Breathing: rhythmicity, plasticity, chemosensitivity

Abstract

Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBötzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2 and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.

Figure 1

Respiratory premotor, putative rhythmogenic, and central chemoreceptor locations in the rat rostral medulla and cerebellum. (Top) Parasagittal view. (Bottom) Transverse view at the caudal level of the facial nucleus (vertical dotted line at top) (modified from Nattie 2000 and Gray et al. 1999). Blue areas in the ventrolateral medulla are the principal location of respiratory bulbospinal premotor neurons that project to phrenic, intercostal, and abdominal motoneurons, which drive muscles of the respiratory pump. The preBötzinger Complex plays a critical role in rhythm generation and central chemoreception. The pre-I neuron population, which may also play a role in rhythmogenesis, appears to be located ventral and rostral to the preBötC with many neurons close to the ventral surface. Red areas represent regions that play a role in central chemoreception. See text for details. Abbreviations: FN, fastigial nucleus; LC, locus ceruleus; NTS, nucleus of the solitary tract; VII, facial nucleus; rVRG, rostral ventral respiratory group; NA, nucleus ambiguus; cNA, compact division of the nucleus ambiguus; LRN, lateral reticular nucleus; RTN, retrotrapezoid nucleus; SO, superior olive; BötC, Bötzinger complex; preBötC, preBötzinger Complex.

Figure 2

Near complete lesion of preBötC NK1R neurons causes an ataxic breathing pattern. (Top) Changes in pressure inside a plethysmograph (which are proportional to tidal volume; inspiration up) of a normal awake adult rat in room air. (Bottom) Similar measure in an awake adult preBötC^NK1R− rat in room air. Redrawn from Gray et al. 2001. Used with permission from Nature (http://www.nature.com/).

Figure 3

Two rhythmogenic networks, the preBötC and the pre-I network, may underlie generation of respiratory rhythm. In slices (top), only the preBötC is present, driving inspiratory activity. In en bloc preparations and in vivo (middle), the two populations interact seamlessly, producing a coordinated respiratory pattern of inspiratory and expiratory activity. When μ-opiates are added (bottom), preBötC neurons are hyperpolarized, whereas pre-I neurons are unaffected. Expiratory activity therefore continues uninterrupted, but inspiratory activity skips cycles because the preBötC rhythmogenicity is lost and its responsiveness to rhythmic drive from the pre-I network is depressed, leading to transmission failure. Based on Janczewski et al. 2002, Mellen et al. 2002.

Figure 4

Working models of phrenic long-term facilitation (LTF). In the upper trace (A) integrated bursts of phrenic neural activity are shown before, during, and after episodic hypoxia (3 episodes, 5 min of 11% O₂ with 5 min interval) in an anesthetized, paralyzed, vagotomized, pump-ventilated 3–4-month-old male rat (tracing modified from Zabka et al. 2001a). In (B), a network model of respiratory LTF is illustrated with a simple schematic indicating the relevant anatomical projections (after Bach et al. 1996). In the network model, raphe serotonergic neurons are activated during intermittent hypoxia, releasing serotonin in the vicinity of brainstem respiratory neurons as well as spinal motoneurons. The relevant serotonin receptors for LTF are proposed to be within the respective motor nuclei, i.e., within the spinal cord for phrenic LTF. A schematic of the cellular and synaptic consequences of serotonin release within the phrenic motor nucleus during intermittent hypoxia is shown in (C). Serotonin release in the vicinity of phrenic dendrites activates 5-HT_2A receptors, thereby activating intracellular signaling molecules, e.g., kinases. The relevant signaling molecules initiate BDNF protein synthesis, presumably from existing BDNF mRNA. Subsequent BDNF release from the phrenic dendrites may activate pre- or postsynaptic tyrosine kinase B (TrkB) receptors, leading to enhanced function at glutamatergic synapses that transmit respiratory drive, or by inhibiting synaptic (GABA) inhibition.

Figure 5

Lesions of NK1R neurons in the retrotrapezoid nucleus blunts ventilatory response to increased PCO₂. (Top) Breathing (inspiration up) in a normal rat in room air and 7% CO₂. (Bottom) Breathing in a rat with significant loss of NK1R neurons in the retrotrapezoid nucleus (RTN^NK1R−) (Nattie & Li 2002b; E. Nattie and A. Li, unpublished data).