Dynamics of neuromodulatory feedback determines frequency modulation in a reduced respiratory network: A computational study

Neuromodulators, such as amines and neuropeptides, alter the activity of neurons and neuronal networks. In this work, we investigate how neuromodulators, which activate Gq-protein second messenger systems, can modulate the bursting frequency of neurons in a critical portion of the respiratory neural network, the pre-Bötzinger complex (preBötC). These neurons are a vital part of the ponto-medullary neuronal network, which generates a stable respiratory rhythm whose frequency is regulated by neuromodulator release from the nearby Raphe nucleus. Using a simulated 50-cell network of excitatory preBötC neurons with a heterogeneous distribution of persistent sodium conductance and Ca2+, we determined conditions for frequency modulation in such a network by simulating interaction between Raphe and preBötC nuclei. We found that the positive feedback between the Raphe excitability and preBötC activity induces frequency modulation in the preBötC neurons. In addition, the frequency of the respiratory rhythm can be regulated via phasic release of excitatory neuromodulators from the Raphe nucleus. We predict that the application of a Gq antagonist will eliminate this frequency modulation by the Raphe and keep the network frequency constant and low. In contrast, application of a Gq agonist will result in a high frequency for all levels of Raphe stimulation. Our modeling results also suggest that high [K+] requirement in respiratory brain slice experiments may serve as a compensatory mechanism for low neuromodulatory tone.

► We model neuromodulatory interactions between the pre-Bötzinger complex (pBC) and Raphe. ► Tonic neuromodulation released by the Raphe did not significantly modulate pBC frequency. ► Tonic and phasic neuromodulation by the Raphe interacting with the pBC did modulate pBC frequency. ► Positive feedback pathways from pBC to Raphe are necessary for effective frequency modulation.