Developmental Origin of PreBötzinger Complex Respiratory Neurons

Gray, Paul A.; Hayes, J. A.; Ling, Guoyu; Llona, Isabel; Tupal, Srinivasan; Picardo, Marina Cristina D; Ross, Sarah E.; Hirata, Tsutomu; Corbin, Joshua G.; Eugenı́n, Jaime; Negro, Christopher A. Del

doi:10.1523/jneurosci.4031-10.2010

Cited by 186 publications

(332 citation statements)

References 98 publications

(166 reference statements)

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“…This is not the first example in which neurons that developmentally express the same transcription factors in the brainstem and spinal cord differentiate into different subpopulations in each of these structures. For example, the majority of neurons expressing Dbx1 in the spinal cord are inhibitory interneurons (Pierani et al, 2001;Lanuza et al, 2004), whereas in the brainstem, Dbx1-expressing neurons are glutamatergic (Bouvier et al, 2010;Gray et al, 2010). In summary, our data support that, in contrast to the spinal cord, the majority of Lhx3ϩ neurons in the medRF differentiate into glutamatergic Chx10ϩ neurons.…”

Section: Brainstem Versus Spinal Cord Lhx3 and Chx10 Neuronssupporting

confidence: 71%

Lhx3-Chx10 Reticulospinal Neurons in Locomotor Circuits

2013

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Motor behaviors result from the interplay between the brain and the spinal cord. Reticulospinal neurons, situated between the supraspinal structures that initiate motor movements and the spinal cord that executes them, play key integrative roles in these behaviors. However, the molecular identities of mammalian reticular formation neurons that mediate motor behaviors have not yet been determined, thus limiting their study in health and disease. In the medullary reticular formation of the mouse, we identified neurons that express the transcription factors Lhx3 and/or Chx10, and demonstrate that these neurons form a significant component of glutamatergic reticulospinal pathways. Lhx3-positive medullary reticular formation neurons express Fos following a locomotor task in the adult, indicating that they are active during walking. Furthermore, they receive functional inputs from the mesencephalic locomotor region and have electrophysiological properties to support tonic repetitive firing, both of which are necessary for neurons that mediate the descending command for locomotion. Together, these results suggest that Lhx3/Chx10 medullary reticular formation neurons are involved in locomotion.

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Section: Brainstem Versus Spinal Cord Lhx3 and Chx10 Neuronssupporting

confidence: 71%

Lhx3-Chx10 Reticulospinal Neurons in Locomotor Circuits

2013

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“…An important consideration is that neuroanatomical evidence shows that approximately one-half of the neurons in the preBötC are inhibitory, either glycinergic or GABAergic, and one-half are glutamatergic (13,25). Glutamatergic transmission is obligatory for rhythmogenesis in vitro (26,27), whereas inhibitory transmission is not (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…Disinhibition conditions ensured that deleting inhibitory neurons would not affect the XII output. Inspiratory neurons express both excitatory (25,(30)(31)(32) and inhibitory (12,13) transmitters, but it is not possible to differentiate the two phenotypes based on calcium transients in rhythmically active slices. Therefore, approximately one-half of the targets in our experiments are presumably inhibitory and should be discounted from the lesion tally.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we assume that, on average, fewer than 13 neurons were detected at superficial levels because of slicing-related tissue damage, and that fewer than 13 neurons were detected at deeper levels because of limited dye penetration and scattering of laser pulses (33). Even if technical limitations prevented their detection, we assume an average uniform density of 13 inspiratory neurons per 10 μm per side in the preBötC, which occupies 250 μm in the rostrocaudal axis, bilaterally (9,25,34). Thus, we calculate 650 inspiratory neurons comprise the preBötC.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we calculate 650 inspiratory neurons comprise the preBötC. If one-half are inhibitory (13,25), then the rhythm-generating glutamatergic core contains 325 interneurons.…”

Section: Discussionmentioning

confidence: 99%

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Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Hayes

Wang²,

Negro³

2012

Proc. Natl. Acad. Sci. U.S.A.

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How brain functions degenerate in the face of progressive cell loss is an important issue that pertains to neurodegenerative diseases and basic properties of neural networks. We developed an automated system that uses two-photon microscopy to detect rhythmic neurons from calcium activity, and then individually laser ablates the targets while monitoring network function in real time. We applied this system to the mammalian respiratory oscillator located in the pre-Bötzinger Complex (preBötC) of the ventral medulla, which spontaneously generates breathing-related motor activity in vitro. Here, we show that cumulatively deleting preBötC neurons progressively decreases respiratory frequency and the amplitude of motor output. On average, the deletion of 120 ± 45 neurons stopped spontaneous respiratory rhythm, and our data suggest ≈82% of the rhythm-generating neurons remain unlesioned. Cumulative ablations in other medullary respiratory regions did not affect frequency but diminished the amplitude of motor output to a lesser degree. These results suggest that the preBötC can sustain insults that destroy no more than ≈18% of its constituent interneurons, which may have implications for the onset of respiratory pathologies in disease states.central pattern generator | calcium imaging | brainstem C entral pattern generator (CPG) networks produce coordinated motor patterns that underlie behaviors such as breathing, locomotion, and chewing (1, 2). A key issue is not just which cell types generate these patterns of activity, but how many? This question pertains to whether and how cumulative cell loss will impair and, possibly preclude, network function.Breathing consists of inspiratory and expiratory phases. The preBötzinger Complex (preBötC) of the medulla putatively contains the inspiratory CPG (3, 4). Over several days in vivo, saporinmediated destruction of preBötC neurons that express neurokinin-1 receptors (NK1Rs) causes sleep-disordered breathing and fatal respiratory pathology (5, 6). Similarly, acute cell-silencing of a subset of the same NK1R-expressing population of preBötC neurons stops spontaneous breathing in awake adult rats (7). These studies helped to determine the cellular composition of the preBötC and confirmed that it was essential for breathing in an otherwise intact animal, but could not measure the resiliency of the preBötC when faced with silencing or deleting its core piecewise.We examined this issue by using slice preparations that capture the preBötC and spontaneously generate fictive breathing-related activity in vitro. We developed a computer-automated system that detects rhythmically active interneurons via two-photon calcium imaging, stores their physical locations in memory, and then laser ablates the targets sequentially, while electrophysiologically monitoring the motor output of the circuit. We applied this system to the preBötC to test the hypothesis that piecewise destruction of the CPG core would cause graded loss of motor activity up to rhythm cessation. We surmised that this effect ...

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Human IPSC‐Derived PreBötC‐Like Neurons and Development of an Opiate Overdose and Recovery Model

Guo,

Akanda,

Fiorino

et al. 2023

Advanced Biology

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Opioid overdose is the leading cause of drug overdose lethality, posing an urgent need for investigation. The key brain region for inspiratory rhythm regulation and opioid‐induced respiratory depression (OIRD) is the preBötzinger Complex (preBötC) and current knowledge has mainly been obtained from animal systems. This study aims to establish a protocol to generate human preBötC neurons from induced pluripotent cells (iPSCs) and develop an opioid overdose and recovery model utilizing these iPSC‐preBötC neurons. A de novo protocol to differentiate preBötC‐like neurons from human iPSCs is established. These neurons express essential preBötC markers analyzed by immunocytochemistry and demonstrate expected electrophysiological responses to preBötC modulators analyzed by patch clamp electrophysiology. The correlation of the specific biomarkers and function analysis strongly suggests a preBötC‐like phenotype. Moreover, the dose‐dependent inhibition of these neurons’ activity is demonstrated for four different opioids with identified IC50's comparable to the literature. Inhibition is rescued by naloxone in a concentration‐dependent manner. This iPSC‐preBötC mimic is crucial for investigating OIRD and combating the overdose crisis and a first step for the integration of a functional overdose model into microphysiological systems.

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Developmental Origin of PreBötzinger Complex Respiratory Neurons

Cited by 186 publications

References 98 publications

Lhx3-Chx10 Reticulospinal Neurons in Locomotor Circuits

Lhx3-Chx10 Reticulospinal Neurons in Locomotor Circuits

Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Human IPSC‐Derived PreBötC‐Like Neurons and Development of an Opiate Overdose and Recovery Model

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