title: RNASeq-derived transcriptome comparisons reveal neuromodulatory deficiency in the CO₂ insensitive brown Norway rat.
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.
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Madeleine M
authors: MM
authors: Puissant
authors: Ashley E
authors: AE
authors: Echert
authors: Chun
authors: C
authors: Yang
authors: Gary C
authors: GC
authors: Mouradian
authors: Tyler
authors: T
authors: Novotny
authors: Pengyuan
authors: P
authors: Liu
authors: Mingyu
authors: M
authors: Liang
authors: Matthew R
authors: MR
authors: Hodges
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D006935:Hypercapnia / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D012018:Reflex; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D018377:Neurotransmitter Agents; D012333:RNA, Messenger; C065049:TA 0910; D002245:Carbon Dioxide; D012701:Serotonin; D013973:Thyrotropin-Releasing Hormone
references: N Engl J Med. 2009 Aug 20;361(8):795-805
references: 19692691
references: J Neurosci. 2008 Nov 26;28(48):12748-58
references: 19036967
references: JAMA. 2010 Feb 3;303(5):430-7
references: 20124538
references: J Neurosci. 2010 Jun 16;30(24):8251-62
references: 20554877
references: Nat Neurosci. 2010 Oct;13(10):1190-8
references: 20818386
references: Exp Gerontol. 2011 Feb-Mar;46(2-3):116-23
references: 20888895
references: Respir Physiol Neurobiol. 2011 Jul 31;177(2):133-40
references: 21453797
references: Science. 2011 Jul 29;333(6042):637-42
references: 21798952
references: Brain Res. 2011 Sep 26;1414:50-7
references: 21872219
references: Eur J Neurosci. 2012 Jan;35(1):85-96
references: 22151329
references: J Neurosci. 2012 Feb 29;32(9):3032-43
references: 22378876
references: Experientia. 1964 Jul 15;20(7):398-9
references: 5856530
references: N Engl J Med. 1975 Mar 27;292(13):662-5
references: 1113761
references: N Engl J Med. 1977 Oct 6;297(14):747-50
references: 895805
references: J Appl Physiol (1985). 1997 Jan;82(1):317-23
references: 9029232
references: Arzneimittelforschung. 1998 Apr;48(4):353-9
references: 9608876
references: J Physiol. 1998 Sep 1;511 ( Pt 2):433-50
references: 9706021
references: J Appl Physiol (1985). 1999 Aug;87(2):673-82
references: 10444627
references: Am J Physiol Cell Physiol. 2004 Dec;287(6):C1493-526
references: 15525685
references: Nat Neurosci. 2004 Dec;7(12):1360-9
references: 15558061
references: J Physiol. 2005 Jul 15;566(Pt 2):543-57
references: 15878953
references: Pharmacol Biochem Behav. 2005 Dec;82(4):646-51
references: 16368129
references: J Neurosci. 2006 Oct 4;26(40):10305-14
references: 17021186
references: J Appl Physiol (1985). 2007 Nov;103(5):1780-8
references: 17823301
references: Hypertension. 2013 Jan;61(1):208-15
references: 23184381
references: Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):222-32
references: 18595785
references: J Neurosci. 2009 Mar 25;29(12):3720-37
references: 19321769
references: J Physiol. 2012 Jul 15;590(14):3335-47
references: 22615434
references: J Neurosci. 2007 Dec 19;27(51):14128-38
references: 18094252
references: Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20120536
references: 23440470
references: Respir Physiol Neurobiol. 2013 Apr 1;186(2):221-8
references: 23454023
references: Physiol Genomics. 2013 Dec 1;45(23):1144-56
references: 24085797
references: Hypertension. 2014 Apr;63(4):827-38
references: 24420542
references: J Appl Physiol (1985). 2014 Oct 15;117(8):848-56
references: 25150225
references: Annu Rev Neurosci. 1979;2:113-68
references: 231924
references: Am J Med. 1988 May;84(5):877-83
references: 3364447
references: J Med Chem. 1990 Aug;33(8):2130-7
references: 2115588
references: Neuroscience. 1990;36(1):207-16
references: 2120613
references: Acta Physiol Scand. 1991 Mar;141(3):309-18
references: 1907074
references: Physiol Rev. 1992 Jan;72(1):165-229
references: 1731370
references: J Appl Physiol (1985). 1993 Jul;75(1):5-14
references: 8376301
references: J Neurosci. 1994 Feb;14(2):821-33
references: 8301363
references: Neuroscience. 1993 Dec;57(3):811-22
references: 7508579
references: Eur J Clin Invest. 1996 Nov;26(11):989-95
references: 8957205
references: J Appl Physiol (1985). 2001 Apr;90(4):1247-57
references: 11247921
references: J Neurophysiol. 2001 May;85(5):2224-35
references: 11353037
references: Biol Reprod. 2002 May;66(5):1359-66
references: 11967198
references: J Appl Physiol (1985). 2002 Sep;93(3):974-83
references: 12183493
references: J Neurosci. 2002 Dec 15;22(24):11055-64
references: 12486201
references: J Comp Neurol. 2004 May 17;473(1):73-85
references: 15067719
references: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1067-72
references: 18198276
references: J Neurosci. 2008 Mar 5;28(10):2495-505
references: 18322094
references: Nat Neurosci. 2008 Apr;11(4):417-9
references: 18344997
references: Physiol Genomics. 2008 Jun 12;34(1):54-64
references: 18430809
references: J Appl Physiol (1985). 2008 Jul;105(1):83-90
references: 18450988
references: J Neurosci. 2010 Jan 13;30(2):670-84
references: 20071532