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.
Highlights
It induces the activity of central pattern generators (CPGs), which are responsible for vital functions such as breathing (Ramirez et al, 2004, 2013; Peña, 2009), whose CPG is located in the preBötzinger Complex
We have recently shown that supplementation of the respiratory network with the metabolic intermediate isocitrate increases preBötzinger Complex (preBötC) activity in normoxia and favors gasping generation in hypoxia both in vitro and in vivo (Rivera-Angulo and PeñaOrtega, 2014)
The reconfiguration of the respiratory CPG that transforms the preBötC network from a control configuration that generates fictive-eupnea in normoxia to a hypoxic configuration that generates fictive-gasping involves complex changes at single-cell and network levels (Ramirez et al, 2007, 2013; Peña, 2009). We studied this reconfiguration by multielectrode arrays (MEAs) recordings and analyzed three possible contributions to such a change: changes either in the number of respiratory elements recorded by the MEA electrodes, changes in the functional connections among elements, and/or changes in the strength of these connections assessed by their correlated firing
Summary
Neuronal assemblies are embedded in complex networks that act in concert to generate the function of a given brain region (Lindsey et al, 2000; Ramirez et al, 2004, 2007; Carrillo-Reid et al, 2008; Segers et al, 2008; Galan et al, 2010; Jaidar et al, 2010; Ott et al, 2011). Several neural circuits produce spontaneous synchronous activity through the interactions of the intrinsic properties of their neurons and the chemical and electrical synapses that link them into assemblies and networks (Ramirez et al, 2004; Carrillo-Reid et al, 2008; Peña, 2009; Jaidar et al, 2010; Zavala-Tecuapetla et al, 2014). Neuronal assembly bursting is an important feature that ensures the reliability of synaptic transmission, plasticity, and information processing (Lisman, 1997). It induces the activity of central pattern generators (CPGs), which are responsible for vital functions such as breathing (Ramirez et al, 2004, 2013; Peña, 2009), whose CPG is located in the preBötzinger Complex (preBötC; Smith et al, 1991). 1999; Lieske et al, 2000; Thoby-Brisson and Ramirez, 2000; Peña et al, 2004; Paton et al, 2006; Zavala-Tecuapetla et al, 2008; Lalley and Mifflin, 2012; Ramírez-Jarquín et al, 2012), a more detailed description of respiratory circuit configurations is emerging from structural imaging (Hartelt et al, 2008; Mironov, 2009) and the evaluation of cell assemblies while maintaining single-cell resolution using www.frontiersin.org
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