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RNASeq-derived transcriptome comparisons reveal neuromodulatory deficiency in the CO₂ insensitive brown Norway rat. J Physiol 2015 01 15;593(2):415-30

Date

01/30/2015

Pubmed ID

25630262

Pubmed Central ID

PMC4303386

DOI

10.1113/jphysiol.2014.285171

Scopus ID

2-s2.0-84921032820   10 Citations

Abstract

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 MR

Authors

Matthew R. Hodges PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Mingyu Liang PhD Center Director, Professor in the Physiology department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Gary C. Mouradian PhD Instructor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Carbon 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
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d