New advances in the neural control of breathing

This issue contains three review articles based on talks given as part of a symposium entitled ‘New advances in the neural control of breathing’ that took place during the 1st PanAmerican Congress of Physiological Sciences (PanAm-2014) in Iguassu Falls on August 3rd, 2014, hosted by the Brazilian Society of Physiology and sponsored by The Journal of Physiology. The symposium drew together an international collection of neuroscientists to discuss cellular and molecular mechanisms by which the brain controls breathing. The speakers discussed a range of topics including the network basis of respiratory rhythmogenesis, the role of purinergic signalling in central and peripheral chemoreception, and the role of serotonergic raphe neurons in the control of breathing. Although many brain regions contribute to various aspects of respiratory control (Nattie & Li, 2012), we chose to focus this issue on recent advances made in the areas of respiratory rhythm generation by the pre-Bötzinger complex (pre-BötC), roles of purinergic signalling in peripheral and central chemoreception, and molecular mechanisms regulating the activity of chemosensitive neurons in the retrotrapezoid nucleus (RTN).

The brainstem region contains several nuclei with interconnected structures that are necessary for the production of eupnoea. The components of this complex network include many types of neurons and satellite cells and are located in a long column in the lateral brainstem that extends from the caudal medulla along the ventrolateral medulla to the dorsolateral pons, and dorsally to the nucleus of the solitary tract (NTS) (Feldman et al. 2013). On the basis of functional and anatomical criteria, the ventral respiratory column (VRC) located in the ventral lateral medulla is divided into at least five functionally distinct structures. The most rostral segment of the VRC (retrotrapezoid nucleus/parafacial region) contains a group of neurons that provide a CO₂/H⁺-dependent drive to breathe (i.e. central chemoreceptors), serves as a point of convergence for several other brain regions that control breathing including the NTS and medullary raphe, and contributes to inspiratory respiratory rhythm generation during the perinatal period (Onimaru et al. 2008; Thoby-Brisson et al. 2009). Evidence also suggests that parafacial neurons in this region contribute to active expiration in anaesthetized adult rats (Pagliardini et al. 2011). The next caudal segment of the VRC, the Bötzinger complex, contains GABAergic and/or glycinergic expiratory neurons which modulate respiratory rhythm (Richter & Smith, 2014). The next most rostral region is the pre-BötC; neurons in this region form the core respiratory rhythm-generating circuit and relay this inspiratory drive to more rostral premotor populations that control breathing (Feldman et al. 2013). Finally, the rostral and caudal segments of the VRG contain premotor neurons dedicated to the control of inspiratory and expiratory activities, respectively (Richter & Smith, 2014). A similar, if not overlapping, distribution of neurons has been identified for the cardiovascular control system (Guyenet et al. 2013). Within the same region of the ventrolateral medulla, cardiovascular physiologists have divided the region into three rostrocaudal regions (rostral and caudal ventrolateral medulla, and the caudal pressor area) which contain a complex neural network responsible for the generation, modulation and integration of the sympathetic activity.

The first review ‘Facing the challenge of mammalian neural microcircuits: taking a few breaths may help’ by Feldman and Kam provides a detailed review of experimental and computational evidence of the cellular and network basis of respiratory rhythmogenesis at the level of the pre-BötC (Feldman & Kam, 2015). The authors propose that respiratory rhythm generation by the pre-BötC is not dependent on intrinsic pacemakers per se or fast inhibitory synaptic transmission, but rather is an emergent property of the pre-BötC microcircuit. Specifically, they suggest that pre-inspiratory ‘burstlets’ produced by the convergent activity of a few neurons can produce a subthreshold rhythm that is translated into an inspiratory burst by a recurrently connected network of excitatory preBötC neurons. These exciting new insights will enhance our understanding of mechanisms underlying respiratory rhythmogenesis, and in a broader context, may provide useful insight into the complex underpinnings of other rhythmic microcircuits.

The review by Moreira and colleagues entitled ‘Independent purinergic mecha-nisms of central and peripheral chemoreception in the rostral ventrolateral medulla.’ describes the role of purinergic signalling at the level of the ventrolateral medulla in coordinating cardiorespiratory responses to hypoxia and hypercapnia by activating RTN chemoreceptors and presympathetic C1 neurons (Moreira et al. 2015). In the context of central chemoreception, evidence suggests that RTN astrocytes respond to high CO₂ by releasing ATP via connexin 26 hemichannels (Huckstepp et al. 2010). This purinergic signal up-regulates the activity of local RTN chemoreceptors and contributes to the ventilatory response to CO₂ (Wenker et al. 2012). The authors also describe the contribution of purinergic signalling to peripheral chemoreceptor modulation of breathing and blood pressure by a P2Y₁-receptor-dependent mechanism. In this case, the source of ATP is most likely NTS neurons projecting to the rostral ventrolateral medulla; however, a contribution by astrocytes cannot be ruled out (Wenker et al. 2013). Understanding the roles of purinergic signalling in the regulation of RTN chemoreceptors and C1 cells may allow for novel therapeutic strategies for cardiorespiratory diseases.

The review by Mulkey and colleagues entitled ‘Molecular underpinnings of ventral surface chemoreceptor function: focus on KCNQ channels’ describes key regulators of intrinsic excitability of RTN chemoreceptors (Mulkey et al. 2015). They summarize evidence suggesting that KCNQ channels regulate the activity of RTN chemoreceptors and may represent a common substrate for both respiratory problems and epilepsy. They also put forth a model where KCNQ and TASK-2 channels work together to limit activity under control conditions and during activation by high CO₂/H⁺. However, when KCNQ channels are blocked (e.g. in the presence of serotonin) small-conductance Ca²⁺-dependent K⁺ (SK) channels function as a secondary brake on cellular activity and provide a mechanism for scaling neuronal responsiveness to CO₂. Considering that respiratory failure is thought to be an underlying cause of sudden unexplained death in epilepsy (SUDEP), and since KCNQ channels regulate the activity of neurons that control breathing and loss of function mutations in certain KCNQ channels can cause certain types of epilepsy, the authors propose that KCNQ channels represent a common substrate for epilepsy and respiratory problems associated with SUDEP.

We thank The Journal of Physiology for supporting this symposium and this area of research with this issue of The Journal. The articles presented in this issue will provide readers with an overview of some emerging ideas related to the central neural control of the autonomic and respiratory functions in physiological and pathophysiological conditions.

Additional information

Competing interests

None declared.