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Dbx1 precursor cells are a source of inspiratory XII premotoneurons.

Revill AL, Vann NC, Akins VT, Kottick A, Gray PA, Del Negro CA, Funk GD - Elife (2015)

Bottom Line: Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014).Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency.Laser ablation of Dbx1 IRt neurons, 57% of which are glutamatergic, decreased ipsilateral inspiratory motor output without affecting frequency.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Neuroscience and Mental Health Institute, Women and Children's Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.

ABSTRACT
All behaviors require coordinated activation of motoneurons from central command and premotor networks. The genetic identities of premotoneurons providing behaviorally relevant excitation to any pool of respiratory motoneurons remain unknown. Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014). Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency. Laser ablation of Dbx1 IRt neurons, 57% of which are glutamatergic, decreased ipsilateral inspiratory motor output without affecting frequency. We conclude that a subset of Dbx1 IRt neurons is a source of premotor excitatory drive, contributing to the inspiratory behavior of XII motoneurons, as well as a key component of the airway control network whose dysfunction contributes to sleep apnea.

No MeSH data available.


Related in: MedlinePlus

Electrophysiological characteristics of Dbx1 IRt neurons.(A) Membrane potential recording (Vm) from an inspiratory Dbx1 IRt neuron and integrated XII nerve (∫XII) activity showing inspiratory burst characteristics. Inspiratory drive amplitude for neurons that generated action potentials during inspiratory bursts was estimated based on the shape of the underlying drive potential (double-ended red arrow). Inspiratory drive area was calculated as the integral of membrane potential over time (shaded area). Panel inset: inspiratory drive latency was defined as the delay between the onset of inspiratory depolarization (upward green arrow) and the onset of XII inspiratory nerve burst (downward green arrow). Inspiratory drive duration was measured as the length of time the membrane potential was above baseline (joined blue arrows). Membrane potential scale bar applies to inset as well. Group data (median, box: interquartile range, whiskers: 10th and 90th percentiles) and individual values (solid circles) measuring passive membrane properties and inspiratory drive characteristics in Dbx1 neurons of the IRt and preBötC: (B) neuronal input resistance, RN, n = 8 (IRt), n = 27 (preBötC); (C) rheobase, Irh, n = 9 (IRt), n = 26 (preBötC); (D) membrane time constant, τ, n = 7 (IRt), n = 26 (preBötC); (E) whole-cell capacitance, Cm, n = 7 (IRt), n = 26 (preBötC); (F) inspiratory drive amplitude, n = 14 (IRt), n = 82 (preBötC); (G) inspiratory drive area, n = 14 (IRt), n = 82 (preBötC); (H) inspiratory drive latency, n = 13 (IRt), n = 70 (preBötC); (I) inspiratory drive duration, n = 13 (IRt); All preBötC data from (Picardo et al., 2013). IRt – intermediate reticular formation. *, p < 0.05, unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.12301.004
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fig3: Electrophysiological characteristics of Dbx1 IRt neurons.(A) Membrane potential recording (Vm) from an inspiratory Dbx1 IRt neuron and integrated XII nerve (∫XII) activity showing inspiratory burst characteristics. Inspiratory drive amplitude for neurons that generated action potentials during inspiratory bursts was estimated based on the shape of the underlying drive potential (double-ended red arrow). Inspiratory drive area was calculated as the integral of membrane potential over time (shaded area). Panel inset: inspiratory drive latency was defined as the delay between the onset of inspiratory depolarization (upward green arrow) and the onset of XII inspiratory nerve burst (downward green arrow). Inspiratory drive duration was measured as the length of time the membrane potential was above baseline (joined blue arrows). Membrane potential scale bar applies to inset as well. Group data (median, box: interquartile range, whiskers: 10th and 90th percentiles) and individual values (solid circles) measuring passive membrane properties and inspiratory drive characteristics in Dbx1 neurons of the IRt and preBötC: (B) neuronal input resistance, RN, n = 8 (IRt), n = 27 (preBötC); (C) rheobase, Irh, n = 9 (IRt), n = 26 (preBötC); (D) membrane time constant, τ, n = 7 (IRt), n = 26 (preBötC); (E) whole-cell capacitance, Cm, n = 7 (IRt), n = 26 (preBötC); (F) inspiratory drive amplitude, n = 14 (IRt), n = 82 (preBötC); (G) inspiratory drive area, n = 14 (IRt), n = 82 (preBötC); (H) inspiratory drive latency, n = 13 (IRt), n = 70 (preBötC); (I) inspiratory drive duration, n = 13 (IRt); All preBötC data from (Picardo et al., 2013). IRt – intermediate reticular formation. *, p < 0.05, unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.12301.004

Mentions: IRt neurons and rhythmogenic preBötC neurons (Picardo et al., 2013) are both derived from Dbx1 precursors (Bouvier et al., 2010; Gray et al., 2010). Their passive membrane properties are indistinguishable but the peak amplitude and area of inspiratory drive potentials are smaller in Dbx1 IRt compared to Dbx1 preBötC neurons (Figure 3A-G). In addition, the inspiratory drive potential in Dbx1 IRt neurons begins 90 ± 32 ms (n=13) prior to the onset of XII motor output (inset, green arrows, Figure 3A,H), which is later than drive potential onset in Dbx1 preBötC neurons (308 ± 17 ms prior to XII motor output (p=9E-7, unpaired t-test) (Picardo et al., 2013) (Figure 3H). Despite statistical differences, overlap between populations is such that no single parameter can definitively distinguish a Dbx1 preBötC neuron from a Dbx1 IRt neuron.10.7554/eLife.12301.004Figure 3.Electrophysiological characteristics of Dbx1 IRt neurons.


Dbx1 precursor cells are a source of inspiratory XII premotoneurons.

Revill AL, Vann NC, Akins VT, Kottick A, Gray PA, Del Negro CA, Funk GD - Elife (2015)

Electrophysiological characteristics of Dbx1 IRt neurons.(A) Membrane potential recording (Vm) from an inspiratory Dbx1 IRt neuron and integrated XII nerve (∫XII) activity showing inspiratory burst characteristics. Inspiratory drive amplitude for neurons that generated action potentials during inspiratory bursts was estimated based on the shape of the underlying drive potential (double-ended red arrow). Inspiratory drive area was calculated as the integral of membrane potential over time (shaded area). Panel inset: inspiratory drive latency was defined as the delay between the onset of inspiratory depolarization (upward green arrow) and the onset of XII inspiratory nerve burst (downward green arrow). Inspiratory drive duration was measured as the length of time the membrane potential was above baseline (joined blue arrows). Membrane potential scale bar applies to inset as well. Group data (median, box: interquartile range, whiskers: 10th and 90th percentiles) and individual values (solid circles) measuring passive membrane properties and inspiratory drive characteristics in Dbx1 neurons of the IRt and preBötC: (B) neuronal input resistance, RN, n = 8 (IRt), n = 27 (preBötC); (C) rheobase, Irh, n = 9 (IRt), n = 26 (preBötC); (D) membrane time constant, τ, n = 7 (IRt), n = 26 (preBötC); (E) whole-cell capacitance, Cm, n = 7 (IRt), n = 26 (preBötC); (F) inspiratory drive amplitude, n = 14 (IRt), n = 82 (preBötC); (G) inspiratory drive area, n = 14 (IRt), n = 82 (preBötC); (H) inspiratory drive latency, n = 13 (IRt), n = 70 (preBötC); (I) inspiratory drive duration, n = 13 (IRt); All preBötC data from (Picardo et al., 2013). IRt – intermediate reticular formation. *, p < 0.05, unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.12301.004
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fig3: Electrophysiological characteristics of Dbx1 IRt neurons.(A) Membrane potential recording (Vm) from an inspiratory Dbx1 IRt neuron and integrated XII nerve (∫XII) activity showing inspiratory burst characteristics. Inspiratory drive amplitude for neurons that generated action potentials during inspiratory bursts was estimated based on the shape of the underlying drive potential (double-ended red arrow). Inspiratory drive area was calculated as the integral of membrane potential over time (shaded area). Panel inset: inspiratory drive latency was defined as the delay between the onset of inspiratory depolarization (upward green arrow) and the onset of XII inspiratory nerve burst (downward green arrow). Inspiratory drive duration was measured as the length of time the membrane potential was above baseline (joined blue arrows). Membrane potential scale bar applies to inset as well. Group data (median, box: interquartile range, whiskers: 10th and 90th percentiles) and individual values (solid circles) measuring passive membrane properties and inspiratory drive characteristics in Dbx1 neurons of the IRt and preBötC: (B) neuronal input resistance, RN, n = 8 (IRt), n = 27 (preBötC); (C) rheobase, Irh, n = 9 (IRt), n = 26 (preBötC); (D) membrane time constant, τ, n = 7 (IRt), n = 26 (preBötC); (E) whole-cell capacitance, Cm, n = 7 (IRt), n = 26 (preBötC); (F) inspiratory drive amplitude, n = 14 (IRt), n = 82 (preBötC); (G) inspiratory drive area, n = 14 (IRt), n = 82 (preBötC); (H) inspiratory drive latency, n = 13 (IRt), n = 70 (preBötC); (I) inspiratory drive duration, n = 13 (IRt); All preBötC data from (Picardo et al., 2013). IRt – intermediate reticular formation. *, p < 0.05, unpaired t-test.DOI:http://dx.doi.org/10.7554/eLife.12301.004
Mentions: IRt neurons and rhythmogenic preBötC neurons (Picardo et al., 2013) are both derived from Dbx1 precursors (Bouvier et al., 2010; Gray et al., 2010). Their passive membrane properties are indistinguishable but the peak amplitude and area of inspiratory drive potentials are smaller in Dbx1 IRt compared to Dbx1 preBötC neurons (Figure 3A-G). In addition, the inspiratory drive potential in Dbx1 IRt neurons begins 90 ± 32 ms (n=13) prior to the onset of XII motor output (inset, green arrows, Figure 3A,H), which is later than drive potential onset in Dbx1 preBötC neurons (308 ± 17 ms prior to XII motor output (p=9E-7, unpaired t-test) (Picardo et al., 2013) (Figure 3H). Despite statistical differences, overlap between populations is such that no single parameter can definitively distinguish a Dbx1 preBötC neuron from a Dbx1 IRt neuron.10.7554/eLife.12301.004Figure 3.Electrophysiological characteristics of Dbx1 IRt neurons.

Bottom Line: Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014).Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency.Laser ablation of Dbx1 IRt neurons, 57% of which are glutamatergic, decreased ipsilateral inspiratory motor output without affecting frequency.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Neuroscience and Mental Health Institute, Women and Children's Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.

ABSTRACT
All behaviors require coordinated activation of motoneurons from central command and premotor networks. The genetic identities of premotoneurons providing behaviorally relevant excitation to any pool of respiratory motoneurons remain unknown. Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014). Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency. Laser ablation of Dbx1 IRt neurons, 57% of which are glutamatergic, decreased ipsilateral inspiratory motor output without affecting frequency. We conclude that a subset of Dbx1 IRt neurons is a source of premotor excitatory drive, contributing to the inspiratory behavior of XII motoneurons, as well as a key component of the airway control network whose dysfunction contributes to sleep apnea.

No MeSH data available.


Related in: MedlinePlus