Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea

Abstract

Hyperventilation is a common feature of disordered breathing. Apnea ensues if CO2 drive is sufficiently reduced. We tested the hypothesis that medullary raphé, ventral respiratory column (VRC), and pontine neurons have functional connectivity and persistent or evoked activities appropriate for roles in the suppression of drive and rhythm during hyperventilation and apnea. Phrenic nerve activity, arterial blood pressure, end-tidal CO2, and other parameters were monitored in 10 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated cats. Multielectrode arrays recorded spiking activity of 649 neurons. Loss and return of rhythmic activity during passive hyperventilation to apnea were identified with the S-transform. Diverse fluctuating activity patterns were recorded in the raphé-pontomedullary respiratory network during the transition to hypocapnic apnea. The firing rates of 160 neurons increased during apnea; the rates of 241 others decreased or stopped. VRC inspiratory neurons were usually the last to cease firing or lose rhythmic activity during the transition to apnea. Mayer wave-related oscillations (0.04-0.1 Hz) in firing rate were also disrupted during apnea. Four-hundred neurons (62%) were elements of pairs with at least one hyperventilation-responsive neuron and a correlational signature of interaction identified by cross-correlation or gravitational clustering. Our results support a model with distinct groups of chemoresponsive raphé neurons contributing to hypocapnic apnea through parallel processes that incorporate disfacilitation and active inhibition of inspiratory motor drive by expiratory neurons. During apnea, carotid chemoreceptors can evoke rhythm reemergence and an inspiratory shift in the balance of reciprocal inhibition via suppression of ongoing tonic expiratory neuron activity.

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

“…It is widely accepted that the respiratory rhythm emerges from a highly interconnected brainstem network located within the medulla (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52). Neurons within this wider respiratory network are synchronized to generate the specific phases and patterns of breathing (42,45,46,49,50,(53)(54)(55). For example, synchrony critically contributes to network stability, rhythmogenesis, and transmission of motor drive to inspiratory muscles (56)(57)(58).…”

Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations

“…Peripheral chemoreceptors of the carotid body detect changes in arterial O 2 and CO 2 -pH and tune ventilation (Kumar and Prabhakar 2012) by adjusting the frequency and depth of breathing. When driven by hypoxia during hypocapnic apnea, as may occur during sleep-disordered breathing, these chemoreceptors can evoke the reemergence of respiratory rhythmogenesis (Lovering et al 2012;Nuding et al 2015). Breathing may be switched on transiently or it may persist under the prior hypocapnic drive conditions due to induced long-term facilitation, a "respiratory memory" (Barnett et al 2017;Fuller and Mitchell 2016;Millhorn et al 1980;Morris et al 1996bMorris et al , 2001b.…”

“…Some chemoresponsive NTS neurons receive convergent baroreceptor and pharyngesophageal receptor influences, suggesting a role for chemoreceptor circuits in the coordination of breathing with swallowing, coughing, and other behaviors for airway protection, which also involve circuits in the medial medulla (Bolser et al 2015;Paton et al 1999). However, the links to "downstream" circuits of the ventral respiratory column (VRC), and chemoresponsive elements of the raphe-pontomedullary network in which it is embedded, remain incompletely understood (Guyenet 2014;Kline et al 2010;Koshiya and Guyenet 1996;Li et al 1999b;Miura and Reis 1972;Morris et al 1996aMorris et al , 1996bMorris et al , 2001aNuding et al 2009bNuding et al , 2015Song et al 2011;Takakura et al 2006).…”

Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats

“…Raphe serotonergic neurons are CO 2 sensitive, responding rapidly to increased CO 2 or decreased pH (Hodges and Richerson, 2010;Teran et al, 2014). Since raphe neurons decrease their activity with hypocapnia (Nuding et al, 2015), they may have a greater relative increase in (but lower level of) activity in response to hypoxia at low background PaCO 2 levels. Further, hypoxia and CO 2 are synergistic in their actions on carotid body chemoreceptors (Lahiri and DeLaney, 1975), predicting greater absolute raphe neuron activity and serotonin release in relative hypercapnia, although the physiological impact of serotonin release during hypoxia may be greatest at low background PaCO 2 levels.…”