Facing the challenge of mammalian neural microcircuits: taking a few breaths may help

Abstract

Breathing in mammals is a seemingly straightforward behaviour controlled by the brain. A brainstem nucleus called the preBötzinger Complex sits at the core of the neural circuit generating respiratory rhythm. Despite the discovery of this microcircuit almost 25 years ago, the mechanisms controlling breathing remain elusive. Given the apparent simplicity and well-defined nature of regulatory breathing behaviour, the identification of much of the circuitry, and the ability to study breathing in vitro as well as in vivo, many neuroscientists and physiologists are surprised that respiratory rhythm generation is still not well understood. Our view is that conventional rhythmogenic mechanisms involving pacemakers, inhibition or bursting are problematic and that simplifying assumptions commonly made for many vertebrate neural circuits ignore consequential detail. We propose that novel emergent mechanisms govern the generation of respiratory rhythm. That a mammalian function as basic as rhythm generation arises from complex and dynamic molecular, synaptic and neuronal interactions within a diverse neural microcircuit highlights the challenges in understanding neural control of mammalian behaviours, many (considerably) more elaborate than breathing. We suggest that the neural circuit controlling breathing is inimitably tractable and may inspire general strategies for elucidating other neural microcircuits.

Defining preBötzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo

“…These results are consistent with our current models of preBötC rhythm generation in which (a subset of) recurrently connected, preinspiratory, glutamatergic preBötC Dbx1 + neurons generate low level burstlets that (normally) trigger, within this preinspiratory Dbx1 + subpopulation as well as in inspiratory Dbx1 + /SST + subpopulations, the collective, high amplitude bursts that drive premotoneuronal and, ultimately, motoneuronal activity (Feldman and Kam, 2015; Kam et al, 2013a; Kam et al, 2013b). …”

“…We postulated that preBötC burst generation is a sequential process initiated by a low amplitude rhythmogenic preinspiratory component that triggers a high amplitude (pattern generating) inspiratory burst (Feldman and Kam, 2015; Kam et al, 2013a). Here, we propose that preinspiratory Dbx1 + neurons (Figure 8, Pre-I Dbx1 + Glu + ) are an essential element of the rhythmogenic microcircuit that determines timing, i.e., onset of each inspiratory phase.…”

“…preBötC heterogeneity is reflected in various molecularly-defined subpopulations that may underlie different functions during breathing (Feldman and Kam, 2015; Stornetta et al, 2003; Tan et al, 2012; Winter et al, 2009). …”

Neural Control of Breathing and CO2 Homeostasis

“…The rostral-most module is the Bötzinger region, followed by the preBötzinger complex. The latter contains a bilateral cluster of glutamatergic bursters that operate as rhythm generator for breathing (Bouvier et al, 2010; Feldman et al, 2013; Feldman and Kam, 2015). The rostral ventral respiratory group (rVRG) and the caudal VRG (cVRG) reside more caudally in the VRC and harbor inspiratory and expiratory premotor neurons, respectively (Smith et al, 2013).…”

Inhibition, Not Excitation, Drives Rhythmic Whisking

“…This activity, denoted whisking, is controlled by a neuronal oscillator located in the intermediate reticular formation (IRt) of the medulla, adjacent to the inspiratory oscillator for respiration, i.e., the pre-Bötzinger complex (preBötC; Moore et al, 2013; Feldman and Kam, 2015). This proximity is likely to be functionally relevant since whisking is tightly coupled to fast breathing, typically called sniffing.…”