The coordination of swallowing with breathing, in particular inspiration, is essential for homeostasis in most organisms. While much has been learned about the neuronal network critical for inspiration in mammals, the pre–Bötzinger complex (preBötC), little is known about how this network interacts with swallowing. Here we activate within the preBötC excitatory neurons (defined as Vglut2 and Sst neurons) and inhibitory neurons (defined as Vgat neurons) and inhibit and activate neurons defined by the transcription factor Dbx1 to gain an understanding of the coordination between the preBötC and swallow behavior. We found that stimulating inhibitory preBötC neurons did not mimic the premature shutdown of inspiratory activity caused by water swallows, suggesting that swallow-induced suppression of inspiratory activity is not directly mediated by the inhibitory neurons in the preBötC. By contrast, stimulation of preBötC Dbx1 neurons delayed laryngeal closure of the swallow sequence. Inhibition of Dbx1 neurons increased laryngeal closure duration and stimulation of Sst neurons pushed swallow occurrence to later in the respiratory cycle, suggesting that excitatory neurons from the preBötC connect to the laryngeal motoneurons and contribute to the timing of swallowing. Interestingly, the delayed swallow sequence was also caused by chronic intermittent hypoxia (CIH), a model for sleep apnea, which is 1) known to destabilize inspiratory activity and 2) associated with dysphagia. This delay was not present when inhibiting Dbx1 neurons. We propose that a stable preBötC is essential for normal swallow pattern generation and disruption may contribute to the dysphagia seen in obstructive sleep apnea.
Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stress—an important driver of the clinical presentation of RTT.
26The expiratory neurons of the Bötzinger complex (BötC) provide inhibitory inputs to 27 the respiratory network, which, during eupnea, are critically important for respiratory phase 28 transition and duration control. Herein, we investigated how the BötC neurons interact with the 29 expiratory oscillator located in the parafacial respiratory group (pFRG) and control the 30 abdominal activity during active expiration. Using the decerebrated, arterially perfused in situ 31 rat preparations, we recorded the neuronal activity and performed pharmacological 32 manipulations of the BötC and pFRG during hypercapnia or after the exposure to short-term 33 sustained hypoxia -conditions that generate active expiration. The experimental data were 34 integrated in a mathematical model to gain new insights in the inhibitory connectome within 35 the respiratory central pattern generator. Our results reveal a complex inhibitory circuitry within 36 the BötC that provides inhibitory inputs to the pFRG thus restraining abdominal activity under 37 resting conditions and contributing to abdominal expiratory pattern formation during active 38 expiration. 39 40 41 Keywords: abdominal activity, hypercapnia, hypoxia, parafacial respiratory group, ventral 42 respiratory column. 48 et al., 2015, Harris-Warrick, 2010, Ramirez and Baertsch, 2018. In mammals, rhythmical 49 contraction and relaxation of respiratory muscles emerges from interacting excitatory and 50 inhibitory neurons with specific cellular properties, distributed within the pons and the medulla 51 oblongata (Richter and Smith, 2014, Del Negro et al., 2018, Lindsey et al., 2012. Coupled 52 oscillators embedded in this brainstem respiratory network are essential to generate and 53 distribute synaptic inputs for the initiation of respiratory rhythmicity and the control of pattern 54 formation (Anderson and Ramirez, 2017, Del Negro et al., 2018). Defining the arrangement 55 and connections of the respiratory oscillators and circuitries are essential to understand how 56 breathing is generated and adjusted to attend metabolic and behavior demands.57
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