Pre-Bötzinger Complex Functions as a Central Hypoxia Chemosensor for Respiration In Vivo

Abstract

Recently, we identified a region located in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) in which activation of ionotropic excitatory amino acid receptors using DL-homocysteic acid (DLH) elicits a variety of excitatory responses in the phrenic neurogram, ranging from tonic firing to a rapid series of high-amplitude, rapid rate of rise, short-duration inspiratory bursts that are indistinguishable from gasps produced by severe systemic hypoxia. Therefore we hypothesized that this unique region is chemosensitive to hypoxia. To test this hypothesis, we examined the response to unilateral microinjection of sodium cyanide (NaCN) into the pre-BötC in chloralose- or chloralose/urethan-anesthetized vagotomized, paralyzed, mechanically ventilated cats. In all experiments, sites in the pre-BötC were functionally identified using DLH (10 mM, 21 nl) as we have previously described. All sites were histologically confirmed to be in the pre-BötC after completion of the experiment. Unilateral microinjection of NaCN (1 mM, 21 nl) into the pre-BötC produced excitation of phrenic nerve discharge in 49 of the 81 sites examined. This augmentation of inspiratory output exhibited one of the following changes in cycle timing and/or pattern: 1) a series of high-amplitude, short-duration bursts in the phrenic neurogram (a discharge similar to a gasp), 2) a tonic excitation of phrenic neurogram output, 3) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a gasplike burst), or 4) an increase in frequency of phrenic bursts accompanied by small increases or decreases in the amplitude of integrated phrenic nerve discharge. Our findings identify a locus in the brain stem in which focal hypoxia augments respiratory output. We propose that the respiratory rhythm generator in the pre-BötC has intrinsic hypoxic chemosensitivity that may play a role in hypoxia-induced gasping.

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

“…At these two ages, and especially at P12, reduced CO activity suggests a transient adjustment in synaptic activity of the PBC, possibly involving decreased excitatory drive and/or enhanced inhibitory drive. The PBC, being the presumed center of respiratory rhythm generation (42) and a central hypoxia chemosensor for respiration (44), may be less responsive to abnormal respiratory demands during these periods of low CO. Consequently, the system may be more vulnerable to failure when stressed by insults such as ischemia, hypoxia, and other respiratory distress. Changes in CO activity and neurochemical immunoreactivity at P3-P4 and P12 occur despite a steady increase in neuronal size with age, indicating that they are not related to cell growth per se.…”

“…All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43).…”

Fatal breathing dysfunction in a mouse model of Leigh syndrome

“…The preBötzinger complex (preBötC) in the ventral medulla is critical for respiratory rhythm generation (25,26) and may play a role in the hypoxic response (27,28). Extracellular recordings of brain stem slices containing the preBötC were obtained from P8-P10 KO mice and their control littermates.…”

Graded Reductions in Oxygenation Evoke Graded Reconfiguration of the Isolated Respiratory Network

“…To address this issue we recorded from the pre-Bötzinger complex (preBötC) and characterized its response to graded reductions in O 2 . The preBötC is a neuronal network involved in respiratory rhythmogenesis during both well-oxygenated and hypoxic conditions (Peña 2008;Solomon et al 2000). Previous studies of the isolated brain stem slice [postnatal day zero (P0) to P18] have shown that exposure to very low levels of O 2 (i.e., 0% O 2 or hypoxia) affects both the frequency of the in vitro respiratory rhythm (Ramirez 1997a(Ramirez , 1998Telgkamp and Ramirez 1999) and the waveform of the extracellularly recorded population bursts (Lieske et al 2000).…”