RNASeq-derived transcriptome comparisons reveal neuromodulatory deficiency in the CO₂ insensitive brown Norway rat. J Physiol 2015 Jan 15;593(2):415-30
Date
01/30/2015Pubmed ID
25630262Pubmed Central ID
PMC4303386DOI
10.1113/jphysiol.2014.285171Scopus ID
2-s2.0-84921032820 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Raphé-derived serotonin (5-HT) and thyrotropin-releasing hormone (TRH) play important roles in fundamental, homeostatic control systems such as breathing and specifically the ventilatory CO2 chemoreflex. Brown Norway (BN) rats exhibit an inherent and severe ventilatory insensitivity to hypercapnia but also exhibit relatively normal ventilation at rest and during other conditions, similar to multiple genetic models of 5-HT system dysfunction in mice. Herein, we tested the hypothesis that the ventilatory insensitivity to hypercapnia in BN rats is due to altered raphé gene expression and the consequent deficiencies in raphé-derived neuromodulators such as TRH. Medullary raphé transcriptome comparisons revealed lower expression of multiple 5-HT neuron-specific genes in BN compared to control Dahl salt-sensitive rats, predictive of reduced central nervous system monoamines by bioinformatics analyses and confirmed by high-performance liquid chromatography measurements. In particular, raphé Trh mRNA and peptide levels were significantly reduced in BN rats, and injections of the stable TRH analogue Taltirelin (TAL) stimulated breathing dose-dependently, with greater effects in BN versus control Sprague-Dawley rats. Importantly, TAL also effectively normalized the ventilatory CO2 chemoreflex in BN rats, but TAL did not affect CO2 sensitivity in control Sprague-Dawley rats. These data establish a molecular basis of the neuromodulatory deficiency in BN rats, and further suggest an important functional role for TRH signalling in the mammalian CO2 chemoreflex.
Author List
Puissant MM, Echert AE, Yang C, Mouradian GC Jr, Novotny T, Liu P, Liang M, Hodges MRAuthors
Matthew R. Hodges PhD Professor in the Physiology department at Medical College of WisconsinGary C. Mouradian PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCarbon Dioxide
Hypercapnia
Neurotransmitter Agents
RNA, Messenger
Raphe Nuclei
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Rats, Sprague-Dawley
Reflex
Serotonin
Species Specificity
Thyrotropin-Releasing Hormone
Transcriptome