Medullary raphé transcriptome comparisons among inbred rat strains differing in ventilatory sensitivity to CO2

Abstract

Brown Norway (BN) rats exhibit reduced ventilatory CO2 sensitivity relative to the Dahl salt‐Sensitive (SS) rats. The medullary raphé nuclei contain serotonergic (5‐HT) neurons, which are putative CO2 chemoreceptors and provide neuromodulatory input to respiratory control nuclei. Here we tested the hypothesis that the reduced CO2 sensitivity in the BN rat is due in part to altered medullary raphé gene expression using mRNA sequencing and qPCR validation. cDNA libraries (n=3/strain, 3–4 rats/library) were prepared from caudal and rostral raphe punches from adult BN (n=11) and SS (n=11) rats and sequenced. We found 74 differentially expressed (p=0.005, q<0.25) genes between caudal and rostral raphe in both strains, which pointed to the caudal raphe having a greater capacity for excitatory neuromodulation. Strain differences were also detected in multiple 5‐HT‐specific genes in the rostral, but not caudal medullary raphé, predictive of a reduced quantity of monoamines in the BN rat by bioinformatics pathway analyses. Brain tissue HPLC verified this as 5‐HT and norepinephrine levels in multiple brain regions including the medulla were lower in the BN despite equal numbers of 5‐HT‐producing neurons. The expression data suggest altered gene regulation and perhaps function of rostral raphe 5‐HT neurons in BN rats relative to SS rats, which may contribute to the reduced ventilatory CO2 sensitivity in BN rats.