Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice

Vann, Nikolas C.; Pham, Francis D.; Hayes, J. A.; Kottick, Andrew; Negro, Christopher A. Del

doi:10.1371/journal.pone.0162418

Cited by 37 publications

(40 citation statements)

References 52 publications

(75 reference statements)

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“…Optogenetic techniques have already been used in transgenic mice to investigate the functional role of the preBötC in the control of breathing (see e.g. Alsahafi et al, 2015;Cui et al, 2016;Koizumi et al, 2016;Vann et al, 2016). Conceivably, some brainstem areas should be considered in more detail: for instance, the RTN/pFRG, that may be important in the generation of the expiratory thrusts, and the PiCo that may be involved in the control of postinspiratory behaviours, including coughing and swallowing (Anderson et al, 2016).…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Brainstem mechanisms underlying the cough reflex and its regulation

Mutolo

2017

Respiratory Physiology & Neurobiology

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A B S T R A C TCough is a very important airway protective reflex. Cough-related inputs are conveyed to the caudal nucleus tractus solitarii (cNTS) that projects to the brainstem respiratory network. The latter is reconfigured to generate the cough motor pattern. A high degree of modulation is exerted on second-order neurons and the brainstem respiratory network by sensory inputs and higher brain areas. Two medullary structures proved to have key functions in cough production and to be strategic sites of action for centrally active drugs: the cNTS and the caudal ventral respiratory group (cVRG). Drugs microinjected into these medullary structures caused downregulation or upregulation of the cough reflex. The results suggest that inhibition and disinhibition are prominent regulatory mechanisms of this reflex and that both the cNTS and the cVRG are essential in the generation of the entire cough motor pattern. Studies on the basic neural mechanisms subserving the cough reflex may provide hints for novel therapeutic approaches. Different proposals for further investigations are advanced.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Brainstem mechanisms underlying the cough reflex and its regulation

Mutolo

2017

Respiratory Physiology & Neurobiology

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“…; Vann et al . ), the role of inhibitory neurons is disputed (Richter & Smith, ; Feldman & Kam, ). Pharmacological blockade of synaptic inhibition has produced contradictory results, ranging from complete loss of rhythmic activity (Pierrefiche et al .…”

Section: Introductionmentioning

confidence: 99%

“…The neuronal mechanisms of network activity that underlie the fundamental process of breathing are still not completely understood. Although it is accepted that excitatory neurons in the preBötzinger complex (preBötC) are indispensable for generation of the underlying rhythm (Gray et al 2001;Tan et al 2008;Vann et al 2016), the role of inhibitory neurons is disputed (Richter & Smith, 2014;Feldman & Kam, 2015). Pharmacological blockade of synaptic inhibition has produced contradictory results, ranging from complete loss of rhythmic activity (Pierrefiche et al 1998) or major perturbations of respiratory rhythm and pattern (Marchenko et al 2016) to only subtle alterations of frequency and amplitude (Janczewski et al 2013;Cui et al 2016;Baertsch et al 2018).…”

Section: Introductionmentioning

confidence: 99%

The postnatal development of ultrasonic vocalization‐associated breathing is altered in glycine transporter 2‐deficient mice

Hülsmann

Oke

Mesuret

et al. 2018

The Journal of Physiology

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Key points Newborn mice produce ultrasonic vocalization to communicate with their mother. The neuronal glycine transporter (GlyT2) is required for efficient loading of synaptic vesicles in glycinergic neurons. Mice lacking GlyT2 develop a phenotype that resembles human hyperekplexia and the mice die in the second postnatal week. In the present study, we show that GlyT2‐knockout mice do not acquire adult ultrasonic vocalization‐associated breathing patterns. Despite the strong impairment of glycinergic inhibition, they can produce sufficient expiratory airflow to produce ultrasonic vocalization. Because mouse ultrasonic vocalization is a valuable read‐out in translational research, these data are highly relevant for a broad range of research fields. Abstract Mouse models are instrumental with respect to determining the genetic basis and neural foundations of breathing regulation. To test the hypothesis that glycinergic synaptic inhibition is required for normal breathing and proper post‐inspiratory activity, we analysed breathing and ultrasonic vocalization (USV) patterns in neonatal mice lacking the neuronal glycine transporter (GlyT2). GlyT2‐knockout (KO) mice have a profound reduction of glycinergic synaptic currents already at birth, develop a severe motor phenotype and survive only until the second postnatal week. At this stage, GlyT2‐KO mice are smaller, have a reduced respiratory rate and still display a neonatal breathing pattern with active expiration for the production of USV. By contrast, wild‐type mice acquire different USV‐associated breathing patterns that depend on post‐inspiratory control of air flow. Nonetheless, USVs per se remain largely indistinguishable between both genotypes. We conclude that GlyT2‐KO mice, despite the strong impairment of glycinergic inhibition, can produce sufficient expiratory airflow to produce ultrasonic vocalization.

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“…We examined how individual preBötC inspiratory neurons contribute to collective events detected in field 245 recordings (bursts and burstlets) via whole-cell recordings in CD-1 (n = 7) and Dbx1;Ai148 mouse slices (n = 3). Dbx1;Ai148 pups express genetically encoded Ca 2+ reporter GCaMP6f in Dbx1-derived preBötC neurons obligatory for breathing rhythmogenesis (Baertsch, Baertsch, and Ramirez 2018;Bouvier et al 2010;Cui et al 2016Cui et al , 2016Gray et al 2010;Vann et al 2016Vann et al , 2018Wang et al 2014).…”

Section: Burstlets Are the Summation Of Epsps In Prebötc Neuronsmentioning

confidence: 99%

“…There is an existing framework for understanding both rhythm and pattern generation of the preBötC. Dbx1-derived preBötC neurons are inspiratory rhythmogenic (Baertsch, Baertsch, and Ramirez 2018;Bouvier et al 2010;Cui et al 2016;Gray et al 2010;Koizumi et al 2016;Vann et al 2016Vann et al , 2018Wang et al 2014), playing key preinspiratory and burst-generating roles (Cui et al 2016;Picardo et al 2013) and 395 some serving exclusively premotor function (Revill et al 2015). It may be possible to identify subsets of predominantly rhythmogenic versus predominantly premotor or pattern-related Dbx1-derived preBötC neurons based on intrinsic membrane properties (Picardo et al 2013) or neuropeptide somatostatin expression (Cui et al 2016).…”

Section: Pattern Generationmentioning

confidence: 99%

Evaluating the burstlet theory of inspiratory rhythm and pattern generation

Kallurkar

Grover

Picardo

et al. 2019

Preprint

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The preBötzinger complex (preBötC) generates the rhythm and rudimentary motor pattern for inspiratory 15 breathing movements. Here, we test 'burstlet' theory (Kam, Worrell, Janczewski, et al. 2013), which posits that low amplitude burstlets, subthreshold from the standpoint of inspiratory bursts, reflect the fundamental oscillator of the preBötC. In turn, a discrete suprathreshold process transforms burstlets into full amplitude inspiratory bursts that drive motor output, measurable via hypoglossal nerve (XII) discharge in vitro. We recap observations by Kam & Feldman: field recordings from preBötC demonstrate bursts and 20 concurrent XII motor output intermingled with lower amplitude burstlets that do not produce XII motor output. Manipulations of excitability affect the relative prevalence of bursts and burstlets and modulate their frequency. Whole-cell and photonic recordings of preBötC neurons suggest that burstlets involve inconstant subsets of rhythmogenic interneurons. We conclude that discrete rhythm-and patterngenerating mechanisms coexist in the preBötC and that burstlets reflect its fundamental rhythmogenic 25 nature.

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Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice

Cited by 37 publications

References 52 publications

Brainstem mechanisms underlying the cough reflex and its regulation

Brainstem mechanisms underlying the cough reflex and its regulation

The postnatal development of ultrasonic vocalization‐associated breathing is altered in glycine transporter 2‐deficient mice

Evaluating the burstlet theory of inspiratory rhythm and pattern generation

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