Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing

Cleary, Colin; Milla, Brenda M; Kuo, Fu-Shan; James, Shaun; Flynn, William F.; Robson, Paul; Mulkey, Daniel K.

doi:10.7554/elife.60317

Cited by 12 publications

(7 citation statements)

References 80 publications

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“…In addition, there were neurons that were inhibited by hypercapnia (I). Inhibition of RTN neuronal firing by hypercapnia has been previously observed ( Cleary et al, 2021 ; Nattie et al, 1993 ; Ott et al, 2011 ).…”

Section: Discussionmentioning

confidence: 74%

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Bhandare

Wiel

Roberts

et al. 2022

eLife

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Regulation of systemic PCO2 is a life-preserving homeostatic mechanism. In the medulla oblongata, the retrotrapezoid nucleus (RTN) and rostral medullary Raphe are proposed as CO2 chemosensory nuclei mediating adaptive respiratory changes. Hypercapnia also induces active expiration, an adaptive change thought to be controlled by the lateral parafacial region (pFL). Here we use GCaMP6 expression and head-mounted mini-microscopes to image Ca2+ activity in these nuclei in awake adult mice during hypercapnia. Activity in the pFL supports its role as a homogenous neuronal population that drives active expiration. Our data show that chemosensory responses in the RTN and Raphe differ in their temporal characteristics and sensitivity to CO2, raising the possibility these nuclei act in a coordinated way to generate adaptive ventilatory responses to hypercapnia. Our analysis revises the understanding of chemosensory control in awake adult mouse and paves the way to understanding how breathing is coordinated with complex non-ventilatory behaviours.

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Section: Discussionmentioning

confidence: 74%

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Bhandare

Wiel

Roberts

et al. 2022

eLife

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“…For example, in the context of Dravet syndrome (caused by loss of function mutations in SCN1A), we showed that Scn1a transcript is expressed by inhibitory parafacial neurons in the region of the RTN (Kuo et al, 2019). We also showed that inhibitory somatostatin (SST)-expressing neurons in the region of the RTN are inhibited by CO 2 /H + and contribute to RTN chemoreception by disinhibition of CO 2 /H + -activated glutamatergic neurons (i.e., RTN chemoreceptors; Cleary et al, 2021). Therefore, in addition to causing cortical seizure activity, Dravet syndrome-associated Scn1a mutations may disrupt the inhibitory modulation of RTN chemoreception.…”

Section: Direct Effect Of Epilepsy Associated Mutations On Brainstem ...mentioning

confidence: 97%

Perspectives on the basis of seizure-induced respiratory dysfunction

Mulkey

Milla

2022

Front. Neural Circuits

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Epilepsy is an umbrella term used to define a wide variety of seizure disorders and sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in epilepsy. Although some SUDEP risk factors have been identified, it remains largely unpredictable, and underlying mechanisms remain poorly understood. Most seizures start in the cortex, but the high mortality rate associated with certain types of epilepsy indicates brainstem involvement. Therefore, to help understand SUDEP we discuss mechanisms by which seizure activity propagates to the brainstem. Specifically, we highlight clinical and pre-clinical evidence suggesting how seizure activation of: (i) descending inhibitory drive or (ii) spreading depolarization might contribute to brainstem dysfunction. Furthermore, since epilepsy is a highly heterogenous disorder, we also considered factors expected to favor or oppose mechanisms of seizure propagation. We also consider whether epilepsy-associated genetic variants directly impact brainstem function. Because respiratory failure is a leading cause of SUDEP, our discussion of brainstem dysfunction focuses on respiratory control.

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“…In this study, to determine the relative contribution of the RTN neuronal population to the hypercapnic respiratory J Physiol 602.1 response, we used a viral vector with a pan-neuronal promoter. We did not target the specific subpopulation of RTN neurons that express the specific markers of the chemosensitive neurons, and inhibition of other neurons within the region could potentially have changed the respiratory response to CO 2 (Cleary et al, 2021). The physiological data showing complete blockade of active expirations and significant (by ∼40%) reduction in the inspiratory response to CO 2 were found to be very similar to that reported in the preceding studies (Marina et al 2010;Nattie & Li, 2002Takakura et al, 2014), suggesting that a critical number of RTN neurons were successfully inhibited in these experiments.…”

Section: Experimental Limitationsmentioning

confidence: 99%

Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO₂‐sensitive drive for breathing

SheikhBahaei,

Marina,

Rajani

et al. 2023

The Journal of Physiology

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Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm‐generating region of the medulla oblongata – the preBötzinger complex (preBötC). There is also evidence that astrocytes, non‐neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi‐coupled designer receptors exclusively activated by designer drug (DREADDGi) by application of clozapine‐N‐oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2‐induced respiratory response by ∼70%. These data further support the hypothesis that the CO2‐sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2, either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. imageKey points This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2‐sensitive drive to breathe. The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia. These data provide further support for the hypothesis that the CO2‐sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.

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Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing

Cited by 12 publications

References 80 publications

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Perspectives on the basis of seizure-induced respiratory dysfunction

Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO₂‐sensitive drive for breathing

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Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing

Cited by 12 publications

References 80 publications

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Analyzing the brainstem circuits for respiratory chemosensitivity in freely moving mice

Perspectives on the basis of seizure-induced respiratory dysfunction

Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO2‐sensitive drive for breathing

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Product

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Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBötzinger complex astrocytes to the CO₂‐sensitive drive for breathing