Robust network oscillations during mammalian respiratory rhythm generation driven by synaptic dynamics

Abstract

How might synaptic dynamics generate synchronous oscillations in neuronal networks? We address this question in the preBötzinger complex (preBötC), a brainstem neural network that paces robust, yet labile, inspiration in mammals. The preBötC is composed of a few hundred neurons that alternate bursting activity with silent periods, but the mechanism underlying this vital rhythm remains elusive. Using a computational approach to model a randomly connected neuronal network that relies on short-term synaptic facilitation (SF) and depression (SD), we show that synaptic fluctuations can initiate population activities through recurrent excitation. We also show that a two-step SD process allows activity in the network to synchronize (bursts) and generate a population refractory period (silence). The model was validated against an array of experimental conditions, which recapitulate several processes the preBötC may experience. Consistent with the modeling assumptions, we reveal, by electrophysiological recordings, that SF/SD can occur at preBötC synapses on timescales that influence rhythmic population activity. We conclude that nondeterministic neuronal spiking and dynamic synaptic strengths in a randomly connected network are sufficient to give rise to regular respiratory-like rhythmic network activity and lability, which may play an important role in generating the rhythm for breathing and other coordinated motor activities in mammals.central pattern generator | synaptic depression | mathematical modeling | numerical simulations | breathing C entral pattern generators (CPGs) are neuronal circuits that generate coordinated activity in the absence of sensory input (1). One such mammalian CPG, the preBötzinger complex (preBötC), gives rise to the eupneic respiratory rhythm (2, 3). Located in the medulla, the preBötC preserves a spontaneous respiratory-like rhythm when isolated in transverse slices, but the precise nature of the cellular and synaptic mechanisms underlying rhythmogenesis remains elusive (3-7). An early hypothesis was that the neuronal activity is driven by intrinsically bursting pacemaker neurons synchronized via excitatory synaptic connections (2,6,8,9). However, electrophysiological and modeling studies (7, 10-12) now suggest the rhythm emerges through stochastic activation of intrinsic currents conveyed by recurrent synaptic connections, without the need for pacemaker neurons (3,4,11,13,14). In either case, excitatory synapses are required for rhythm generation; the possibility that synaptic properties also underlie periodic burst initiation and termination is yet to be demonstrated.Synaptic transmission relies on the release of vesicles, which can be modulated at the presynaptic terminal. Synaptic depression (SD), based on vesicular release, consists of decaying release probability after sustained activity, which subsequently decreases excitability within the underlying connected network. Conversely, synaptic facilitation (SF) enhances vesicular release probability and promotes neuronal synchronizatio...

Energetic substrate availability regulates synchronous activity in an excitatory neural network

“…Finally, to conceptualize how these features lead to the emergence of synchronous bursting initiated by spontaneous action potential firing we have built upon the results of Guerrier et al (42) to describe our excitatory network with a model based on random, sparse synaptic connections equipped with short-time synaptic plasticity (STSP), three synaptic vesicle pools, and a mechanism linking vesicle maintenance and recovery rates to energetic substrate availability. In our implementation of this computational model we explored the possibility of simplifying STSP dynamics further and found that the assumption of just a single vesicle pool ( Fig.…”

“…We simulated a modified version of the excitatory neural network model described by Guerrier et al (42) consisting of 20x20 (400) connected neurons organized on a square lattice.…”

“…We cultured human iNs together with rat astrocytes on multi-electrode arrays (MEAs); extensive characterization of their electrophysiology has been performed previously (39)(41) and suggests individual iNs constitute excitatory cortical layer 2/3 neurons equipped with AMPA receptors. For computational conceptualization of our experimental results we extended a simplified version of the spiking neural network model used by Guerrier et al (2015) to describe the emergence of synchronous bursting driven by synaptic dynamics (42). We found a reduced version of this model captured the same effects and incorporated metabolic regulation of synaptic vesicle recovery in order to interpret experimental data derived from cultured excitatory networks.…”

Functional roles of short-term synaptic plasticity with an emphasis on inhibition

“…However, no clear mechanism for burst termination, and therefore rhythmicity, was found. Recent computational work suggests that rhythm generation can be driven by mixed short-term synaptic dynamics of excitatory connections [58]**. In the model, the initiation of inspiratory bursts depends on synaptic facilitation, whereas early-stage depression terminates the bursts and late-stage depression produces the refractoriness of the neurons between bursts.…”

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

“…Mechanisms commonly found in rhythm generating networks include reciprocal inhibition [26 • ,27,28], rhythmic pacemaker properties [11 • ,29–33] and recurrent excitatory network mechanisms [10,34 • ,35,36 • ]. However, their roles within a given network vary and are often different than originally hypothesized.…”