title: Decreased Hering-Breuer input-output entrainment in a mouse model of Rett syndrome.
abstract: Rett syndrome, a severe X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (Mecp2), is associated with a highly irregular respiratory pattern including severe upper-airway dysfunction. Recent work suggests that hyperexcitability of the Hering-Breuer reflex (HBR) pathway contributes to respiratory dysrhythmia in Mecp2 mutant mice. To assess how enhanced HBR input impacts respiratory entrainment by sensory afferents in closed-loop in vivo-like conditions, we investigated the input (vagal stimulus trains) - output (phrenic bursting) entrainment via the HBR in wild-type and MeCP2-deficient mice. Using the in situ perfused brainstem preparation, which maintains an intact pontomedullary axis capable of generating an in vivo-like respiratory rhythm in the absence of the HBR, we mimicked the HBR feedback input by stimulating the vagus nerve (at threshold current, 0.5 ms pulse duration, 75 Hz pulse frequency, 100 ms train duration) at an inter-burst frequency matching that of the intrinsic oscillation of the inspiratory motor output of each preparation. Using this approach, we observed significant input-output entrainment in wild-type mice as measured by the maximum of the cross-correlation function, the peak of the instantaneous relative phase distribution, and the mutual information of the instantaneous phases. This entrainment was associated with a reduction in inspiratory duration during feedback stimulation. In contrast, the strength of input-output entrainment was significantly weaker in Mecp2 (-/+) mice. However, Mecp2 (-/+) mice also had a reduced inspiratory duration during stimulation, indicating that reflex behavior in the HBR pathway was intact. Together, these observations suggest that the respiratory network compensates for enhanced sensitivity of HBR inputs by reducing HBR input-output entrainment.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Case Western Reserve University Cleveland, OH, USA ; Department of Neurosciences, Case Western Reserve University Cleveland, OH, USA.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Dhingra
authors.forename: Yenan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Jacono
authors.forename: David M
authors.initials: DM
authors.lastname: Katz
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Galán
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dick
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000473:pathology*; D015656:Respiratory Mechanics / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
keywords: Hering–Breuer reflex; Mecp2; closed-loop; entrainment; vagus
references.citation: J Appl Physiol (1985). 2006 Aug;101(2):618-27
references.pmid: 16645192
references.citation: J Physiol. 2008 May 1;586(9):2331-43
references.pmid: 18339694
references.citation: Acta Neurobiol Exp (Wars). 1980;40(3):543-62
references.pmid: 7435267
references.citation: J Physiol. 2009 Oct 15;587(Pt 20):4931-48
references.pmid: 19703965
references.citation: Respir Physiol Neurobiol. 2010 Sep 30;173(2):146-56
references.pmid: 20659592
references.citation: J Neurosci. 2010 Apr 14;30(15):5303-10
references.pmid: 20392952
references.citation: Neuroreport. 1998 Feb 16;9(3):411-4
references.pmid: 9512381
references.citation: J Neurosci. 2005 Dec 14;25(50):11521-30
references.pmid: 16354910
references.citation: J Neurosci. 1996 Oct 15;16(20):6526-36
references.pmid: 8815930
references.citation: Front Integr Neurosci. 2011 May 02;5:6
references.pmid: 21629824
references.citation: Eur J Neurosci. 2006 Aug;24(4):1071-84
references.pmid: 16930433
references.citation: J Neurosci. 2009 Sep 30;29(39):12187-95
references.pmid: 19793977
references.citation: J Neurosci Methods. 1996 Mar;65(1):63-8
references.pmid: 8815310
references.citation: J Comp Neurol. 2002 Apr 22;446(1):81-94
references.pmid: 11920722
references.citation: J Physiol. 1938 Jun 14;93(1):10-23
references.pmid: 16994990
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18208-13
references.pmid: 20921395
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Feb;87(2):022709
references.pmid: 23496550
references.citation: Acta Neurobiol Exp (Wars). 1981;41(1):87-94
references.pmid: 7270255
references.citation: J Physiol. 2007 Mar 15;579(Pt 3):863-76
references.pmid: 17204503
references.citation: Am J Physiol. 1996 Oct;271(4 Pt 2):R1054-62
references.pmid: 8898000
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Aug;289(2):R450-R455
references.pmid: 15831763
references.citation: J Neural Eng. 2011 Dec;8(6):065003
references.pmid: 22058274
references.citation: Pediatr Res. 2006 Oct;60(4):443-9
references.pmid: 16940240
references.citation: Brain Res. 1977 Oct 28;135(2):231-54
references.pmid: 922474
references.citation: Nat Genet. 2001 Mar;27(3):322-6
references.pmid: 11242117
references.citation: J Physiol. 1954 Aug 27;125(2):336-51
references.pmid: 13192823
references.citation: J Comp Neurol. 1990 Mar 22;293(4):540-80
references.pmid: 1691748
references.citation: J Appl Physiol (1985). 1994 Mar;76(3):1138-43
references.pmid: 8005856
references.citation: Trends Neurosci. 1997 Dec;20(12):553-7
references.pmid: 9416664
references.citation: Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):101-8
references.pmid: 19394452
references.citation: J Appl Physiol. 1974 Nov;37(5):723-35
references.pmid: 4373429
references.citation: J Neurophysiol. 2008 Jan;99(1):112-21
references.pmid: 18032561
references.citation: J Appl Physiol (1985). 2011 Jul;111(1):272-84
references.pmid: 21527661
references.citation: Respir Physiol Neurobiol. 2004 Nov 15;143(2-3):127-40
references.pmid: 15519550
references.citation: Neurosci Lett. 1996 Sep 6;215(2):123-6
references.pmid: 8888011
references.citation: Respir Physiol. 1975 Jan;23(1):23-30
references.pmid: 1129548
references.citation: J Physiol. 2000 Mar 1;523 Pt 2:479-91
references.pmid: 10699090
references.citation: J Physiol. 1970 Nov;211(1):63-71
references.pmid: 5500999
references.citation: Compr Physiol. 2012 Oct;2(4):2443-69
references.pmid: 23720253
references.citation: Kidney Int. 1974 May;5(5):215-22
references.pmid: 4416275
references.citation: Dis Model Mech. 2012 Nov;5(6):733-45
references.pmid: 23115203
references.citation: Respir Physiol. 1994 May;96(2-3):177-88
references.pmid: 7914709
references.citation: J Neurophysiol. 2000 May;83(5):3165-8
references.pmid: 10805712
references.citation: Am J Physiol. 1986 May;250(5 Pt 2):R902-9
references.pmid: 3706575
references.citation: J Neurosci. 2012 Feb 1;32(5):1803-10
references.pmid: 22302819
references.citation: Nat Genet. 2001 Mar;27(3):327-31
references.pmid: 11242118
references.citation: Neural Comput. 1996 Apr 1;8(3):567-81
references.pmid: 8868568
references.citation: J Neurophysiol. 1983 May;49(5):1168-81
references.pmid: 6864244
references.citation: J Neurosci. 2012 Oct 3;32(40):13860-72
references.pmid: 23035095
references.citation: Pflugers Arch. 1983 Feb;396(2):121-7
references.pmid: 6835815
references.citation: Am J Physiol. 1984 Mar;246(3 Pt 2):R311-20
references.pmid: 6584038
references.citation: J Physiol. 2008 Sep 1;586(17):4265-82
references.pmid: 18599543