Role of the RTN Neurons in the Control of Breathing

Neuronal circuitry controlling breathing automaticity is primarily located in the lower brainstem. The retrotrapezoid nucleus/parafacial respiratory group (RTN/pfRG) plays a critical role in initiation of breathing at birth and its regulation throughout life. A group of Phox2b expressing, VGluT2/NK1R positive neurons, located at the ventral medullary surface, the ccRTN neurones, produce a tonic, excitatory drive to the respiratory network in response to changes in arterial gas composition, and serve the role of central chemoreceptors in adult animals.;In embryos and neonates, however, presumed precursors of adult ccRTN neurons, the pfRG pre-I neurons, display pacemaker properties and are believed to be vital for respiratory rhythm generation. The pre-I bursting activity characteristic of the pfRG has never been observed in the adult rodents and the phenotype of the pfRG neurons is unknown. One objective of this dissertation was to determine whether the RTN/pfRG region in the adult anesthetized rat contains pre-I bursting cells, and if so, under what conditions and what the phenotype of these neurons may be (are they ccRTN?). The second objective was to investigate the possibility that the ccRTN neurones are regulated not only by chemical drives (CNS acidification, carotid bodies) but also by inputs from higher brain centers involved in the feed-forward control of respiration.;This dissertation shows that a pfRG-pattern can be elicited in anesthetized adult rats by hypoxic hypercapnia. Retroambiguual expiratory premotor neurons and Botzinger E-AUG glycinergic neurons developed the pre-I pattern under hypoxia but the ccRTN chemoreceptors did not. This finding suggests that the pfRG could be a heterogeneous collection of neurons that develop a pre-I firing mode because of a general reconfiguration of the respiratory network.;Further, we show that ccRTN neurons, which provide a pH-regulated excitatory drive to the respiratory network, also participate in the feed-forward control of breathing that originates from the posterior hypothalamus, a region that regulates breathing during sleep, stress and exercise. Using single-unit recording and c-Fos expression as indicators of the activity of the ccRTN neurons, we show that these cells are activated equally powerfully by hypothalamic stimulation and by CNS acidification in vivo. Moreover, the ccRTN neurons retain their ability to respond to changes in brain pH regardless of their level of activity or type of anesthesia. These results suggest that the ccRTN neurons are a site of integration between the chemical drive to breathe and the feed-forward command of breathing.