Opioids modulate an emergent rhythmogenic process to depress breathing

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Dec. 16, 2019

How mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For rhythm generation is localized to a brainstem nucleus, the preBötzinger Complex (preBötC). Rhythmic preBötC population consists of strong inspiratory bursts, which drive motoneuronal activity, weaker burstlets, we hypothesize reflect an emergent rhythmogenic process. If burstlets underlie rhythmogenesis, respiratory depressants, opioids, should reduce burstlet frequency. Indeed, medullary slices from neonatal mice, μ-opioid receptor (μOR) agonist DAMGO slowed generation. Genetic deletion μORs glutamatergic subpopulation abolished opioid-mediated depression, neuropeptide Substance P, but not blockade inhibitory synaptic transmission, reduced opioidergic effects. We conclude that rhythmogenesis process, modulated by does rely on bursts associated with output. These findings also point strategies for ameliorating opioid-induced depression breathing.

Language: Английский

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Trpm4 ion channels in pre-Bötzinger complex interneurons are essential for breathing motor pattern but not rhythm

PLoS Biology, Journal Year: 2019, Volume and Issue: 17(2), P. e2006094 - e2006094

Published: Feb. 21, 2019

Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca2+)-activated nonselective cationic current (ICAN) to generate robust neural bursts. Hypothesized be rhythmogenic, reducing ICAN is predicted slow down or stop breathing; its contributions motor pattern would reflected in the magnitude of (output). We tested role(s) using reverse genetic techniques diminish putative ion channels Trpm4 Trpc3 preBötC neurons vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased tidal volume breaths yet surprisingly increased frequency, often followed by gasping and fatal respiratory failure. Mice Trpc3-targeted shRNA survived no changes breathing. Patch-clamp field recordings from mouse slices also showed an increase frequency a decrease bursts presence antagonist 9-phenanthrol, whereas pyrazole-3 (pyr-3) inconsistent effects effect frequency. These data suggest mediates ICAN, whose influence contradicts direct role rhythm generation. conclude Trpm4-mediated indispensable for output but not rhythmogenic core mechanism central generator.

Language: Английский

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Correlation between neuroanatomical and functional respiratory changes observed in an experimental model of Parkinson's disease

Experimental Physiology, Journal Year: 2018, Volume and Issue: 103(10), P. 1377 - 1389

Published: Aug. 7, 2018

New Findings What is the central question of this study? relationship between neuroanatomical and functional respiratory changes in an experimental model Parkinson's disease? main finding its importance? Sixty days after induction disease a rat model, there are decreases baseline breathing number neurons, density neurokinin‐1 receptor astrocytes ventrolateral region. These results provide first evidence that occur before deficits positive correlation those sets changes. The impair activity presumably major cause problems observed disease. Abstract We showed previously 60 (PD) phox2b‐expressing neurons retrotrapezoid nucleus (RTN) solitary tract (NTS), as well reduction (NK1r) pre‐Bötzinger complex (preBötC) rostral group (rVRG). Here, our aim was to evaluate PD. Male Wistar rats with bilateral injections 6‐hydroxydopamine (6‐OHDA, 24 μg μl −1 ) or vehicle into striatum had parameters assessed by whole‐body plethysmography 1 day 30, 40 ablation. From 30th ablation, we phox2b RTN NTS rVRG. At NK1r preBötC rVRG days, regions. data resting hypercapnia‐induced rates tidal volume from 40–60 injury. Our suggest

Language: Английский

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Mixed-mode oscillations and population bursting in the pre-Bötzinger complex

eLife, Journal Year: 2016, Volume and Issue: 5

Published: March 14, 2016

This study focuses on computational and theoretical investigations of neuronal activity arising in the pre-Bötzinger complex (pre-BötC), a medullary region generating inspiratory phase breathing mammals. A progressive increase excitability slices containing pre-BötC produces mixed-mode oscillations (MMOs) characterized by large amplitude population bursts alternating with series small bursts. Using two different models, we demonstrate that MMOs emerge within heterogeneous excitatory neural network because recruitment synchronization. The MMO pattern depends distributed excitability, density weights interconnections, cellular properties underlying endogenous bursting. Critically, latter should provide reduction spiking frequency increasing burst dependence after-burst recovery period amplitude. Our highlights novel mechanism which heterogeneity naturally leads to dynamics rhythmic populations.

Language: Английский

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CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture

eLife, Journal Year: 2016, Volume and Issue: 5

Published: June 27, 2016

Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies result sudden infant death. To elucidate underlying mechanisms, we present a novel brainstem organotypic culture that generates rhythmic neural network motor activity for 3 weeks. We show increased elicits gap junction-dependent PGE2. alters preBötzinger rhythm-generating complex chemosensitive respiratory regions, thereby increasing sigh frequency depth inspiration. used mice lacking eicosanoid prostanoid receptors (EP3R), slices optogenetic inhibition EP3R+/+ cells demonstrate EP3R is important ventilatory hypercapnia. Our study identifies pathway linking inflammatory systems, with implications inspiration sighs throughout life, ability autoresuscitate when fails.

Language: Английский

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