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.

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…C, hypoxia alters bursting properties: it inhibits bursting properties that depend on the Ca 2+ -activated non-specific cation current (I CAN ), while bursting mechanisms that depend on the persistent sodium current (I Nap ) remain relatively unaffected. increased dependency on I Nap , but also by weakened connectivity between respiratory neurons (Nieto-Posadas et al 2014). The selective dependency of the hypoxic state on the activation of the 5-HT 2A receptor subtype is interesting in the context of sudden infant death syndrome (SIDS).…”

“…This hypoxic network state is characterized not only by an increased dependency on I Nap , but also by weakened connectivity between respiratory neurons (Nieto‐Posadas et al . ).…”

“…1). Neuronal and glial functions within this network are responsive to hypoxia even when the network is isolated in a slice preparation Tryba et al 2006;Gourine et al 2010;Huckstepp et al 2010a;Hill et al 2011;Nieto-Posadas et al 2014;Rivera-Angula & Peña-Ortega, 2014;Angelova et al 2015;Lorea-Hernandez et al 2016;Peña-Ortega, 2017). Hypoxia evokes a biphasic response: a rapid augmentation with the generation of sighs is followed by a respiratory depression ( Fig.…”

Chronic Intermittent Hypoxia Differentially Impacts Different States of Inspiratory Activity at the Level of the preBötzinger Complex

“…While eupneic inspiratory activity is characteristic for the normoxic state, gasping activity is characteristic for the hypoxic state of the network. These different network states are characterized by different cellular and network properties (Hill et al, 2011 ; Garcia et al, 2013 ; Nieto-Posadas et al, 2014 ; Rivera-Angulo and Pena-Ortega, 2014 ). Indeed, the central respiratory network is very responsive to changes in oxygenation and undergoes a complex network reconfiguration as it transitions from a well-oxygenated to a hypoxic state.…”

Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives

“…However, their roles within a given network vary and are often different than originally hypothesized. We learned that the relative contribution of neuronal mechanisms is not fixed, but dynamically regulated, resulting in state-dependent re-configuration of neuronal networks [37–40]. Mechanisms that are essential in one condition can become non-essential contributors in another state even within the same network [41].…”