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1.
Chaos ; 34(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427934

RESUMO

The brain is known to be plastic, i.e., capable of changing and reorganizing as it develops and accumulates experience. Recently, a novel form of brain plasticity was described which is activity-dependent myelination of nerve fibers. Since the speed of propagation of action potentials along axons depends significantly on their degree of myelination, this process leads to adaptive change of axonal delays depending on the neural activity. To understand the possible influence of the adaptive delays on the behavior of neural networks, we consider a simple setup, a neuronal oscillator with delayed feedback. We show that introducing the delay plasticity into this circuit can lead to the occurrence of slow oscillations which are impossible with a constant delay.


Assuntos
Bainha de Mielina , Neurônios , Bainha de Mielina/fisiologia , Neurônios/fisiologia , Axônios/fisiologia , Potenciais de Ação/fisiologia , Encéfalo/fisiologia
2.
PLoS Comput Biol ; 20(3): e1011891, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38466752

RESUMO

Recent developments in experimental techniques have enabled simultaneous recordings from thousands of neurons, enabling the study of functional cell assemblies. However, determining the patterns of synaptic connectivity giving rise to these assemblies remains challenging. To address this, we developed a complementary, simulation-based approach, using a detailed, large-scale cortical network model. Using a combination of established methods we detected functional cell assemblies from the stimulus-evoked spiking activity of 186,665 neurons. We studied how the structure of synaptic connectivity underlies assembly composition, quantifying the effects of thalamic innervation, recurrent connectivity, and the spatial arrangement of synapses on dendrites. We determined that these features reduce up to 30%, 22%, and 10% of the uncertainty of a neuron belonging to an assembly. The detected assemblies were activated in a stimulus-specific sequence and were grouped based on their position in the sequence. We found that the different groups were affected to different degrees by the structural features we considered. Additionally, connectivity was more predictive of assembly membership if its direction aligned with the temporal order of assembly activation, if it originated from strongly interconnected populations, and if synapses clustered on dendritic branches. In summary, reversing Hebb's postulate, we showed how cells that are wired together, fire together, quantifying how connectivity patterns interact to shape the emergence of assemblies. This includes a qualitative aspect of connectivity: not just the amount, but also the local structure matters; from the subcellular level in the form of dendritic clustering to the presence of specific network motifs.


Assuntos
Neurônios , Tálamo , Neurônios/fisiologia , Simulação por Computador , Potenciais de Ação/fisiologia , Sinapses/fisiologia , Rede Nervosa/fisiologia , Modelos Neurológicos
3.
Nat Commun ; 15(1): 2190, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467602

RESUMO

The precise temporal coordination of neural activity is crucial for brain function. In the hippocampus, this precision is reflected in the oscillatory rhythms observed in CA1. While it is known that a balance between excitatory and inhibitory activity is necessary to generate and maintain these oscillations, the differential contribution of feedforward and feedback inhibition remains ambiguous. Here we use conditional genetics to chronically silence CA1 pyramidal cell transmission, ablating the ability of these neurons to recruit feedback inhibition in the local circuit, while recording physiological activity in mice. We find that this intervention leads to local pathophysiological events, with ripple amplitude and intrinsic frequency becoming significantly larger and spatially triggered local population spikes locked to the trough of the theta oscillation appearing during movement. These phenotypes demonstrate that feedback inhibition is crucial in maintaining local sparsity of activation and reveal the key role of lateral inhibition in CA1 in shaping circuit function.


Assuntos
Hipocampo , Células Piramidais , Camundongos , Animais , Retroalimentação , Hipocampo/fisiologia , Células Piramidais/fisiologia , Neurônios , Região CA1 Hipocampal/fisiologia , Interneurônios/fisiologia , Potenciais de Ação/fisiologia
4.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473860

RESUMO

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing.


Assuntos
Interneurônios , Ocitocina , Camundongos , Animais , Potenciais de Ação , Ocitocina/farmacologia , Interneurônios/fisiologia , Neurônios , Hipocampo , Células Piramidais , Mamíferos
5.
PLoS Comput Biol ; 20(3): e1011833, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38427699

RESUMO

BACKGROUND: Peripheral nerve recordings can enhance the efficacy of neurostimulation therapies by providing a feedback signal to adjust stimulation settings for greater efficacy or reduced side effects. Computational models can accelerate the development of interfaces with high signal-to-noise ratio and selective recording. However, validation and tuning of model outputs against in vivo recordings remains computationally prohibitive due to the large number of fibers in a nerve. METHODS: We designed and implemented highly efficient modeling methods for simulating electrically evoked compound nerve action potential (CNAP) signals. The method simulated a subset of fiber diameters present in the nerve using NEURON, interpolated action potential templates across fiber diameters, and filtered the templates with a weighting function derived from fiber-specific conduction velocity and electromagnetic reciprocity outputs of a volume conductor model. We applied the methods to simulate CNAPs from rat cervical vagus nerve. RESULTS: Brute force simulation of a rat vagal CNAP with all 1,759 myelinated and 13,283 unmyelinated fibers in NEURON required 286 and 15,860 CPU hours, respectively, while filtering interpolated templates required 30 and 38 seconds on a desktop computer while maintaining accuracy. Modeled CNAP amplitude could vary by over two orders of magnitude depending on tissue conductivities and cuff opening within experimentally relevant ranges. Conduction distance and fiber diameter distribution also strongly influenced the modeled CNAP amplitude, shape, and latency. Modeled and in vivo signals had comparable shape, amplitude, and latency for myelinated fibers but not for unmyelinated fibers. CONCLUSIONS: Highly efficient methods of modeling neural recordings quantified the large impact that tissue properties, conduction distance, and nerve fiber parameters have on CNAPs. These methods expand the computational accessibility of neural recording models, enable efficient model tuning for validation, and facilitate the design of novel recording interfaces for neurostimulation feedback and understanding physiological systems.


Assuntos
Potenciais Evocados , Fibras Nervosas , Ratos , Animais , Potenciais de Ação/fisiologia , Nervos Periféricos , Simulação por Computador , Condução Nervosa/fisiologia
6.
Sci Rep ; 14(1): 5167, 2024 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431662

RESUMO

Magnetic fields are widely used for neuromodulation in clinical settings. The intended effect of magnetic stimulation is that neural activity resumes its pre-stimulation state right after stimulation. Many theoretical and experimental works have focused on the cellular and molecular basis of the acute neural response to magnetic field. However, effects of magnetic stimulation can still last after the termination of the magnetic stimulation (named "carry-over effects"), which could generate profound effects to the outcome of the stimulation. However, the cellular and molecular mechanisms of carry-over effects are largely unknown, which renders the neural modulation practice using magnetic stimulation unpredictable. Here, we investigated carry-over effects at the cellular level, using the combination of micro-magnetic stimulation (µMS), electrophysiology, and computation modeling. We found that high frequency magnetic stimulation could lead to immediate neural inhibition in ganglion neurons from Aplysia californica, as well as persistent, carry-over inhibition after withdrawing the magnetic stimulus. Carry-over effects were found in the neurons that fired action potentials under a variety of conditions. The carry-over effects were also observed in the neurons when the magnetic field was applied across the ganglion sheath. The state of the neuron, specifically synaptic input and membrane potential fluctuation, plays a significant role in generating the carry-over effects after magnetic stimulation. To elucidate the cellular mechanisms of such carry-over effects under magnetic stimulation, we simulated a single neuron under magnetic stimulation with multi-compartment modeling. The model successfully replicated the carry-over effects in the neuron, and revealed that the carry-over effect was due to the dysfunction of the ion channel dynamics that were responsible for the initiation and sustaining of membrane excitability. A virtual voltage-clamp experiment revealed a compromised Na conductance and enhanced K conductance post magnetic stimulation, rendering the neurons incapable of generating action potentials and, therefore, leading to the carry over effects. Finally, both simulation and experimental results demonstrated that the carry-over effects could be controlled by disturbing the membrane potential during the post-stimulus inhibition period. Delineating the cellular and ion channel mechanisms underlying carry-over effects could provide insights to the clinical outcomes in brain stimulation using TMS and other modalities. This research incentivizes the development of novel neural engineering or pharmacological approaches to better control the carry-over effects for optimized clinical outcomes.


Assuntos
Canais Iônicos , Neurônios , Neurônios/fisiologia , Potenciais da Membrana/fisiologia , Potenciais de Ação , Canais Iônicos/fisiologia , Fenômenos Magnéticos , Estimulação Elétrica
7.
J Math Biol ; 88(3): 39, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38441655

RESUMO

The presence or absence of synaptic plasticity can dramatically influence the collective behavior of populations of coupled neurons. In this work, we consider spike-timing dependent plasticity (STDP) and its resulting influence on phase cohesion in computational models of heterogeneous populations of conductance-based neurons. STDP allows for the influence of individual synapses to change over time, strengthening or weakening depending on the relative timing of the relevant action potentials. Using phase reduction techniques, we derive an upper bound on the critical coupling strength required to retain phase cohesion for a network of synaptically coupled, heterogeneous neurons with STDP. We find that including STDP can significantly alter phase cohesion as compared to a network with static synaptic connections. Analytical results are validated numerically. Our analysis highlights the importance of the relative ordering of action potentials emitted in a population of tonically firing neurons and demonstrates that order switching can degrade the synchronizing influence of coupling when STDP is considered.


Assuntos
Plasticidade Neuronal , Neurônios , Potenciais de Ação
8.
J Acoust Soc Am ; 155(3): 1813-1824, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38445988

RESUMO

This study assessed whether the effects of contralateral acoustic stimulation (CAS) are consistent with eliciting the medial olivocochlear (MOC) reflex for measurements sensitive to outer hair cell (otoacoustic emissions, OAEs), auditory-nerve (AN; compound action potential, CAP), and brainstem/cortical (envelope-following response, EFR) function. The effects of CAS were evaluated for simultaneous measurement of OAEs, CAPs, and EFRs in participants with normal hearing. Clicks were presented at 40 or 98 Hz in three ipsilateral noise conditions (no noise, 45 dB SPL, and 55 dB SPL). For the no noise condition, CAS suppressed or enhanced EFR amplitudes for 40- and 98-Hz clicks, respectively, while CAS had no significant effect on CAP amplitudes. A follow-up experiment using slower rates (4.4-22.2 Hz) assessed whether this insignificant CAS effect on CAPs was from ipsilateral MOC stimulation or AN adaptation; however, CAS effects remained insignificant despite favorable signal-to-noise ratios. CAS-related enhancements of EFR and CAP amplitudes in ipsilateral noise were not observed, contrary to the anti-masking effect of the MOC reflex. EFR and OAE suppression from CAS were not significantly correlated. Thus, the effects of CAS on EFRs may not be solely mediated by the MOC reflex and may be partially mediated by higher auditory centers.


Assuntos
Potenciais Evocados , Emissões Otoacústicas Espontâneas , Humanos , Potenciais de Ação , Estimulação Acústica , Reflexo
9.
Front Neural Circuits ; 18: 1280604, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38505865

RESUMO

A feature of the brains of intelligent animals is the ability to learn to respond to an ensemble of active neuronal inputs with a behaviorally appropriate ensemble of active neuronal outputs. Previously, a hypothesis was proposed on how this mechanism is implemented at the cellular level within the neocortical pyramidal neuron: the apical tuft or perisomatic inputs initiate "guess" neuron firings, while the basal dendrites identify input patterns based on excited synaptic clusters, with the cluster excitation strength adjusted based on reward feedback. This simple mechanism allows neurons to learn to classify their inputs in a surprisingly intelligent manner. Here, we revise and extend this hypothesis. We modify synaptic plasticity rules to align with behavioral time scale synaptic plasticity (BTSP) observed in hippocampal area CA1, making the framework more biophysically and behaviorally plausible. The neurons for the guess firings are selected in a voluntary manner via feedback connections to apical tufts in the neocortical layer 1, leading to dendritic Ca2+ spikes with burst firing, which are postulated to be neural correlates of attentional, aware processing. Once learned, the neuronal input classification is executed without voluntary or conscious control, enabling hierarchical incremental learning of classifications that is effective in our inherently classifiable world. In addition to voluntary, we propose that pyramidal neuron burst firing can be involuntary, also initiated via apical tuft inputs, drawing attention toward important cues such as novelty and noxious stimuli. We classify the excitations of neocortical pyramidal neurons into four categories based on their excitation pathway: attentional versus automatic and voluntary/acquired versus involuntary. Additionally, we hypothesize that dendrites within pyramidal neuron minicolumn bundles are coupled via depolarization cross-induction, enabling minicolumn functions such as the creation of powerful hierarchical "hyperneurons" and the internal representation of the external world. We suggest building blocks to extend the microcircuit theory to network-level processing, which, interestingly, yields variants resembling the artificial neural networks currently in use. On a more speculative note, we conjecture that principles of intelligence in universes governed by certain types of physical laws might resemble ours.


Assuntos
Neocórtex , Sinapses , Animais , Potenciais de Ação/fisiologia , Sinapses/fisiologia , Células Piramidais/fisiologia , Dendritos/fisiologia , Neocórtex/fisiologia , Atenção
10.
PLoS Comput Biol ; 20(3): e1011846, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38489374

RESUMO

In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (NaVs) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of NaVs with gating properties that are "right-shifted" to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of NaV subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation, suggesting that the choice of orthodromic versus antidromic stimulation can bias or even invert experimental findings regarding the role of NaV subtypes in the AIS. We implemented a range of hypothetical NaV distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of NaV subtypes is varied. With axonal stimulation, proximal NaV availability dominates, such that concentrating right-shifted NaVs in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability kinetics. Instead, the higher activation threshold of right-shifted NaVs in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of NaV1.2 and NaV1.6 in the AIS differentially impact activation and availability. The observed effects on backpropagation, and potentially learning via its putative role in synaptic plasticity (e.g. through spike-timing-dependent plasticity), are opposite for orthodromic versus antidromic stimulation, which should inform hypotheses about the impact of the developmentally regulated subcellular localization of these NaV subtypes.


Assuntos
Segmento Inicial do Axônio , Canais de Sódio Disparados por Voltagem , Segmento Inicial do Axônio/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.6/ultraestrutura , Axônios/fisiologia , Neurônios/fisiologia , Potenciais de Ação/fisiologia
11.
Phys Rev E ; 109(2-1): 024406, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38491595

RESUMO

The construction of transfer functions in theoretical neuroscience plays an important role in determining the spiking rate behavior of neurons in networks. These functions can be obtained through various fitting methods, but the biological relevance of the parameters is not always clear. However, for stationary inputs, such functions can be obtained without the adjustment of free parameters by using mean-field methods. In this work, we expand current Fokker-Planck approaches to account for the concurrent influence of colored and multiplicative noise terms on generic conductance-based integrate-and-fire neurons. We reduce the resulting stochastic system through the application of the diffusion approximation to a one-dimensional Langevin equation. An effective Fokker-Planck is then constructed using Fox Theory, which is solved numerically using a newly developed double integration procedure to obtain the transfer function and the membrane potential distribution. The solution is capable of reproducing the transfer function and the stationary voltage distribution of simulated neurons across a wide range of parameters. The method can also be easily extended to account for different sources of noise with various multiplicative terms, and it can be used in other types of problems in principle.


Assuntos
Modelos Neurológicos , Neurônios , Neurônios/fisiologia , Potenciais da Membrana , Potenciais de Ação/fisiologia
12.
Phys Rev E ; 109(2-1): 024410, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38491656

RESUMO

Intracellular ions, including sodium (Na^{+}), calcium (Ca^{2+}), and potassium (K^{+}), etc., accumulate slowly after a change of the state of the heart, such as a change of the heart rate. The goal of this study is to understand the roles of slow ion accumulation in the genesis of cardiac memory and complex action-potential duration (APD) dynamics that can lead to lethal cardiac arrhythmias. We carry out numerical simulations of a detailed action potential model of ventricular myocytes under normal and diseased conditions, which exhibit memory effects and complex APD dynamics. We develop a low-dimensional iterated map (IM) model to describe the dynamics of Na^{+}, Ca^{2+}, and APD and use it to uncover the underlying dynamical mechanisms. The development of the IM model is informed by simulation results under the normal condition. We then use the IM model to perform linear stability analyses and computer simulations to investigate the bifurcations and complex APD dynamics, which depend on the feedback loops between APD and intracellular Ca^{2+} and Na^{+} concentrations and the steepness of the APD response to the ion concentrations. When the feedback between APD and Ca^{2+} concentration is positive, a Hopf bifurcation leading to periodic oscillatory behavior occurs as the steepness of the APD response to the ion concentrations increases. The negative feedback loop between APD and Na^{+} concentration is required for the Hopf bifurcation. When the feedback between APD and Ca^{2+} concentration is negative, period-doubling bifurcations leading to high periodicity and chaos occurs. In this case, Na^{+} accumulation plays little role in the dynamics. Finally, we carry out simulations of the detailed action potential model under two diseased conditions, which exhibit steep APD responses to ion concentrations. Under both conditions, Hopf bifurcations leading to slow oscillations or period-doubling bifurcations leading to high periodicity and chaotic APD dynamics occur, depending on the strength of the ion pump-Na^{+}-Ca^{2+} exchanger. Using functions reconstructed from the simulation data, the IM model accurately captures the bifurcations and dynamics under the two diseased conditions. In conclusion, besides using computer simulations of a detailed high-dimensional action-potential model to investigate the effects of slow ion accumulation and short-term memory on bifurcations and genesis of complex APD dynamics in cardiac myocytes under diseased conditions, this study also provides a low-dimensional mathematical tool, i.e., the IM model, to allow stability analyses for uncovering the underlying mechanisms.


Assuntos
Cardiopatias , Modelos Cardiovasculares , Humanos , Potenciais de Ação/fisiologia , Miócitos Cardíacos , Íons
13.
Phys Rev E ; 109(2-1): 024407, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38491664

RESUMO

The steady-state firing rate and firing-rate response of the leaky and exponential integrate-and-fire models receiving synaptic shot noise with excitatory and inhibitory reversal potentials is examined. For the particular case where the underlying synaptic conductances are exponentially distributed, it is shown that the master equation for a population of such model neurons can be reduced from an integrodifferential form to a more tractable set of three differential equations. The system is nevertheless more challenging analytically than for current-based synapses: where possible, analytical results are provided with an efficient numerical scheme and code provided for other quantities. The increased tractability of the framework developed supports an ongoing critical comparison between models in which synapses are treated with and without reversal potentials, such as recently in the context of networks with balanced excitatory and inhibitory conductances.


Assuntos
Modelos Neurológicos , Neurônios , Potenciais de Ação/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Ruído , Simulação por Computador
14.
PLoS Comput Biol ; 20(3): e1011874, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38437226

RESUMO

The biophysical properties of neurons not only affect how information is processed within cells, they can also impact the dynamical states of the network. Specifically, the cellular dynamics of action-potential generation have shown relevance for setting the (de)synchronisation state of the network. The dynamics of tonically spiking neurons typically fall into one of three qualitatively distinct types that arise from distinct mathematical bifurcations of voltage dynamics at the onset of spiking. Accordingly, changes in ion channel composition or even external factors, like temperature, have been demonstrated to switch network behaviour via changes in the spike onset bifurcation and hence its associated dynamical type. A thus far less addressed modulator of neuronal dynamics is cellular morphology. Based on simplified and anatomically realistic mathematical neuron models, we show here that the extent of dendritic arborisation has an influence on the neuronal dynamical spiking type and therefore on the (de)synchronisation state of the network. Specifically, larger dendritic trees prime neuronal dynamics for in-phase-synchronised or splayed-out activity in weakly coupled networks, in contrast to cells with otherwise identical properties yet smaller dendrites. Our biophysical insights hold for generic multicompartmental classes of spiking neuron models (from ball-and-stick-type to anatomically reconstructed models) and establish a connection between neuronal morphology and the susceptibility of neural tissue to synchronisation in health and disease.


Assuntos
Modelos Neurológicos , Neurônios , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Canais Iônicos/fisiologia , Biofísica
15.
J Neurosci ; 44(11)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38479812

RESUMO

The axon is a neuronal structure capable of processing, encoding, and transmitting information. This assessment contrasts with a limiting, but deeply rooted, perspective where the axon functions solely as a transmission cable of somatodendritic activity, sending signals in the form of stereotypical action potentials. This perspective arose, at least partially, because of the technical difficulties in probing axons: their extreme length-to-diameter ratio and intricate growth paths preclude the study of their dynamics through traditional techniques. Recent findings are challenging this view and revealing a much larger repertoire of axonal computations. Axons display complex signaling processes and structure-function relationships, which can be modulated via diverse activity-dependent mechanisms. Additionally, axons can exhibit patterns of activity that are dramatically different from those of their corresponding soma. Not surprisingly, many of these recent discoveries have been driven by novel technology developments, which allow for in vitro axon electrophysiology with unprecedented spatiotemporal resolution and signal-to-noise ratio. In this review, we outline the state-of-the-art in vitro toolset for axonal electrophysiology and summarize the recent discoveries in axon function it has enabled. We also review the increasing repertoire of microtechnologies for controlling axon guidance which, in combination with the available cutting-edge electrophysiology and imaging approaches, have the potential for more controlled and high-throughput in vitro studies. We anticipate that a larger adoption of these new technologies by the neuroscience community will drive a new era of experimental opportunities in the study of axon physiology and consequently, neuronal function.


Assuntos
Axônios , Neurônios , Axônios/fisiologia , Potenciais de Ação/fisiologia , Fenômenos Eletrofisiológicos , Eletrofisiologia
16.
Sci Rep ; 14(1): 6761, 2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514708

RESUMO

Voltage-gated sodium channels (NaV) are pivotal proteins responsible for initiating and transmitting action potentials. Emerging evidence suggests that proteolytic cleavage of sodium channels by calpains is pivotal in diverse physiological scenarios, including ischemia, brain injury, and neuropathic pain associated with diabetes. Despite this significance, the precise mechanism by which calpains recognize sodium channels, especially given the multiple calpain isoforms expressed in neurons, remains elusive. In this work, we show the interaction of Calpain-10 with NaV's C-terminus through a yeast 2-hybrid assay screening of a mouse brain cDNA library and in vitro by GST-pulldown. Later, we also obtained a structural and dynamic hypothesis of this interaction by modeling, docking, and molecular dynamics simulation. These results indicate that Calpain-10 interacts differentially with the C-terminus of NaV1.2 and NaV1.6. Calpain-10 interacts with NaV1.2 through domains III and T in a stable manner. In contrast, its interaction with NaV1.6 involves domains II and III, which could promote proteolysis through the Cys-catalytic site and C2 motifs.


Assuntos
Calpaína , Canais de Sódio Disparados por Voltagem , Camundongos , Animais , Calpaína/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Isoformas de Proteínas/metabolismo , Neurônios/metabolismo , Potenciais de Ação
17.
Arq Bras Cardiol ; 121(1): e20230179, 2024.
Artigo em Português, Inglês | MEDLINE | ID: mdl-38451560

RESUMO

BACKGROUND: Prolongation of the PQ interval, generally associated with an atrioventricular conduction delay, may be related to changes in intraventricular impulse spreading. OBJECTIVE: To assess, using body surface potential mapping (BSPM), the process of ventricular depolarization in athletes with prolonged PQ intervals at rest and after exercise. METHODS: The study included 7 cross-country skiers with a PQ interval of more than 200 ms (Prolonged-PQ group) and 7 with a PQ interval of less than 200 ms (Normal-PQ group). The BSPM from 64 unipolar torso leads was performed before (Pre-Ex) and after the bicycle exercise test (Post-Ex). Body surface equipotential maps were analyzed during ventricular depolarization. The significance level was 5%. RESULTS: Compared to Normal-PQ athletes, the first and second periods of the stable position of cardiac potentials on the torso surface were longer, and the formation of the "saddle" potential distribution occurred later, at Pre-Ex, in Prolonged-PQ athletes. At Post-Ex, the Prolonged-PQ group showed a shortening of the first and second periods of stable potential distributions and a decrease in appearance time of the "saddle" phenomenon relative to Pre-Ex (to the values near to those of the Normal-PQ group). Additionally, at Post-Ex, the first inversion of potential distributions and the total duration of ventricular depolarization in Prolonged-PQ athletes decreased compared to Pre-Ex and with similar values in Normal-PQ athletes. Compared to Normal-PQ athletes, the second inversion was longer at Pre-Ex and Post-Ex in Prolonged-PQ athletes. CONCLUSION: Prolonged-PQ athletes had significant differences in the temporal characteristics of BSPM during ventricular depolarization both at rest and after exercise as compared to Normal-PQ athletes.


FUNDAMENTO: O prolongamento do intervalo PQ, geralmente associado a um atraso na condução atrioventricular, pode estar relacionado a alterações na propagação do impulso intraventricular. OBJETIVO: Avaliar, por meio do mapeamento do potencial de superfície corporal (BSPM), o processo de despolarização ventricular em atletas com intervalos PQ prolongados em repouso e após o exercício. MÉTODOS: O estudo incluiu 7 esquiadores cross-country com intervalo PQ superior a 200 ms (grupo PQ Prolongado) e 7 com intervalo PQ inferior a 200 ms (grupo PQ Normal). O BSPM de 64 derivações unipolares do tronco foi realizado antes (Pré-Ex) e após o teste ergométrico de bicicleta (Pós-Ex). Mapas equipotenciais da superfície corporal foram analisados durante a despolarização ventricular. O nível de significância foi de 5%. RESULTADOS: Comparado com atletas com PQ Normal, o primeiro e o segundo períodos de posição estável dos potenciais cardíacos na superfície do tronco foram mais longos, e a formação da distribuição de potencial "sela" ocorreu mais tarde, no Pré-Ex, nos atletas com PQ Prolongado. No Pós-Ex, o grupo PQ Prolongado apresentou um encurtamento do primeiro e segundo períodos de distribuições de potencial estáveis e uma diminuição no tempo de aparecimento do fenômeno "sela" em relação ao Pré-Ex (para valores próximos aos do Normal -Grupo PQ). Além disso, no Pós-Ex, a primeira inversão das distribuições de potencial e a duração total da despolarização ventricular em atletas com PQ Prolongado diminuíram em comparação com o Pré-Ex e com valores semelhantes em atletas com PQ Normal. Em comparação com atletas com PQ Normal, a segunda inversão foi mais longa no Pré-Ex e Pós-Ex em atletas com PQ Prolongado. CONCLUSÃO: Atletas com PQ prolongado apresentaram diferenças significativas nas características temporais do BSPM durante a despolarização ventricular, tanto em repouso quanto após o exercício, em comparação com atletas com PQ normal.


Assuntos
Mapeamento Potencial de Superfície Corporal , Exercício Físico , Humanos , Potenciais de Ação , Coração , Atletas
18.
Nat Neurosci ; 27(3): 390, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38454059
19.
Sci Rep ; 14(1): 5817, 2024 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461365

RESUMO

There is an increasing need to implement neuromorphic systems that are both energetically and computationally efficient. There is also great interest in using electric elements with memory, memelements, that can implement complex neuronal functions intrinsically. A feature not widely incorporated in neuromorphic systems is history-dependent action potential time adaptation which is widely seen in real cells. Previous theoretical work shows that power-law history dependent spike time adaptation, seen in several brain areas and species, can be modeled with fractional order differential equations. Here, we show that fractional order spiking neurons can be implemented using super-capacitors. The super-capacitors have fractional order derivative and memcapacitive properties. We implemented two circuits, a leaky integrate and fire and a Hodgkin-Huxley. Both circuits show power-law spiking time adaptation and optimal coding properties. The spiking dynamics reproduced previously published computer simulations. However, the fractional order Hodgkin-Huxley circuit showed novel dynamics consistent with criticality. We compared the responses of this circuit to recordings from neurons in the weakly-electric fish that have previously been shown to perform fractional order differentiation of their sensory input. The criticality seen in the circuit was confirmed in spontaneous recordings in the live fish. Furthermore, the circuit also predicted long-lasting stimulation that was also corroborated experimentally. Our work shows that fractional order memcapacitors provide intrinsic memory dependence that could allow implementation of computationally efficient neuromorphic devices. Memcapacitors are static elements that consume less energy than the most widely studied memristors, thus allowing the realization of energetically efficient neuromorphic devices.


Assuntos
Encéfalo , Neurônios , Animais , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Simulação por Computador , Encéfalo/fisiologia
20.
Phys Biol ; 21(2)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38382117

RESUMO

Dopaminergic neurons are specialized cells in the substantia nigra, tasked with dopamine secretion. This secretion relies on intracellular calcium signaling coupled to neuronal electrical activity. These neurons are known to display spontaneous calcium oscillationsin-vitroandin-vivo, even in synaptic isolation, controlling the basal dopamine levels. Here we outline a kinetic model for the ion exchange across the neuronal plasma membrane. Crucially, we relax the assumption of constant, cytoplasmic sodium and potassium concentration. We show that sodium-potassium dynamics are strongly coupled to calcium dynamics and are essential for the robustness of spontaneous firing frequency. The model predicts several regimes of electrical activity, including tonic and 'burst' oscillations, and predicts the switch between those in response to perturbations. 'Bursting' correlates with increased calcium amplitudes, while maintaining constant average, allowing for a vast change in the calcium signal responsible for dopamine secretion. All the above traits provide the flexibility to create rich action potential dynamics that are crucial for cellular function.


Assuntos
Cálcio , Neurônios Dopaminérgicos , Potenciais de Ação , Dopamina , Sinalização do Cálcio , Potássio , Sódio
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