Trends in Neurosciences
ReviewBrainstem respiratory networks: building blocks and microcircuits
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.
References (114)
- et al.
Measured motion: searching for simplicity in spinal locomotor networks
Curr. Opin. Neurobiol.
(2009) Biological pattern generation: the cellular and computational logic of networks in motion
Neuron
(2006)- et al.
The chemical neuroanatomy of breathing
Respir. Physiol. Neurobiol.
(2008) Multiple pontomedullary mechanisms of respiratory rhythmogenesis
Respir. Physiol. Neurobiol.
(2009)Caudal nuclei of the rat nucleus of the solitary tract differentially innervate respiratory compartments within the ventrolateral medulla
Neuroscience
(2011)Determination of the human brainstem respiratory control network and its cortical connections in vivo using functional and structural imaging
Neuroimage
(2009)- et al.
Studying rhythmogenensis of breathing: comparison of in vivo and in vitro models
Trend Neurosci.
(2001) Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation
Prog. Brain Res.
(2007)The rhombencephalon and breathing: a view from the pons
Respir. Physiol. Neurobiol.
(2004)Synaptically activated burst-generating conductances may underlie a group-pacemaker mechanism for respiratory rhythm generation in mammals
Prog. Brain Res.
(2010)
Pacemaker neurons and neuronal networks: an integrative view
Curr. Opin. Neurobiol.
Retrotrapezoid nucleus and parafacial respiratory group
Respir. Physiol. Neurobiol.
Somatostatin selectively ablates post-inspiratory activity after injection into the Botzinger complex
Neuroscience
Serotonin receptors: guardians of stable breathing
Trend Mol. Med.
In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome
Respir. Physiol. Neurobiol.
The story of Rett syndrome: from clinic to neurobiology
Neuron
Rhythms of the Brain
The cortex as a central pattern generator
Nat. Rev. Neurosci.
Microcircuits in the motor system
Structural and functional architecture of respiratory networks in the mammalian brainstem
Philos. Trans. R. Soc. Lond. B: Biol. Sci.
Respiratory central pattern generator
Opioids depress cortical centers responsible for the volitional control of respiration
J. Neurosci.
Spatial and functional architecture of the mammalian brain stem respiratory network: a hierarchy of three oscillatory mechanisms
J. Neurophysiol.
Functional connectivity in the pontomedullary respiratory network
J. Neurophysiol.
Developmental basis of the rostro–caudal organization of the brainstem respiratory rhythm generator
Philos. Trans. R. Soc. Lond. B: Biol. Sci.
Breathing with Phox2b
Philos. Trans. R. Soc. Lond. B: Biol. Sci.
Developmental origin of pre-Bötzinger complex respiratory neurons
J. Neurosci.
Hindbrain interneurons and axon guidance signaling critical for breathing
Nat. Neurosci.
Galanin is a selective marker of the retrotrapezoid nucleus in rats
J. Comp. Neurol.
Projections of preBotzinger complex neurons in adult rats
J. Comp. Neurol.
Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons
Nat. Neurosci.
Distinct rhythm generators for inspiration and expiration in the juvenile rat
J. Physiol.
Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat
Nat. Neurosci.
Essential role of Phox2b-expressing ventrolateral brainstem neurons in the chemosensory control of inspiration and expiration
J. Neurosci.
Photostimulation of retrotrapezoid nucleus Phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats
J. Neurosci.
Active expiration induced by excitation of ventral medulla in adult anesthetized rats
J. Neurosci.
Pre-Botzinger complex in the cat
J. Neurophysiol.
Computational models and emergent properties of respiratory neural networks
Compr. Physiol.
Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals
Science
Noeud vital for breathing in the brainstem: gasping – yes, eupnoea – doubtful
Philos. Trans. R. Soc. Lond. B: Biol. Sci.
Multiple rhythmic states in a model of the respiratory central pattern generator
J. Neurophysiol.
A group of glutamatergic interneurons expressing high levels of both neurokinin-1 receptors and somatostatin identifies the region of the pre-Botzinger complex
J. Comp. Neurol.
Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger complex in vitro
J. Neurosci.
Location and properties of respiratory neurones with putative intrinsic bursting properties in the rat in situ
J. Physiol.
Looking for inspiration: new perspectives on respiratory rhythm
Nat. Rev. Neurosci.
Oscillatory bursting mechanisms in respiratory pacemaker neurons and networks
Functional imaging, spatial reconstruction, and biophysical analysis of a respiratory motor circuit isolated in vitro
J. Neurosci.
TASK channels contribute to the K+-dominated leak current regulating respiratory rhythm generation in vitro
J. Neurosci.
Intrinsic bursters increase the robustness of rhythm generation in an excitatory network
J. Neurophysiol.
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Present address: Department of Animal Physiology, Biocenter, University of Cologne, Cologne, Germany.