On the Role of Theory and Modeling in Neuroscience

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(7), P. 1074 - 1088

Published: Feb. 15, 2023

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in use quantitative computational methods. This growth created need for clearer analyses theory modeling approaches used field. issue is particularly complex because studies phenomena that cross wide range scales often require consideration at varying degrees abstraction, from precise biophysical interactions to computations they implement. We argue pragmatic perspective science, which descriptive, mechanistic, normative models theories each play distinct role defining bridging levels will facilitate neuroscientific practice. analysis leads methodological suggestions, including selecting level abstraction appropriate given problem, identifying transfer functions connect data, themselves as form experiment.

Language: Английский

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Differential impact of two critical respiratory centres in opioid‐induced respiratory depression in awake mice

The Journal of Physiology, Journal Year: 2019, Volume and Issue: 598(1), P. 189 - 205

Published: Oct. 7, 2019

Key points The main cause of death from opioid overdose is respiratory depression due to the activation µ‐opioid receptors (MORs). We conditionally deleted MORs neurons in two key areas brainstem circuitry (the Kölliker–Fuse nucleus (KF) and pre‐Bötzinger complex (preBötC)) determine their role opioid‐induced disturbances adult, awake mice. Deletion KF attenuated rate at all doses morphine. preBötC low dose, but had no effect on following high Instead, morphine increased occurrence apnoeas. results indicate that opioids affect distributed network a dose‐dependent manner countering effects dose via may be an effective approach combat overdose. Abstract primary failure. High severe risk fatal apnoea, which correlate with increasing irregularities breathing pattern. µ‐Opioid (MORs) are widely throughout network, mechanisms underlying poorly understood. medullary (preBötC) pontine considered critical for inducing opioid‐related disturbances. used conditional knockout investigate roles relative contribution adult revealed region‐specific control both Respiratory induced by anti‐nociceptive was significantly deletion either or preBötC, suggesting cumulative doses. also relieved near‐maximal depressant Meanwhile, administration ataxic pattern emerged many conclude cannot attributed only one area isolation. However, near maximal powerful

Language: Английский

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Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity

Archives of Toxicology, Journal Year: 2021, Volume and Issue: 95(8), P. 2627 - 2642

Published: May 11, 2021

Language: Английский

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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

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Mechanisms of opioid-induced respiratory depression

Archives of Toxicology, Journal Year: 2022, Volume and Issue: 96(8), P. 2247 - 2260

Published: April 26, 2022

Language: Английский

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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

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The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea

Journal of neurosurgery, Journal Year: 2019, Volume and Issue: 132(5), P. 1313 - 1323

Published: April 9, 2019

OBJECTIVE Sudden unexpected death in epilepsy (SUDEP) is the leading cause of for patients with refractory epilepsy, and there increasing evidence a centrally mediated respiratory depression as pathophysiological mechanism. The brain regions responsible seizure’s inducing are unclear—the nuclei brainstem thought to be involved, but involvement forebrain structures not yet understood. aim this study was analyze intracranial EEGs combination results monitoring investigate relationship between seizure spread specific mesial temporal onset dysfunction apnea. METHODS authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 identify those cases which 1) multiple electrodes (amygdala hippocampal) were placed, 2) seizures captured, 3) patients’ respiration monitored. They identified 8 investigations meeting these criteria lobe yielded data on total 22 analysis. RESULTS ictal apnea associated each highly correlated amygdala. Onset occurred 2.7 ± 0.4 (mean SEM) seconds after amygdala, significantly earlier than hippocampus (10.2 0.7 seconds; p < 0.01). CONCLUSIONS findings suggest that activation amygdalar networks central during seizures. This builds authors’ prior work demonstrates role amygdala voluntary control suggests further dysfunctional breathing states seen seizures, implications SUDEP pathophysiology.

Language: Английский

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A spatially dynamic network underlies the generation of inspiratory behaviors

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(15), P. 7493 - 7502

Published: March 27, 2019

Significance Breathing is a vital rhythmic behavior that originates from neural networks within the brainstem. It hypothesized breathing rhythm generated by spatially distinct localized to discrete kernels or compartments. Here, we provide evidence functional boundaries of these compartments expand and contract dynamically based on behavioral physiological demands. The ability change in size may allow be very reliable, yet flexible enough accommodate large repertoire mammalian behaviors must integrated with breathing.

Language: Английский

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Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

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

Published: Aug. 17, 2021

The analgesic utility of opioid-based drugs is limited by the life-threatening risk respiratory depression. Opioid-induced depression (OIRD), mediated μ-opioid receptor (MOR), characterized a pronounced decrease in frequency and regularity inspiratory rhythm, which originates from medullary preBötzinger Complex (preBötC). To unravel cellular- network-level consequences MOR activation preBötC, MOR-expressing neurons were optogenetically identified manipulated transgenic mice vitro vivo. Based on these results, model OIRD was developed silico. We conclude that hyperpolarization - expressing preBötC alone does not phenocopy OIRD. Instead, effects are twofold: (1) pre-inspiratory spiking reduced (2) excitatory synaptic transmission suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms opioid action act synergistically to make normally robust rhythm-generating network particularly prone collapse when challenged with exogenous opioids.

Language: Английский

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Parabrachial tachykinin1-expressing neurons involved in state-dependent breathing control

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 21, 2023

Abstract Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing also modified behavior and emotion. Mice have rapid patterns that are unique awake state distinct from those driven automatic reflexes. Activation of medullary neurons control does not reproduce these patterns. By manipulating transcriptionally defined parabrachial nucleus, we identify a subset express Tac1 , Calca gene exerts potent precise conditional awake, anesthetized, via projections ventral intermediate reticular zone medulla. Activating drives frequencies match physiological maximum through mechanisms differ underlie breathing. We postulate this circuit important for integration with state-dependent behaviors emotions.

Language: Английский

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