Modernizing the NEURON Simulator for Sustainability, Portability, and Performance

Frontiers in Neuroinformatics, Год журнала: 2022, Номер 16

Опубликована: Июнь 27, 2022

The need for reproducible, credible, multiscale biological modeling has led to the development of standardized simulation platforms, such as widely-used NEURON environment computational neuroscience. Developing and maintaining over several decades required attention competing needs backwards compatibility, evolving computer architectures, addition new scales physical processes, accessibility users, efficiency flexibility specialists. In order meet these challenges, we have now substantially modernized NEURON, providing continuous integration, an improved build system release workflow, better documentation. With help a source-to-source compiler NMODL domain-specific language enhanced NEURON's ability run efficiently, via CoreNEURON engine, on variety hardware including GPUs. Through implementation optimized in-memory transfer mechanism this performance backend is made easily accessible training model-development paths from laptop workstation supercomputer cloud platform. Similarly, been able accelerate reaction-diffusion through use just-in-time compilation. We show that efforts growing developer base, simpler more robust software distribution, wider range supported integration with other scientific workflows, biophysical biochemical models.

Язык: Английский

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Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Май 3, 2023

Abstract Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy field research: ability disparate elements cause an analogous function or malfunction. Here, review examples epilepsy-related at multiple levels brain organisation, ranging from cellular network systems level. Based on these insights, outline new multiscale population modelling approaches disentangle web interactions underlying design personalised multitarget therapies.

Язык: Английский

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Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn

Neuron, Год журнала: 2024, Номер 112(8), С. 1302 - 1327.e13

Опубликована: Март 6, 2024

Язык: Английский

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Emotional component of pain perception in the medicinal leech?

Animal Sentience, Год журнала: 2022, Номер 7(32)

Опубликована: Янв. 1, 2022

Crump et al. have provided a series of criteria to assess animal sentience that is focused on the perception pain, which known both sensory and emotional components. They also provide qualitative scoring system data address eight apply this paradigm decapod crustaceans. The laid out potential be applied other invertebrates typically thought response tissue damage, but no component pain perception.

Язык: Английский

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Modulation of SK Channels via Calcium Buffering Tunes Intrinsic Excitability of Parvalbumin Interneurons in Neuropathic Pain: A Computational and Experimental Investigation

Journal of Neuroscience, Год журнала: 2023, Номер 43(31), С. 5608 - 5622

Опубликована: Июль 14, 2023

Parvalbumin-expressing interneurons (PVINs) play a crucial role within the dorsal horn of spinal cord by preventing touch inputs from activating pain circuits. In both male and female mice, nerve injury decreases PVINs' output via mechanisms that are not fully understood. this study, we show PVINs nerve-injured mice change their firing pattern tonic to adaptive. To examine ionic responsible for decreased output, used reparametrized Hodgkin-Huxley type model PVINs, which predicted (1) transition is because an increased contribution small conductance calcium-activated potassium (SK) channels, enabled (2) impairment in intracellular calcium buffering systems. Analyzing dynamics further demonstrated generalized Hopf bifurcation differentiates two types state transitions observed transient PVINs. Importantly, mechanism holds true when embed PVIN neuronal circuit horn. experimentally validate hypothesized mechanism, pharmacological modulators SK channels naive become adaptive exposed channel activator, adapting return on blockade. Our work provides important insights into cellular underlying after highlights potential targets new effective treatment approaches neuropathic pain.

Язык: Английский

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Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

eLife, Год журнала: 2024, Номер 12

Опубликована: Апрель 30, 2024

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in voltage-gated sodium channel Na V 1.7 cause insensitivity pain (presumably by reducing nociceptor excitability) but clinical trials seeking treat inhibiting pharmacologically have struggled. This may reflect variable contribution of excitability. Contrary claims that is necessary for nociceptors initiate potentials, we show can achieve similar excitability different combinations 1.3, 1.7, and 1.8. Selectively blocking one those subtypes reduces only if other are weakly expressed. For example, relies on 1.8 acutely dissociated responsibility shifts 1.3 fourth day culture. A shift dependence occurs vivo after inflammation, impacting ability 1.7-selective inhibitor PF-05089771 reduce behavioral tests. Flexible use exemplifies degeneracy – achieving function components compromises reliable modulation subtype-selective inhibitors. Identifying dominant subtype predict drug efficacy not trivial. Degeneracy at cellular level must be considered when choosing targets molecular level.

Язык: Английский

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Pareto optimality, economy–effectiveness trade-offs and ion channel degeneracy: improving population modelling for single neurons

Open Biology, Год журнала: 2022, Номер 12(7)

Опубликована: Июль 1, 2022

Neurons encounter unavoidable evolutionary trade-offs between multiple tasks. They must consume as little energy possible while effectively fulfilling their functions. Cells displaying the best performance for such multi-task are said to be Pareto optimal, with ion channel configurations underpinning functionality. Ion degeneracy, however, implies that can lead functionally similar behaviour. Therefore, instead of a single model, neuroscientists often use populations models distinct combinations ionic conductances. This approach is called population (database or ensemble) modelling. It remains unclear, which parameters in vast functional more likely found brain. Here we argue optimality serve guiding principle addressing this issue by helping identify subpopulations conductance-based perform trade-off economy and In way, high-dimensional parameter space neuronal might reduced geometrically simple low-dimensional manifolds, potentially explaining experimentally observed correlations. Conversely, inference also help deduce functions from Patch-seq data. summary, promising framework improving modelling neurons circuits.

Язык: Английский

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Pain modulation in the spinal cord

Frontiers in Pain Research, Год журнала: 2022, Номер 3

Опубликована: Сен. 13, 2022

The sensory inflow from the periphery that triggers innocuous and painful sensations is highly complex, capturing key elements of nature any stimulus, its location, intensity, duration, converting this to dynamic action potential firing across a wide population afferents. While afferents are specialized detect these features, their input spinal cord also active processing modulation there which determines output, drive percept experienced behavioral responses. Focus on such was arguably first introduced by Melzack Wall in Spinal Cord Gate Control theory. This theory has had profound influence our understanding pain, especially processing, as well leading directly development clinical interventions, historical importance certainly needs be fully recognized. However, enormous progress we making function somatosensory system, means it time incorporate newly discovered features into more complex accurate model modulation.

Язык: Английский

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Large-scale biophysically detailed model of somatosensory thalamocortical circuits in NetPyNE

Frontiers in Neuroinformatics, Год журнала: 2022, Номер 16

Опубликована: Сен. 22, 2022

The primary somatosensory cortex (S1) of mammals is critically important in the perception touch and related sensorimotor behaviors. In 2015, Blue Brain Project (BBP) developed a groundbreaking rat S1 microcircuit simulation with over 31,000 neurons 207 morpho-electrical neuron types, 37 million synapses, incorporating anatomical physiological information from wide range experimental studies. We have implemented this highly detailed complex model NetPyNE, using data available Neocortical Microcircuit Collaboration Portal. NetPyNE provides Python high-level interface to NEURON allows defining complicated multiscale models an intuitive declarative standardized language. It also facilitates running parallel simulations, automates optimization exploration parameters supercomputers, built-in analysis functions. This will make more accessible simpler scale, modify extend order explore research questions or interconnect other existing models. Despite some implementation differences, preserved original cell morphologies, electrophysiological responses spatial distribution for all types; connectivity properties 1941 pathways, including synaptic dynamics short-term plasticity (STP). simulations produced reasonable firing rates activity patterns across populations. When STP was included, network generated 1 Hz oscillation comparable vitro -like state. By then reducing extracellular calcium concentration, reproduced vivo states asynchronous activity. These results validate study new modeling tool. Simulated local field potentials (LFPs) exhibited realistic oscillatory features, distance- frequency-dependent attenuation. extended by adding thalamic circuits, 6 distinct populations intrathalamic, thalamocortical (TC) corticothalamic derived data. single known circuit-level dynamics, burst tonic modes patterns, providing input enabling TC interactions. Overall, our work widely accessible, data-driven biophysically-detailed circuits that can be employed as community tool researchers neural function disease.

Язык: Английский

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Finding new analgesics: Computational pharmacology faces drug discovery challenges

Biochemical Pharmacology, Год журнала: 2024, Номер 222, С. 116091 - 116091

Опубликована: Фев. 25, 2024

Язык: Английский

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