The Kölliker–Fuse nucleus acts as a timekeeper for late-expiratory abdominal activity

Abstract

While the transition from the inspiratory to the post-inspiratory (post-I) phase is dependent on the pons, little attention has been paid to understanding the role of the pontine respiratory nuclei, specifically the Kölliker–Fuse nucleus (KF), in transitioning from post-I to the late expiratory (late-E) activity seen with elevated respiratory drive. To elucidate this, we used the in situ working heart-brainstem preparation of juvenile male Holtzman rats and recorded from the vagus (cVN), phrenic (PN) and abdominal nerves (AbN) during baseline conditions and during chemoreflex activation [with potassium cyanide (KCN; n = 13) or hypercapnia (8% CO2; n = 10)] to recruit active expiration. Chemoreflex activation with KCN increased PN frequency and cVN post-I and AbN activities. The inhibition of KF with isoguvacine microinjections (10 mM) attenuated the typical increase in PN frequency and cVN post-I activity, and amplified the AbN response. During hypercapnia, AbN late-E activity emerged in association with a significant reduction in expiratory time. KF inhibition during hypercapnia significantly decreased PN frequency and reduced the duration and amplitude of post-I cVN activity, while the onset of the AbN late-E bursts occurred significantly earlier. Our data reveal a negative relationship between KF-induced post-I and AbN late-E activities, suggesting that the KF coordinates the transition between post-I to late-E activity during conditions of elevated respiratory drive.

Inhibitory control of active expiration by the Bötzinger complex in rats

“…This hypothesis is in agreement with previous observations that the depressed the activity of post-I neurons in SH is synaptically mediated (Moraes et al, 2014). In this scenario, we consider that changes in the pontine excitatory drive to the VRC, specially from the Kölliker-Fuse (Dutschmann and Herbert, 2006, Geerling et al, 2017, Barnett et al, 2018, Jenkin et al, 2017), or reductions in the excitatory drive from the recently described post-inspiratory complex (Anderson et al, 2016), may represent possible mechanisms underlying the depressed activity of post-I neurons in the BötC after SH – hypotheses that still require additional studies to be addressed.…”

“…In silico studies propose that the inhibitory drive to the pFRG originates, at least in part, from the ventral respiratory column (Molkov et al, 2010). Specifically, computational modeling suggests that neurons of the BötC might be a source of inhibition to the pFRG oscillator, and the reduction of this inhibitory drive might be an important stage for the emergence of active expiration in conditions of elevated excitatory drive (Barnett et al, 2018, Jenkin et al, 2017). However, experimental and functional evidence is still required to confirm the possible inhibitory control of the BötC neurons over the pFRG expiratory oscillator.…”

Hypercapnia‐induced active expiration increases in sleep and enhances ventilation in unanaesthetized rats

“…An increased respiratory drive leads to emergence of expiratory abdominal activity in humans (Badr et al 1990;Wakai et al 1992;Abe et al 1996), dogs (Oliven et al 1985;Smith et al 1989Smith et al , 1990 and rodents (Sherrey et al 1988;Iizuka & Fregosi, 2007;Lemes & Zoccal, 2014). In rats, evidence of hypercapnia-induced expiratory ABD EMG activity extends from in situ preparations (Abdala et al 2009;de Britto & Moraes, 2016;Jenkin et al 2017) to in vivo anaesthetized animals (Iizuka & Fregosi, 2007;Lemes & Zoccal, 2014). Fewer studies, however, have examined its occurrence in unanaesthetized rats in different vigilance states.…”

“…Interestingly, however, under eupnoeic conditions, where active expiration is absent normally, abdominal activity emerges in the REM-like sleep state in urethane-anaesthetized rats as well as in REM sleep, providing stability to breathing (Pagliardini et al 2012;Andrews & Pagliardini, 2015). Evidence of hypercapnia-induced expiratory abdominal activity in rats extends from in situ preparations (Abdala et al 2009;de Britto & Moraes, 2016;Jenkin et al 2017) to in vivo anaesthetized animals (Iizuka & Fregosi, 2007;Lemes & Zoccal, 2014), but whether active expiration occurs in unanaesthetized animals under hypercapnic conditions in a state-dependent manner, i.e. differently in sleep and wakefulness, remains to be seen.…”

“…; de Britto & Moraes, ; Jenkin et al . ) to in vivo anaesthetized animals (Iizuka & Fregosi, ; Lemes & Zoccal, ), but whether active expiration occurs in unanaesthetized animals under hypercapnic conditions in a state‐dependent manner, i.e. differently in sleep and wakefulness, remains to be seen.…”