Dorsal and ventral aspects of the most caudal medullary reticular formation have differential roles in modulation and formation of the respiratory motor pattern in rat

Abstract

The respiratory pattern generator of mammals is anatomically organized in lateral respiratory columns (LRCs) within the brainstem. LRC compartments serve specific functions in respiratory pattern and rhythm generation. While the caudal medullary reticular formation (cMRF) has respiratory functions reportedly related to the mediation of expulsive respiratory reflexes, it remains unclear whether neurons of the cMRF functionally belong to the LRC. In the present study we specifically investigated the respiratory functions of the cMRF. Tract tracing shows that the cMRF has substantial connectivity with key compartments of the LRC, particularly the parafacial respiratory group and the Kölliker-Fuse nuclei. These neurons have a loose topography and are located in the ventral and dorsal cMRF. Systematic mapping of the cMRF with glutamate stimulation revealed potent respiratory modulation of the respiratory motor pattern from both dorsal and ventral injection sites. Pharmacological inhibition of the cMRF with the GABA-receptor agonist isoguvacine produced significant and robust changes to the baseline respiratory motor pattern (decreased laryngeal post-inspiratory and abdominal expiratory motor activity, delayed inspiratory off-switch and increased respiratory frequency) after dorsal cMRF injection, while ventral injections had no effect. The present data indicate that the ventral cMRF is not an integral part of the respiratory pattern generator and merely serves as a relay for sensory and/or higher command-related modulation of respiration. On the contrary, the dorsal aspect of the cMRF clearly has a functional role in respiratory pattern formation. These findings revive the largely abandoned concept of a dorsal respiratory group that contributes to the generation of the respiratory motor pattern.

Brainstem mechanisms underlying the cough reflex and its regulation

“…Similar findings have been obtained by Poliacek et al (2007). Respiratory modulation triggered by EAA receptor stimulation of the NRA region, comprising the cVRG, has been confirmed and analyzed in more detail by recent studies (Subramanian and Holstege 2009;Jones et al, 2016). The hypothesis was advanced that cVRG neurons may affect the pattern of breathing, possibly through axon collaterals when strongly activated (Bongianni et al, 1994).…”

“…This could be relevant to some physiological conditions, such as airway defensive reflexes including coughing and sneezing (Bongianni et al, 1994;Iscoe 1998). This hypothesis is corroborated by anatomical studies showing cVRG projections to other brainstem respiration-related regions, such as the rostral VRG, the parabrachialis medialis/Kölliker Fuse nuclei and the NTS (Smith et al, 1989;Gerrits and Holstege 1996;Iscoe 1998;Zheng et al, 1998;Jones et al, 2016).…”

“…They may arise from more rostral expiration-related regions such as the BötC (Bongianni et al, 1998;Shannon et al, 2000; for review see also Iscoe 1998;Pantaleo et al, 2002;Shannon et al, 2004) or the RTN/ pFRG (Onimaru and Homma 2003;Mulkey et al, 2004;Janczewski and Feldman 2006;Guyenet and Mulkey 2010;Guyenet et al, 2016;Ikeda et al, 2017) as well as from the limbic system and the periaqueductal gray (Subramanian and Holstege 2009;Jones et al, 2016). Some recent findings are in contrast with the current concept that structures caudal to the obex are unnecessary for eupneic breathing.…”

“…However, at variance with the hypothesis advanced for the gating mechanism, some antitussive drugs have been found to greatly influence also coughrelated timing probably affecting neurons unrelated to vagal tussigenic inputs, but implicated in the control of respiratory timing and intensity (Budzinska et al, 1985a;Von Euler 1986;Bianchi et al, 1995). This obviously implies that NTS ascending projections provide synaptic interactions with neurons responsible for respiratory pattern formation Mutolo Respiratory Physiology & Neurobiology 243 (2017) 60-76 (see Jones et al, 2016 also for further Refs.). All these results support the notion that the cNTS is not a mere relay station, but plays more extensive functions in cough motor pattern generation and, in addition, that it is an important location of cough-gating neurons (see Haji et al, 2013;Bolser et al, 2015;Pitts et al, 2016; also for further Refs.).…”

“…Further, the periaqueductal gray, that is the source of one of the major afferent input to the NRA, could be relevant for cough research (e.g. Iscoe 1998;Subramanian and Holstege 2009;Jones et al, 2016). Interestingly, reciprocal connections between the periaqueductal gray and the preBötC have been reported (for review see Ikeda et al, 2017).…”