Breathing matters

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(6), P. 351 - 367

Published: May 8, 2018

Language: Английский

---

Central pattern generators in the brainstem and spinal cord: an overview of basic principles, similarities and differences

Reviews in the Neurosciences, Journal Year: 2018, Volume and Issue: 30(2), P. 107 - 164

Published: Dec. 13, 2018

Central pattern generators (CPGs) are generally defined as networks of neurons capable enabling the production central commands, specifically controlling stereotyped, rhythmic motor behaviors. Several CPGs localized in brainstem and spinal cord areas have been shown to underlie expression complex behaviors such deglutition, mastication, respiration, defecation, micturition, ejaculation, locomotion. Their pivotal roles clearly demonstrated although their organization cellular properties remain incompletely characterized. In recent years, insightful findings about made mainly because (1) several complementary animal models were developed; (2) these enabled a wide variety techniques be used and, hence, plethora characteristics discovered; (3) organizations, functions, cell across all species studied thus far found well-preserved phylogenetically. This article aims at providing an overview for non-experts most important on vivo models, vitro preparations from invertebrate vertebrate well primates. Data CPG adaptation, organization, will summarized with special attention paid network locomotion given its advanced level characterization compared some other CPGs. Similarities differences between also highlighted.

Language: Английский

---

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

Journal of Neurophysiology, Journal Year: 2021, Volume and Issue: 125(5), P. 1899 - 1919

Published: April 7, 2021

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within United States, rate from abuse since early 1990s has grown disproportionally, prompting classification as a nationwide “epidemic.” Since this time, we have begun to unravel many fundamental cellular systems-level mechanisms opioid-related death. However, factors such individual vulnerability, neuromodulatory compensation, redundancy effects across central peripheral nervous systems created barrier concise, integrative view OIRD. review, bring together multiple perspectives in field OIRD create an overarching viewpoint what know, where essential topic research going forward into future.

Language: Английский

---

New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN

Physiological Reviews, Journal Year: 2023, Volume and Issue: 104(1), P. 399 - 472

Published: Aug. 24, 2023

Cell excitability and its modulation by hormones neurotransmitters involve the concerted action of a large repertoire membrane proteins, especially ion channels. Unique complements coexpressed channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that tailored for diverse physiological contributions, dysfunction any component may induce disease state. A crucial parameter controlling is resting potential (RMP) set extra- intracellular concentrations ions, mainly Na + , K Cl − their passive permeation across through leak Indeed, dysregulation RMP causes significant effects on cellular excitability. This review describes molecular channel NALCN, which associates with accessory subunits UNC-79, UNC-80, NLF-1/FAM155 to conduct depolarizing background currents various neurons. Studies animal models clearly demonstrate NALCN contributes fundamental processes nervous system including control respiratory rhythm, circadian sleep, locomotor behavior. Furthermore, associated severe pathological states humans. The critical involvement physiology now well established, but study has been hampered lack specific drugs can block or agonize vitro vivo. Molecular tools available accelerate our understanding how key functions development novel therapies channelopathies.

Language: Английский

---

Gi/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Dec. 17, 2018

Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic - the sodium leak channel, NALCN. We found that activation D2 robustly inhibits isolated currents wild-type mice but not NALCN conditional knockout mice. Intracellular GDP-βS abolished inhibition, indicating protein-dependent signaling mechanism. The application reliably slowed pacemaking even when GIRK were pharmacologically blocked. Furthermore, while spontaneous activity was observed nearly all mice, from knockouts mainly silent. Both observations demonstrate critical importance for neurons. Finally, show GABA-B receptor also produces inhibition NALCN-mediated currents. Therefore, identify as core inhibitory receptors.

Language: Английский

---

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

---

Phasic inhibition as a mechanism for generation of rapid respiratory rhythms

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(48), P. 12815 - 12820

Published: Nov. 13, 2017

Significance Humans breathe ∼20,000 times per day and hundreds of millions over the average life span. The neural mechanisms which control respiratory rate are poorly understood. Although it was previously thought that signal to solely an excitatory command, we show selective stimulation putative CO 2 -chemosensitive neurons likely initiates inspiration through inhibition. These results argue clock determines operates in two distinct modes: a first mode is highly modular allows for flexibility adapt everyday behaviors, second specifically recruited situations elevated .

Language: Английский

---

A Leptin-Mediated Neural Mechanism Linking Breathing to Metabolism

Cell Reports, Journal Year: 2020, Volume and Issue: 33(6), P. 108358 - 108358

Published: Nov. 1, 2020

Breathing is coupled to metabolism. Leptin, a peptide mainly secreted in proportion adipose tissue mass, increases energy expenditure with parallel increase breathing. We demonstrate that optogenetic activation of LepRb neurons the nucleus solitary tract (NTS) mimics respiratory stimulation after systemic leptin administration. show activates sodium leak channel (NALCN), thereby depolarizing subset glutamatergic (VGluT2) NTS expressing galanin. Mice selective deletion NALCN have increased breathing irregularity and central apneas. On high-fat diet, these mice gain weight an associated depression minute ventilation tidal volume, which are not detected control littermates. Anatomical mapping reveals NTS-originating axon terminals brainstem inspiratory premotor region (rVRG) dorsomedial hypothalamus. These findings directly link defined cells matching balance.

Language: Английский

---

TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Aug. 19, 2021

Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold depolarization underlies autonomous pacemaking and determines its rate. However, ion channels determine unknown. Here we show TRPC3 NALCN together form sustained inward currents responsible for of nigral neurons. Specific channel blockade completely blocked neuron pacemaking, but activity in knock-out (KO) mice was perfectly normal, suggesting presence compensating channels. Blocking abolished both KO wild-type mice. The current mRNA protein expression increased mice, indicating compensates currents. In normal conditions, contribute equally to depolarization. Therefore, conclude two major leak drive robust

Language: Английский

---

Role of sodium leak channel (NALCN) in sensation and pain: an overview

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

The sodium leak channel (NALCN) is widely expressed in the central nervous system and plays a pivotal role regulating resting membrane potential (RMP) by mediating Na

Language: Английский

---