Review
Brainstem respiratory networks: building blocks and microcircuits

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Breathing movements in mammals are driven by rhythmic neural activity generated within spatially and functionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcircuits of this CPG from recent multidisciplinary experimental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site- and mechanism-specific interventions to treat various disorders of the neural control of breathing.

Introduction

Breathing in mammals is the primal homeostatic process regulating levels of oxygen and carbon dioxide in the body that is critical for life. Respiratory movements occur automatically and continuously throughout life and are driven by the rhythmic motor activity generated within neural circuits in the brainstem and spinal cord. The underlying neural machinery is robust yet exquisitely flexible for physiological and behavioral integration. The respiratory neural control system not only performs a vital physiological function but is also engaged in volitional (e.g., speech and singing) and emotional (e.g., laughing and crying) motor behaviors. Understanding this neural circuitry may have far-reaching implications for other rhythmic motor behaviors and oscillatory circuits 1, 2, 3.

Respiratory movements, like other innate rhythmic motor behaviors such as locomotion, are produced by semi-autonomous neural networks referred to as central pattern generators (CPGs). These networks are the basic neural substrates for rhythmic motor pattern generation and sensorimotor integration [4]. They consist of core circuits of excitatory and inhibitory interneurons that interact to generate rhythmic patterns of activity for coordinated motor output [5]. A major goal in the motor systems field is to unravel the architecture of these circuits and decipher how cellular-, circuit-, and systems-level properties are integrated functionally [1]. This is critical for revealing mechanisms of operation in both normal and disease states.

New insights into the architecture of respiratory CPG circuits have recently been obtained from the rapid convergence of electrophysiological, imaging, anatomical, genetic, developmental, and computational modeling approaches. Here, we review key developments, with a major focus on advances in understanding, including current hypotheses of circuit organization and operation. The important advantage of this system is that it can be studied not only in conscious and anesthetized animals in vivo but also in various reduced experimental preparations retaining circuit interactions in situ and in vitro. This has allowed high-fidelity measurements at cellular, synaptic, and circuit levels in the context of behaviorally meaningful network activity, which are essential for dissecting the logic of CPG circuits [1] and ultimately for designing novel therapeutic interventions.

Section snippets

The brainstem respiratory network is arrayed within structural–functional compartments

The brainstem circuits generating and controlling respiratory motor activity during normal eupneic breathing in vivo are distributed bilaterally in the pons and medulla oblongata. The current view is that each side of the medulla has a ventral respiratory column (VRC) of respiratory neurons, interacting within the VRC and interconnected with several pontine nuclei 6, 7, 8, 9. The VRC contains key interacting excitatory and inhibitory interneuron populations (Figure 1) representing the

Different breathing patterns are produced by reconfiguration of neural building block circuits

The normal breathing cycle consists of three main phases of neural activity [27]: inspiration (I), post-inspiration, and the later stage 2 of expiration (Box 2). This three-phase pattern is evident in the activity of simultaneously recorded motor outputs 8, 13 and is also reflected in the activity profiles of interneuron populations within the VRC compartments, as determined by simultaneous neuron recordings at multiple VRC sites [14]. Populations of inspiratory interneurons are concentrated in

A model of microcircuits generating different rhythmic patterns

The concept of functional compartmentalization incorporates the hypothesis that excitatory and inhibitory circuits within the pre-BötC and BötC are substrates for the generation of the different rhythmic motor patterns described above. Computational modeling studies suggest that a minimal circuit structure should include inhibitory expiratory (post-I and aug-E) neurons of the BötC and inhibitory inspiratory neurons in the pre-BötC, coupled in a ring-like network with mutual inhibitory

Intrinsic rhythmogenic properties of the pre-BötC

Since the discovery of the pre-BötC [31] there has been intense interest in this structure, particularly since experimental studies in rodents have established that there is a critical interconnected bilateral network of excitatory neurons coupled by ionotropic glutamatergic synaptic mechanisms 17, 18, 35 and a subset of these neurons exhibit intrinsic bursting or pacemaker-like properties in vitro and in situ 36, 37. Pre-BötC circuits can generate inspiratory oscillations when isolated in

Reciprocal synaptic inhibition is essential for inspiratory–expiratory pattern generation

In the intact respiratory system, inhibitory circuit interactions operating in conjunction with pre-BötC excitatory circuit mechanisms contribute to the coordination and shaping of respiratory phases [27]. As discussed above, we have hypothesized that this involves key inhibitory microcircuits in the pre-BötC and BötC (Figure 2). Inhibitory glycinergic or GABAergic inspiratory (early-I) and expiratory (post-I, E-2) neurons have been observed in the pre-BötC and BötC, respectively 58, 59, 60, 61

Excitatory drives control respiratory rhythm and pattern

All concepts of respiratory rhythm and pattern generation incorporate the idea that excitatory drives to VRC circuits regulate network activity. The pontine, RTN/pFRG, and raphé nuclei are considered major sources of excitatory drives (Figure 1), likely acting in concert. These structures contain spontaneously active neurons with tonic and respiratory phasic spiking patterns. Anatomical evidence from anterograde and retrograde labeling has revealed extensive projections from these regions to

Coupling oscillators to generate new patterns of rhythmic expiratory activity

Other oscillatory mechanisms involving RTN/pFRG in perinatal [70] and mature rodents [22] have been proposed. A subpopulation of the Phox2b-expressing neurons has intrinsic oscillatory bursting properties in embryonic [71] and neonatal [72] rodents in vitro, which appear to be dependent on INaP, at least in embryonic mice [71]. These rhythmic cells also exhibit chemosensory properties 72, 73. Several different concepts of the physiological role of RTN/pFRG oscillations have been proposed. These

Summary

Neurophysiologists have investigated mechanisms underlying breathing for more than a century. Here, we considered how the system can be broken down into structural–functional elements and synthesized according to currently available neurobiological approaches. The emerging concept of spatially organized brainstem compartments and their interacting microcircuits provides a framework for understanding the operation of the respiratory CPG and should assist in the identification of loci and

Acknowledgments

This work was supported in part by the Intramural Research Program of the NIH, NINDS, and R01 NS057815 and R01 NS069220 to I.A.R. J.F.R.P. was supported by a Royal Society Wolfson Research Merit Award. A.B. was supported by a Feodor Lynen Research Fellowship from the Alexander von Humboldt Foundation.

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    Present address: Department of Animal Physiology, Biocenter, University of Cologne, Cologne, Germany.

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