Pre-Bötzinger complex
The preBötC is approximately colocated with the hypoglossal (XII) cranial motor nucleus as well as the ‘loop’ portion of the inferior olive in the anterior-posterior axis.
If the central neuraxis from pons to lumbar spinal cord is removed from a newborn rodent, then basic neural motor patterns can be generated and recorded using microelectrodes in vitro.
[3][4] By isolating a rhythmically active newborn rat brainstem-spinal cord in a microsectioning vibratome, Smith and colleagues performed a series of 75 μm-thick transverse sections while monitoring inspiratory-related motor rhythms.
The preBötC represented the portion of the ventral-lateral lower brainstem that was necessary and sufficient to generate inspiratory related rhythm and motor output in vitro.
The authors concluded that these preBötC-retaining slice preparations preserved the core network generating inspiratory rhythm as well as premotor and motor neurons that define a minimal breathing-related circuit suitable for studies under controlled conditions in vitro.
The superset of markers is based largely on neuropeptides and peptide receptors, whose expression patterns have come to define the borders of preBötC and its constituent rhythm-generating and output pattern-related interneurons .
Note, this observation in vitro presaged the 2010-2020's crisis of opioid-drug related deaths by respiratory failure, which are attributable in large part to depression of rhythm-generating function in the preBötC (but also see:[22][23]).
In the late 1980s and early 1990s, following discovery of the preBötC, in vitro preparations from neonates were not yet widely accepted as experimental models of the respiratory neural control system in adults.
The exogenous peptide that activates the fly receptor was ultimately cleared from the central nervous system: injected rats nonetheless needed mechanical ventilation until they recovered from the experiment.
SP accelerated inspiratory rhythms measured in vitro and ablation of NK1R-expressing preBötC neurons caused severe pathologies of breathing that were ultimately fatal.
In slices from early postnatal Dbx1 reporter mice, Dbx1-derived preBötC neurons are rhythmically active in vitro in sync with inspiratory rhythm and motor output.
[44] Third, Dbx1 is an embryonic transcription factor that governs the development of many populations in the brain and central nervous system, notably the V0 interneuron class involved in locomotion.
[45] Nevertheless, Dbx1 expression patterns can be mapped using Cre-Lox recombination in genetically modified mice to find and record preBötC core rhythmogenic interneurons.
[55][40] Without preBötC inhibitory microcircuits, the breathing rhythm is slower overall and 'stiff' in the sense that its oscillation stabilizes even when faced with normally effective respiratory drive like CO2 or SP.
The gasping rhythm is proposed to play a critical role in autoresuscitation, failure of which may contribute to, or underlie, Sudden Infant Death Syndrome (SIDS).
[78][51] The exact mechanism of the rhythm generation and transmission to motor nuclei remains controversial and the topic of much research [79][80][81][82][83][63] There are several inward currents that are proposed to help produce action potentials and bursts in pacemaker neurons.
The neuron can receive synaptic inputs and different amounts of inward and outward currents to regulate the time between each burst, which ultimately helps generate a specific breathing pattern.
NALCN sodium leak channels have been hypothesized to give rise to an inward current that may play an important role in the modulation of bursting and spiking activity.
Since NALCN sodium leak channels may contribute to the depolarization of neurons, their regulation by G-protein coupled receptors may be vital for the alteration of bursting and breathing rhythms.
When A-type potassium currents were blocked with 4-AP in slices of the pre-Bötzinger complex, synchronized bursts in inspiratory neurons was affected as well as communication with hypoglossal motor pools that help regulate breathing.
Since many of these neurons express GABA, glutamate, serotonin[85] and adenosine receptors, chemicals custom tailored to bind at these sites are most effective at altering respiratory rhythm.
[86][87] An adenosine A1 receptor agonist has been shown to depress preBötC rhythmogenesis independent of the neurotransmitters GABA and glycine in in vitro preparations from 0- to 7-day-old mice.
The complex regulation of respiratory rhythm involves the integration of multiple signaling molecules and the activation of numerous diverse metabotropic and ionotropic receptors.
[83] These include norepinephrine, serotonin, acetylcholine, substance P, ATP, TRH, somatostatin, dopamine, endorphins, and adenosine, which in turn activate g-protein coupled receptors to produce the diverse responses mediated by the pre-Bötzinger complex.
The role of synaptic inhibition has been proved widespread and critical within the expiratory Botzinger complex respiratory network, through cross-correlation and antidromic mapping techniques.
In addition to glutamates role in activating the synaptic drive of inspiration, it is also understood that pacemaker neurons, with autonomous voltage-dependent properties, are also responsible for the generation of respiratory rhythm.
However, the generation of respiratory rhythm requires other excitatory components, such as glutamate, in order to produce a wide range of behavioral functions including eupneic and sigh activity.
The pre-Bötzinger complex is capable of generating differential rhythmic activities due to the intricate integration of modulatory, synaptic, and intrinsic properties of the neurons involved.
In addition to its involvement in generating respiratory rhythm, the pre-Bötzinger complex is also capable of integrating sensory information from changes in the biochemical environment, particularly oxygen.
Hypoxia results in gasping due to the increased dependence on the sodium current and the overlap in networks between the generation of respiratory rhythm and intrinsic oxygen sensitization.
