Cells in the female retrotrapezoid region upregulate c-fos in response to 10%, but not 5%, carbon dioxide

The retrotrapezoid nucleus (RTN) is thought to regulate breathing in response to changes in blood carbon dioxide (CO2), and to make a vital contribution to respiratory drive, especially during sleep. However, cells in the female RTN fail to upregulate c-fos in response to low level CO2 exposure, while cells in the male RTN have a robust upregulation of c-fos in response to low level CO2 exposure. In this study, we examined the possibility that the female RTN has a higher threshold for c-fos upregulation in response to CO2. Following exposure of Fos-Tau-LacZ (FTL) transgenic mice to 10% CO2, c-fos was upregulated in just as many cells in the female as in the male RTN. In addition, the male RTN responded equivalently to 5% and 10% CO2, consistent with a lack of a dose response to CO2 in the male RTN. Cells in the nearby facial nucleus upregulated c-fos in the same number of cells regardless of sex or gas exposure, confirming that the sex difference in the RTN is unique to that nucleus. We propose that the male and female RTN upregulate c-fos differently in response to CO2 due to differences in the transcriptional regulation by estrogens of genes that encode proteins related to neuronal excitability or specifically related to central chemoreception, such as potassium channels. These findings could have clinical relevance to sleep related breathing disorders that disproportionately affect males, including the sudden infant death syndrome and sleep apnea.

► Male and female RTN cells upregulate c-fos differently in response to CO2 exposure.
► Male but not female RTN cells upregulate c-fos in response to 5% CO2.
► Male and female RTN cells upregulate c-fos in response to 10% CO2.
► The male RTN upregulates c-fos equivalently regardless of the level of CO2 exposure.
► The sex difference in c-fos upregulation in response to CO2 is unique to the RTN.