Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions

Liu, Shijia; Ye, Mao; Pao, Gerald M.; Song, Samuel M.; Jhang, Jinho; Jiang, Haibei; Kim, Jong-Hyun; Kang, Sukjae Joshua; Kim, Dong-Il; Han, Sung

doi:10.1016/j.neuron.2021.11.029

Cited by 73 publications

(76 citation statements)

References 88 publications

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“…More globally, it is crucial to recognize that areas outside of the preBötC impact dynamics within the preBötC. These effects, which remain to be fully elucidated, may range from ongoing modulation of the level of excitability of preBötC neurons to timed signaling that contributes to preBötC rhythmicity and patterning (e.g., Mulkey et al, 2004 ; Dutschmann and Dick, 2012 ; Phillips et al, 2012 ; Smith et al, 2013 ; Dhingra et al, 2019 ; Richter et al, 2019 ; Liu et al, 2022 ). For example, transection studies suggest that pontine regions may make crucial contributions to respiratory circuit excitability and respiratory pattern formation ( Jones and Dutschmann, 2016 ; Smith et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

Phillips

Rubin

2022

eLife

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Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In in vitro slice preparations containing the preBötC, extracellular potassium must be elevated above physiological levels (to 7 - 9mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBötC projects. Reexamination of how extracellular K+ affects preBötC neuronal activity has revealed that low amplitude oscillations persist at physiological levels. These oscillatory events are sub-threshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBötC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBötC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBötC population requires intracellular Ca2+ dynamics and activation of a calcium-activated non-selective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated non-selective cationic current can reproduce and offer an explanation for many of the key properties associated with the burstlet theory of respiratory rhythm generation. Altogether, our modeling work provides a mechanistic basis that can unify a wide range of experimental findings on rhythm generation and motor output recruitment in the preBötC.

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Section: Discussionmentioning

confidence: 99%

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

Phillips

Rubin

2022

eLife

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“…The axonal inputs to specific clusters of PBN neurons are beginning to be established, either by retrograde rabies virus tracing studies starting with specific Credrivers, e.g., Calca Cre (Liu et al, 2022, Rodriguez et al, 2017 or by candidate approaches starting with expression AAV-DIO-ChR2 into distal sites of Cre-driver lines of mice and recording photoactivated currents in specific PBN neurons, e.g., input from…”

Section: Discussionmentioning

confidence: 99%

Molecular and Anatomical Characterization of Parabrachial Neurons and Their Axonal Projections

Pauli

Chen

Basiri

et al. 2022

Preprint

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The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, pain sensation, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns on dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are localized to distinct PBN subregions. We also describe two major ascending pathways that innervate distinct brain regions by analyzing axonal projections in 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.

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“…The dorsolateral pons includes the lateral parabrachial area and the KF, both of which have been implicated in opioid-induced respiratory depression (Levitt et al ., 2015; Prkic et al ., 2012; Varga et al ., 2020; Liu et al ., 2021). Although effects of MORs in the lateral parabrachial and KF areas appear similar, mechanisms likely differ since the neuronal populations have different projection patterns (Geerling et al ., 2017; Huang et al ., 2021) and are involved in different behaviors besides breathing, especially the lateral parabrachial area (Campos et al ., 2018; Chen et al ., 2018); Liu et al ., 2022). In addition, the distinction between KF and lateral parabrachial area is not clear cut, though recent description of transcription factor expression in the dorsolateral pons provides opportunity to improve this (Karthik et al ., 2022).…”

Section: Discussionmentioning

confidence: 99%

Opioid Suppression of an Excitatory Pontomedullary Respiratory Circuit by Convergent Mechanisms

Bateman

Levitt

2022

Preprint

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Opioids depress breathing by inhibition of inter-connected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons is unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the pre-Bötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. The excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids. Thus, opioids can synergistically inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms—somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla—all of which could contribute to opioid-induced respiratory depression.

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Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions

Cited by 73 publications

References 88 publications

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

Molecular and Anatomical Characterization of Parabrachial Neurons and Their Axonal Projections

Opioid Suppression of an Excitatory Pontomedullary Respiratory Circuit by Convergent Mechanisms

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