Normal breathing requires pre-Bötzinger Complex neurokinin-1 receptor-expressing neurons

Department of Neurobiology, University of California Los Angeles, Box 951763, Los Angeles, California 90095-1763, USA.
Nature Neuroscience (Impact Factor: 16.1). 10/2001; 4(9):927-30. DOI: 10.1038/nn0901-927
Source: PubMed

ABSTRACT The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these approximately 600 neurons seem necessary for the generation of normal breathing in rats.

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Available from: Jack L Feldman, Sep 28, 2015
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    • "However, except for congenital central hypoventilation syndrome (a rare genetic disorder that results in failure of involuntary control of breathing (Perez and Keens, 2013)) and experimental ablation of the rhythmogenic circuits of the pre-Bötzinger complex (Gray et al., 2001), most respiratory disorders implicating dysfunction of the core elements of the respiratory control system are observed during sleep with sudden infant death syndrome, apnea of prematurity , and sleep disordered breathing being the most notable (and studied) clinical manifestations. By contrast, respiratory activity is more robust during wakefulness owing to the increased respiratory drive originating from supra-medullary structures. "
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    ABSTRACT: The control of breathing is commonly viewed as being a “brainstem affair”. As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, “non-brainstem” structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease. There is a clear link between respiration and anxiety and key theories of the psychopathology of anxiety (including panic disorders; PD) focus on respiratory control and related CO2 monitoring system. With that in mind, we briefly present the respiratory manifestations of panic disorder and discuss the role of the dorso-medial/perifornical hypothalamus, the amygdalar complex, and the periaqueductal gray in respiratory control. We then present recent advances in basic research indicating how adult rodent previously subjected to neonatal stress may provide a very good model to investigate the pathophysiology of PD.
    Respiratory Physiology & Neurobiology 12/2014; 204. DOI:10.1016/j.resp.2014.06.013 · 1.97 Impact Factor
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    • "Within mouse and rat preB€ otC, partially overlapping subsets of glutamatergic neurons can be genetically identified by their expression of SST, as well as the neurokinin 1 receptor (NK1R), SST 2a receptor (SST2aR) or l-opioid receptor (lOR) (Gray et al., 1999, 2010; Stornetta et al., 2003; Llona et al., 2004). In adult rats, the near complete (≥ 80%) targeted ablation of preB€ otC NK1R neurons , many of which express SST, leads to ataxic breathing during wakefulness and cessation of breathing during sleep (Gray et al., 2001; McKay & Feldman, 2008). The reversible genetic silencing of preB€ otC neurons transfected with an SST promoter-driven inhibitory G-protein-coupled receptor induces a rapid and prolonged apnea in otherwise normal awake animals (Tan et al., 2008). "
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    ABSTRACT: Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preBötzinger Complex (preBötC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preBötC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre-Lox-mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or μ-opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free-tailed bat, SST peptide-expressing neurons extended beyond the preBötC to the caudal pole of the VII motor nucleus. In the naked mole-rat, however, SST-positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST-Cre;VGlut2(F/F) mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preBötC SST neurons is not essential for breathing but play a species- and behavior-dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time.
    European Journal of Neuroscience 07/2014; 40(7). DOI:10.1111/ejn.12669 · 3.18 Impact Factor
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    • "3.1 Study 1: Abrupt Destruction of the PreBö tC Prior to our studies, Gray et al. (2001) had shown that injection of the neurotoxin saporin conjugated to substance P into the preBötC of rats destroyed neurons expressing neurokinin-1 receptors, resulting in an ataxic or irregular breathing pattern days later. Subsequently, we found that the same injections in goats also induced an irregular breathing pattern (Fig. 1), but in spite of the loss of about 30% of pre- BötC neurons, the goats remained healthy and maintained normal arterial blood gases (Wenninger et al., 2004a). "
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    ABSTRACT: We investigated in three groups of awake and sleeping goats whether there are differences in ventilatory responses after injections of Ibotenic acid (IA, glutamate receptor agonist and neurotoxin) into the pre-Bötzinger complex (preBötC), lateral parabrachial (LPBN), medial (MPBN) parabrachial, or Kölliker-Fuse nuclei (KFN). In one group, within minutes after bilateral injection of 10μl IA (50mM) into the preBötC, there was a 10-fold increase in breathing frequency, but 1.5h later, the goats succumbed to terminal apnea. These data are consistent with findings in reduced preparations that the preBötC is critical to sustaining normal breathing. In a second group, increasing volumes (0.5-10μl) of IA injected at weekly intervals into the preBötC elicited a near-dose-dependent tachypnea and irregular breathing that lasted at least 5h. There were apneas restricted to wakefulness, but none were terminal. Postmortem histology revealed that the preBötC was 90% destroyed, but there was a 25-40% above normal number of neurons in the presumed parafacial respiratory group that may have contributed to maintenance of arterial blood gas homeostasis. In a third group, bilateral injections (1 and 10μl) of IA into the LPBN, MPBN, or KFN did not significantly increase breathing in any group, and there were no terminal apneas. However, 3-5h after the injections into the KFN, breathing frequency was decreased and the three-phase eupneic breathing pattern was eliminated. Between 10 and 15h after the injections, the eupneic breathing pattern was not consistently restored to normal, breathing frequency remained attenuated, and there were apneas during wakefulness. Our findings during wakefulness and NREM sleep warrant concluding that (a) the preBötC is a primary site of respiratory rhythm generation; (b) the preBötC and the KFN are determinants of respiratory pattern generation; (c) after IA-induced lesions, there is time-dependent plasticity within the respiratory control network; and (d) ventilatory control mechanisms are state dependent.
    Progress in brain research 04/2014; 209:73-89. DOI:10.1016/B978-0-444-63274-6.00005-9 · 2.83 Impact Factor
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