Neuromodulation of the Perinatal Respiratory Network

Klaus      Ballanyi

Abstract

Breathing movements are initiated and controlled by a neuronal network within the lower brainstem that is influenced by peripheral and suprapontine inputs. To provide adaptation of breathing to vocalisation, exercise or hypoxia, rhythmogenic neurons of the ventral respiratory group (VRG) within the ventrolateral medulla (VLM) are controlled by numerous neuromodulators. Underlying cellular mechanisms are currently analysed in respiratory active medulla preparations from perinatal rodents. This reveals properties of the perinatal respiratory network pivotal for understanding spontaneous or drug-induced perturbation of breathing in preterm and term infants. Already at birth, ligand-gated anion channels can inhibit VLM-VRG neurons. But impairment of Cl- extrusion by hormones or growth factors may interfere with respiratory functions. During severe hypoxia, resulting in anoxia of the VLM-VRG, perinatal respiratory activity persists for more than twenty minutes, although at a greatly reduced frequency. This frequency depression, associated with a hyperpolarisation of rhythmogenic VLM-VRG neurons, is reversed by K+ channel blockers, thyrotropin-releasing hormone or substance-P, for example. This response may represent an adaptive mechanism for energy conservation during oxygen depletion. Endogenous frequency depression of the normoxic perinatal respiratory rhythm, possibly mediated by endorphins or prostaglandins, may serve to dampen excessive respiratory activity in utero. Opiates and prostaglandins, known to impair breathing in infants during clinical administration, likely act directly to depress rhythmogenic VLM-VRG neurons. Based upon such findings in perinatal rodent models on synaptic inhibition and responses to hypoxia-anoxia or clinically-applicable drugs, novel pharmacological strategies are discussed that aim to stabilise infant breathing by targeting rhythmogenic respiratory neurons.

Keywords: apnoea, anoxia, burster neurons, neuromodulation, rhythmogenesis

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