title: Change in network connectivity during fictive-gasping generation in hypoxia: prevention by a metabolic intermediate.
abstract: The neuronal circuit in charge of generating the respiratory rhythms, localized in the pre-Bötzinger complex (preBötC), is configured to produce fictive-eupnea during normoxia and reconfigures to produce fictive-gasping during hypoxic conditions in vitro. The mechanisms involved in such reconfiguration have been extensively investigated by cell-focused studies, but the actual changes at the network level remain elusive. Since a failure to generate gasping has been linked to Sudden Infant Death Syndrome (SIDS), the study of gasping generation and pharmacological approaches to promote it may have clinical relevance. Here, we study the changes in network dynamics and circuit reconfiguration that occur during the transition to fictive-gasping generation in the brainstem slice preparation by recording the preBötC with multi-electrode arrays and assessing correlated firing among respiratory neurons or clusters of respiratory neurons (multiunits). We studied whether the respiratory network reconfiguration in hypoxia involves changes in either the number of active respiratory elements, the number of functional connections among elements, or the strength of these connections. Moreover, we tested the influence of isocitrate, a Krebs cycle intermediate that has recently been shown to promote breathing, on the configuration of the preBötC circuit during normoxia and on its reconfiguration during hypoxia. We found that, in contrast to previous suggestions based on cell-focused studies, the number and the overall activity of respiratory neurons change only slightly during hypoxia. However, hypoxia induces a reduction in the strength of functional connectivity within the circuit without reducing the number of connections. Isocitrate prevented this reduction during hypoxia while increasing the strength of network connectivity. In conclusion, we provide an overview of the configuration of the respiratory network under control conditions and how it is reconfigured during fictive-gasping. Additionally, our data support the use of isocitrate to favor respiratory rhythm generation under normoxia and to prevent some of the changes in the respiratory network under hypoxic conditions.
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Querétaro, México.
authors.forename: Andrés
authors.initials: A
authors.lastname: Nieto-Posadas
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Querétaro, México.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Flores-Martínez
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Querétaro, México.
authors.forename: Jonathan-Julio
authors.initials: JJ
authors.lastname: Lorea-Hernández
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Querétaro, México.
authors.forename: Ana-Julia
authors.initials: AJ
authors.lastname: Rivera-Angulo
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México México D.F., México.
authors.forename: Jesús-Esteban
authors.initials: JE
authors.lastname: Pérez-Ortega
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México México D.F., México.
authors.forename: José
authors.initials: J
authors.lastname: Bargas
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México Querétaro, México.
authors.forename: Fernando
authors.initials: F
authors.lastname: Peña-Ortega
keywords: Kreb's cycle; SIDS; gasping; network analysis; pre-Bötzinger complex
references.citation: Mol Neurobiol. 2005 Dec;32(3):251-83
references.pmid: 16385141
references.citation: Neurosci Lett. 1993 Feb 19;150(2):203-6
references.pmid: 8469422
references.citation: Pflugers Arch. 1996 Aug;432(4):741-8
references.pmid: 8764977
references.citation: Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1218-28
references.pmid: 19793109
references.citation: J Appl Physiol (1985). 1995 Mar;78(3):856-61
references.pmid: 7775329
references.citation: Curr Biol. 1994 Aug 1;4(8):752-4
references.pmid: 7953569
references.citation: Respir Physiol Neurobiol. 2013 Nov 1;189(2):344-53
references.pmid: 23770311
references.citation: J Physiol. 1991 Nov;443:231-56
references.pmid: 1822528
references.citation: J Neurosci. 2000 Aug 1;20(15):5858-66
references.pmid: 10908629
references.citation: PLoS One. 2012;7(7):e41530
references.pmid: 22848520
references.citation: Neuroscientist. 2009 Apr;15(2):194-208
references.pmid: 19307425
references.citation: J Neurosci. 2003 Apr 15;23(8):3538-46
references.pmid: 12716963
references.citation: Hippocampus. 2010 Jan;20(1):78-96
references.pmid: 19294646
references.citation: Annu Rev Physiol. 2007;69:113-43
references.pmid: 17037981
references.citation: Exp Brain Res. 1993;95(2):277-90
references.pmid: 8224053
references.citation: Respir Physiol Neurobiol. 2003 Dec 16;139(1):113-9
references.pmid: 14637318
references.citation: Am J Physiol. 1964 Aug;207:298-302
references.pmid: 14208160
references.citation: Pflugers Arch. 1976 Sep 3;365(1):49-59
references.pmid: 185580
references.citation: J Physiol. 2012 Oct 1;590(19):4933-44
references.pmid: 22777672
references.citation: Prog Brain Res. 2005;147:263-82
references.pmid: 15581712
references.citation: Prog Brain Res. 2014;209:39-56
references.pmid: 24746042
references.citation: Front Comput Neurosci. 2010 Sep 15;4:
references.pmid: 20890445
references.citation: J Neurophysiol. 2008 Mar;99(3):1435-50
references.pmid: 18184883
references.citation: J Neurophysiol. 1995 Oct;74(4):1800-5
references.pmid: 8989416
references.citation: J Neurosci Res. 2014 Mar;92(3):375-88
references.pmid: 24375766
references.citation: Neuroimage. 2014 Sep;98:460-74
references.pmid: 24814211
references.citation: Neuroscience. 2014 May 30;268:194-211
references.pmid: 24657775
references.citation: J Physiol. 1998 Mar 1;507 ( Pt 2):571-82
references.pmid: 9518714
references.citation: J Appl Physiol (1985). 1997 Jul;83(1):219-28
references.pmid: 9216967
references.citation: Biophys J. 1967 Jul;7(4):419-40
references.pmid: 4292792
references.citation: Peptides. 2012 Apr;34(2):360-72
references.pmid: 22386651
references.citation: J Neurophysiol. 2013 Jan;109(2):296-305
references.pmid: 22993257
references.citation: Neuron. 2004 Jul 8;43(1):105-17
references.pmid: 15233921
references.citation: Neurochem Res. 2014 Jan;39(1):37-45
references.pmid: 24213972
references.citation: Exp Physiol. 2004 Nov;89(6):727-37
references.pmid: 15364882
references.citation: Synapse. 1992 Dec;12(4):322-32
references.pmid: 1334580
references.citation: J Appl Physiol (1985). 2010 Jul;109(1):189-202
references.pmid: 20360432
references.citation: Trends Neurosci. 1997 Jan;20(1):38-43
references.pmid: 9004418
references.citation: Neurochem Res. 2008 Aug;33(8):1492-500
references.pmid: 18273701
references.citation: J Neurosci Methods. 1979 Aug;1(2):107-32
references.pmid: 161793
references.citation: Eur J Neurosci. 2008 Jun;27(11):2871-84
references.pmid: 18445052
references.citation: Pflugers Arch. 1976 Sep 3;365(1):69-75
references.pmid: 185582
references.citation: J Neurophysiol. 2006 Feb;95(2):803-10
references.pmid: 16192335
references.citation: Neurochem Res. 2008 May;33(5):765-75
references.pmid: 17940889
references.citation: Nat Neurosci. 2000 Jun;3(6):600-7
references.pmid: 10816317
references.citation: J Physiol. 1995 Mar 15;483 ( Pt 3):769-81
references.pmid: 7776257
references.citation: Pflugers Arch. 1976 Sep 3;365(1):61-8
references.pmid: 185581
references.citation: Mol Cell Neurosci. 2008 Mar;37(3):425-31
references.pmid: 18203620
references.citation: J Appl Physiol (1985). 2009 Sep;107(3):686-95
references.pmid: 19478196
references.citation: Curr Opin Neurobiol. 2004 Dec;14(6):665-74
references.pmid: 15582367
references.citation: Nat Neurosci. 2006 Mar;9(3):311-3
references.pmid: 16474390
references.citation: J Neurosci. 2010 Aug 25;30(34):11326-36
references.pmid: 20739553
references.citation: J Neurophysiol. 2011 Jun;105(6):2960-75
references.pmid: 21389310
references.citation: Front Comput Neurosci. 2011 Jan 07;5:4
references.pmid: 21344015
references.citation: Respir Physiol. 2000 Sep;122(2-3):183-96
references.pmid: 10967343
references.citation: Respir Physiol. 1999 Jun 1;116(1):47-65
references.pmid: 10421033
references.citation: Front Comput Neurosci. 2011 Feb 18;5:10
references.pmid: 21373358
references.citation: PLoS One. 2013 Apr 08;8(4):e60695
references.pmid: 23593283
references.citation: J Neurosci. 2002 Sep 15;22(18):7850-5
references.pmid: 12223537
references.citation: Science. 1991 Nov 1;254(5032):726-9
references.pmid: 1683005
references.citation: Curr Med Chem. 2006;13(22):2681-93
references.pmid: 17017919
references.citation: Respir Physiol Neurobiol. 2012 Apr 30;181(2):183-93
references.pmid: 22465544
references.citation: Neuroscience. 2006;137(4):1221-7
references.pmid: 16361062
references.citation: J Neurophysiol. 2008 Oct;100(4):1749-69
references.pmid: 18632881
references.citation: J Neurosci. 2002 Dec 15;22(24):11055-64
references.pmid: 12486201
references.citation: Pflugers Arch. 2002 Mar;443(5-6):829-35
references.pmid: 11889582
references.citation: Pediatr Res. 1999 Mar;45(3):350-4
references.pmid: 10088653
references.citation: Neuroreport. 1994 Dec 30;6(1):165-8
references.pmid: 7703406
references.citation: J Physiol. 2003 May 15;549(Pt 1):327-32
references.pmid: 12692183
references.citation: J Neurophysiol. 2011 Feb;105(2):625-39
references.pmid: 21084689
references.citation: J Neurophysiol. 2013 Apr;109(7):1837-51
references.pmid: 23324322
references.citation: Eur J Neurosci. 2000 Mar;12(3):856-62
references.pmid: 10762315
references.citation: J Appl Physiol (1985). 1985 Oct;59(4):1201-7
references.pmid: 4055598
references.citation: Neural Comput. 1997 Aug 15;9(6):1265-75
references.pmid: 9248062
references.citation: J Neurophysiol. 2013 Jan;109(2):285-95
references.pmid: 23076109