Chapter 8 - Synaptically activated burst-generating conductances may underlie a group-pacemaker mechanism for respiratory rhythm generation in mammals
Introduction
Understanding the neural origins of behaviors like walking, running, swimming, chewing, suckling, and breathing will be tenable via the application of a broad spectrum of techniques from biomechanics to molecular genetics. These cross-disciplinary tools will enable us to cohere data from many levels of analysis spanning intact behaving organisms to intrinsic membrane properties and biochemical signaling pathways studied in vitro.
Here we examine breathing behavior in mammals: rhythmic movements of the diaphragm, thorax, and airways to produce ventilation. We seek cellular- and synaptic-level mechanisms that produce the respiratory rhythm. We limit our focus to a specialized region of the lower brain stem (preBötzinger Complex; preBötC), which is essential for breathing in awake intact adult rodents, and is necessary and sufficient for inspiratory motor rhythms in vitro (Feldman and Del Negro, 2006, Rekling and Feldman, 1998, Smith et al., 1991).
To focus on the neural origins of the essential underlying inspiratory rhythm, we necessarily set aside other, equally important, issues related to the neural control of breathing, including—but not limited to—the developmental genetics of preBötC circuits, integrated functions of the preBötC within the larger respiratory network of the lower medulla, formation of an appropriate spatiotemporal motor pattern for ventilatory movements, regulation of the rhythm via neuromodulation, sensorimotor integration, for example, mechanosensitive feedback from the lungs, as well as peripheral and central chemosensation related to oxygen, carbon dioxide, and pH.
Our analysis of rhythm generation in the preBötC addresses the following two linked questions: (1) Which neurons? (2) How? The preBötC is a functionally and anatomically defined site in the lower brain stem containing several thousand neurons in rodents, and we are interested in understanding which ones are rhythmogenic. Here, we consider intrinsic membrane and anatomical properties that may underlie rhythmogenicity.
Several models—conceptual as well as explicitly mathematical—outline two general paradigms for the mechanism underlying respiratory rhythmogenesis: reciprocal inhibition and/or pacemaker neurons. Here we evaluate some straightforward predictions of these models and conclude that the respiratory rhythm cannot be adequately explained using these paradigms. Instead we present an alternative model: group-pacemaker hypothesis (Feldman and Del Negro, 2006, Rekling and Feldman, 1998, Rekling et al., 1996a, Rubin et al., 2009a). In this model, recurrent synaptic excitation boosts and propagates activity like a conventional network oscillator (Grillner, 2006), yet constituent neurons generate spike bursts with an underlying plateau-like depolarization during the active phase, which is behavior typically associated with intrinsic pacemaker properties (Coombes and Bressloff, 2005).
Section snippets
Rhythmic motor behaviors studied in vitro
Central pattern generator (CPG) networks produce neural rhythms for motor behaviors without need of sensory feedback or commands from higher brain centers (Grillner, 2006, Marder, 2001). Invertebrate model systems provide valuable insights into the structure and function of CPGs because these systems comprise a limited number of constituent neurons (~100) that can be identified and, more importantly, selectively recorded in the context of behavior in vitro. Detailed analyses of CPG neurons and
Early models featured a role for chloride-mediated synaptic inhibition
Prior to 1989, the dominant models of respiratory rhythm generation incorporated a critical and obligatory role for synaptic inhibition (Bradley et al., 1975, Feldman and Cowan, 1975). The general structure of these models posited (a minimum of) three interconnected populations of respiratory neurons including inspiratory and expiratory timing circuits, as well as well as a ramp-generator circuit for inspiratory bursts. The interaction of these populations was thought to generate two or three
PreBötC neurons with early-inspiratory activity and robust bursts may be rhythmogenic
If pacemaker properties after synaptic isolation are not necessarily a reliable and accurate phenotype for putative respiratory rhythm-generators, then one should examine how respiratory neurons behave and, what intrinsic properties they utilize in the context of the functioning network, to elucidate the mechanisms of rhythmogenesis. This type of analysis is possible using slice preparations that retain the preBötC in vitro (Fig. 1b and c). An important pioneering work in that regard was the
A new paradigm for respiratory rhythmogenesis based on emergent network properties
In the absence of obligatory pacemaker neurons, one alternative explanation for rhythm generation is based on recurrent synaptic excitation. This concept remained purely hypothetical without the identification of specific mechanisms through which it could be implemented. However, we now recognize that ICAN activation is linked to mGluRs and AMPA receptor-mediated recruitment of Ca2+ channels, which is a viable mechanism for the normally latent ICAN to be evoked synaptically in the lead-up to
Conclusions
CPGs in vertebrates incorporate thousands of highly interconnected neurons, each of which represents a complex dynamical system with many degrees of freedom (Grillner, 2006, Kozlov et al., 2009). To understand CPGs, we must necessarily focus on the essential rhythmogenic modules. Reciprocal inhibition—where active synaptic inhibition acts as a barrier that must be overcome for phase switching to occur—or specialized pacemaker neurons—which provide a rhythmic template for network activity—are
Acknowledgments
The work was supported by NIH HL-40959, NIH NINDS R21, NS070056-01, NIH-NHLBS R01 HL104127-01, and the Undergraduate Biological Sciences Education and Research Training Grant to The College of William & Mary by the Howard Hughes Memorial Institute.
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Cited by (39)
Respiratory rhythm and pattern generation: Brainstem cellular and circuit mechanisms
2022, Handbook of Clinical NeurologyCitation Excerpt :An early computational model of preBötC excitatory networks with emergent rhythm generation was developed by Rubin et al. (2009a) as an example of a possible group pacemaker mechanism. In this model incorporating ICAN, the rhythmogenic mechanism involved synaptic activation of excitatory neuron ionotropic and metabotropic (mGluR1/5) glutamatergic receptors that activate IP3 receptor signaling (Crowder et al., 2007; Mironov, 2008; Pace and Del Negro, 2008; Del Negro et al., 2010) (see Fig. 1.6). This signaling initiates the release of Ca2 + from internal stores, postulated to be within dendrites (Mironov, 2008; Toporikova and Butera, 2011; Del Negro et al., 2011) that activates ICAN (Toporikova and Butera, 2011; Mironov and Skorova, 2011).
Emergent Elements of Inspiratory Rhythmogenesis: Network Synchronization and Synchrony Propagation
2020, NeuronCitation Excerpt :The onset of rhythmic bursting was concomitant with a decrease in their activity during interburst intervals, marking a refractory period for their synchronization. This postburst refractory period is typical of type 1 preBötC neurons (Baertsch et al., 2018; Del Negro et al., 2010; Feldman et al., 2013) and provides another line of evidence that they are rhythmogenic neurons. Under nonrhythmic conditions, rhythmogenic neurons were tonically active with no underlying rhythmicity, as evident by high synaptic noise in the I-M SST+ neurons (Figures 2B1, 5D1, 5H, 6A1, and 6G).
Microcircuits in respiratory rhythm generation: commonalities with other rhythm generating networks and evolutionary perspectives
2016, Current Opinion in NeurobiologyRespiratory neuron characterization reveals intrinsic bursting properties in isolated adult turtle brainstems (Trachemys scripta)
2016, Respiratory Physiology and NeurobiologyCitation Excerpt :Since experimental methods do not currently exist for specifically inactivating the specific ionic currents underlying intrinsic bursting properties in respiratory neurons, attention was redirected toward alternative mechanisms underlying rhythmogenesis. A recent compelling hypothesis is that excitatory glutamatergic synaptic transmission in the dendrites of preBötC neurons triggers postsynaptic calcium-activated calcium currents that initiate a powerful wave of excitation toward the cell soma, resulting in the distinctive respiratory depolarization and burst of action potentials (Rekling and Feldman, 1998; Del Negro et al., 2002; Feldman et al., 2003; Mironov, 2008; Del Negro et al., 2010). Are there other roles that intrinsically bursting respiratory neurons play in respiratory motor control?
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Present address: Neurobiologie & Développement, Institut de Neurobiologie Alfred Fessard, Centre National de la Recherche Scientifique, Gif sur Yvette cedex, France