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: 14.98). 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, Aug 26, 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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    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 · 3.67 Impact Factor
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    • "In order to better understand the mechanism of respiratory rhythm and pattern generation in the medulla oblongata, we aimed to thoroughly elucidate the anatomical pathways and propagating excitation wave dynamics of inspiratory neural information from the preBötC to other respiratory-related medullary regions. To analyze the distribution of neurons projecting to the preBötC region, retrograde tracing was conducted together with immunohistochemistry for neurokinin-1 receptor (NK1R) that indicates putative rhythmogenic neurons in the contralateral preBötC (Gray et al., 2001). Also, to anatomically elucidate the axonal projections from the preBötC region, anterograde tracing was conducted with immunohistochemistry for NK1R and in some rats simultaneously for somatostatin (SST) that is also a marker of putative rhythmogenic neurons in the preBötC (Tan et al., 2010; Wei et al., 2012). "
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    ABSTRACT: The preBötzinger complex (preBötC) of the ventrolateral medulla is the kernel for inspiratory rhythm generation. However, it is not fully understood how inspiratory neural activity is generated in the preBötC and propagates to other medullary regions. We analyzed the detailed anatomical connectivity to and from the preBötC and functional aspects of the inspiratory information propagation from the preBötC on the transverse plane of the medulla oblongata. Tract-tracing with immunohistochemistry in young adult rats demonstrated that neurokinin-1 receptor- and somatostatin-immunoreactive neurons in the preBötC, which could be involved in respiratory rhythmogenesis, are embedded in the plexus of axons originating in the contralateral preBötC. By voltage-imaging in rhythmically active slices of neonatal rats, we analyzed origination and propagation of inspiratory neural activity as depolarizing wave dynamics on the entire transverse plane as well as within the preBötC. Novel combination of pharmacological blockade of glutamatergic transmission and mathematical subtraction of the video images under blockade from the control images enabled to extract glutamatergic signal propagations. By ultra-high-speed voltage-imaging we first demonstrated the inter-preBötC conduction process of inspiratory action potentials. Intra-preBötC imaging with high spatiotemporal resolution during single spontaneous inspiratory cycle unveiled deterministic nonlinearities, i.e., chaos, in the population recruitment. Collectively, we comprehensively elucidated the anatomical pathways to and from the preBötC and dynamics of inspiratory neural information propagation: (1) From the preBötC in one side to the contralateral preBötC, which would synchronize the bilateral rhythmogenic kernels, (2) from the preBötC directly to the bilateral hypoglossal premotor and motor areas as well as to the nuclei tractus solitarius, and (3) from the hypoglossal premotor areas toward the hypoglossal motor nuclei. The coincidence of identified anatomical and functional connectivity between the preBötC and other regions in adult and neonatal rats, respectively, indicates that this fundamental connectivity is already well developed at the time of birth.
    Neuroscience 03/2014; 268. DOI:10.1016/j.neuroscience.2014.03.002 · 3.33 Impact Factor
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