitry, (3) to investigate whether long-term hypercapnia causes changes to recruitment (detected by cFos immunohistochemistry) of respiratory related neural populations including the RTN neurons and their galaninergic subset, in vivo. Collectively, we found that hypercapnia decreases neuropeptide expression in the RTN in the short-term and has the opposite effect over the long-term. Following long term hypercapnia, the number of RTN galanin neurons remains unchanged, and their responsiveness to acute chemoreflex is sustained; in contrast, we identified multiple respiratory related sites that exhibit blunted chemoreflex activation. GalR1 was distributed in 11% of preBötC and 30% of BötC glycinergic neurons. Our working hypothesis is that during long-term hypercapnia, galanin co-release from RTN neurons may counterbalance glutamatergic inputs to respiratory centers to downscale energetically wasteful hyperventilation, thereby having a role in neuroplasticity by contributing to a decrease in ventilation, through the inhibitory effects of galanin.
Highlights
Respiratory conditions including chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS) and obstructive sleep apnea (OSA) are associated with long-term hypercapnia and hypoxia
Hypercapnia is a respiratory stressor that occurs in many disease (e.g., COPD, OHS, OSA, etc.) or non-disease conditions
While the physiologic mechanism that underlies the central respiratory chemoreflex response to long term hypoxia is well established, the mechanisms underlying central neuroplastic changes that occur during longterm hypercapnia are yet to be clarified
Summary
Respiratory conditions including chronic obstructive pulmonary disease (COPD), obesity hypoventilation syndrome (OHS) and obstructive sleep apnea (OSA) are associated with long-term hypercapnia and hypoxia. While the changes in the respiratory chemoreflex mechanisms during long-term hypoxia are extensively investigated (Peng et al, 2001, 2003, 2006; Rey et al, 2004; Huang et al, 2009; Morgan et al, 2016; Barnett et al, 2017) little is known about long-term hypercapnia. Acute hypercapnia causes an increase in ventilatory drive by peripherally and centrally mediated chemoreflex mechanisms (Forster and Smith, 2010; Smith et al, 2010). Many peripheral factors are suggested to contribute to this plasticity including metabolic compensation, muscle fiber transformation in the diaphragm and changes in lung hyaline membrane turnover (Schaefer et al, 1964; Lai et al, 1981; Kondo et al, 2000; Johnson, 2017; Burgraff et al, 2018). Many peripheral factors are suggested to contribute to this plasticity including metabolic compensation, muscle fiber transformation in the diaphragm and changes in lung hyaline membrane turnover (Schaefer et al, 1964; Lai et al, 1981; Kondo et al, 2000; Johnson, 2017; Burgraff et al, 2018). Lai et al (1981) first suggested a contribution from central chemoreceptors to this adaptation; more recently, changes in glutamate receptor expression were observed in central chemoreceptors (Burgraff et al, 2019)
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