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1.
Nat Commun ; 11(1): 1017, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094367

RESUMO

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Potenciais de Ação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Dendritos/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Feminino , Giro do Cíngulo/citologia , Giro do Cíngulo/patologia , Humanos , Interneurônios/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Células Piramidais/metabolismo , Somatostatina/metabolismo , Técnicas Estereotáxicas , Tálamo/citologia , Tálamo/metabolismo
2.
Nat Commun ; 11(1): 1102, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107370

RESUMO

Auditory cortex neurons nonlinearly integrate synaptic inputs from the thalamus and cortex, and generate spiking outputs for simple and complex sounds. Directly comparing synaptic and spiking activity can determine whether this input-output transformation is stimulus-dependent. We employ in vivo whole-cell recordings in the mouse primary auditory cortex, using pure tones and broadband dynamic moving ripple stimuli, to examine properties of functional integration in tonal (TRFs) and spectrotemporal (STRFs) receptive fields. Spectral tuning in STRFs derived from synaptic, subthreshold and spiking responses proves to be substantially more selective than for TRFs. We describe diverse spectral and temporal modulation preferences and distinct nonlinearities, and their modifications between the input and output stages of neural processing. These results characterize specific processing differences at the level of synaptic convergence, integration and spike generation resulting in stimulus-dependent transformation patterns in the primary auditory cortex.


Assuntos
Potenciais de Ação/fisiologia , Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Estimulação Acústica , Animais , Eletrodos Implantados , Feminino , Camundongos , Modelos Neurológicos , Rede Nervosa/fisiologia , Técnicas de Patch-Clamp , Técnicas Estereotáxicas , Sinapses/fisiologia
3.
Nat Commun ; 11(1): 1105, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107381

RESUMO

Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.


Assuntos
Astrócitos/fisiologia , Técnicas de Reprogramação Celular/métodos , Corpo Estriado/patologia , Neurônios GABAérgicos/fisiologia , Terapia Genética/métodos , Doença de Huntington/terapia , Potenciais de Ação/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Técnicas de Observação do Comportamento , Comportamento Animal , Corpo Estriado/citologia , Dependovirus/genética , Modelos Animais de Doenças , Expressão Ectópica do Gene , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Células HEK293 , Proteínas de Homeodomínio , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Longevidade , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Técnicas Estereotáxicas , Fatores de Transcrição
4.
PLoS One ; 15(2): e0229083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32092107

RESUMO

Learning synaptic weights of spiking neural network (SNN) models that can reproduce target spike trains from provided neural firing data is a central problem in computational neuroscience and spike-based computing. The discovery of the optimal weight values can be posed as a supervised learning task wherein the weights of the model network are chosen to maximize the similarity between the target spike trains and the model outputs. It is still largely unknown whether optimizing spike train similarity of highly recurrent SNNs produces weight matrices similar to those of the ground truth model. To this end, we propose flexible heuristic supervised learning rules, termed Pre-Synaptic Pool Modification (PSPM), that rely on stochastic weight updates in order to produce spikes within a short window of the desired times and eliminate spikes outside of this window. PSPM improves spike train similarity for all-to-all SNNs and makes no assumption about the post-synaptic potential of the neurons or the structure of the network since no gradients are required. We test whether optimizing for spike train similarity entails the discovery of accurate weights and explore the relative contributions of local and homeostatic weight updates. Although PSPM improves similarity between spike trains, the learned weights often differ from the weights of the ground truth model, implying that connectome inference from spike data may require additional constraints on connectivity statistics. We also find that spike train similarity is sensitive to local updates, but other measures of network activity such as avalanche distributions, can be learned through synaptic homeostasis.


Assuntos
Conectoma/métodos , Modelos Neurológicos , Rede Nervosa/fisiologia , Aprendizado de Máquina Supervisionado , Potenciais de Ação/fisiologia , Animais , Simulação por Computador , Terminações Pré-Sinápticas/fisiologia
5.
PLoS One ; 15(1): e0224057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910219

RESUMO

There have been relatively few studies of how central synapses age in adult Drosophila melanogaster. In this study we investigate the aging of the synaptic inputs to the Giant Fiber (GF) from auditory Johnston's Organ neurons (JONs). In previously published experiments an indirect assay of this synaptic connection was used; here we describe a new, more direct assay, which allows reliable detection of the GF action potential in the neck connective, and long term recording of its responses to sound. Genetic poisoning using diphtheria toxin expressed in the GF with R68A06-GAL4 was used to confirm that this signal indeed arose from the GF and not from other descending neurons. As before, the sound-evoked action potentials (SEPs) in the antennal nerve were recorded via an electrode inserted at the base of the antenna. It was noted that an action potential in the GF elicited an antennal twitch, which in turn evoked a mechanosensory response from the JONs in the absence of sound. We then used these extracellular recording techniques in males and female of different ages to quantify the response of the JONs to a brief sound impulse, and also to measure the strength of the connection between the JONs and the GF. At no age was there any significant difference between males and females, for any of the parameters measured. The sensitivity of the JONs to a sound impulse approximately doubled between 1 d and 10 d after eclosion, which corresponds to the period when most mating is taking place. Subsequently JON sensitivity decreased with age, being approximately half as sensitive at 20 d and one-third as sensitive at 50 d, as compared to 10 d. However, the strength of the connection between the auditory input and the GF itself remained unchanged with age, although it did show some variability that could mask any small changes.


Assuntos
Percepção Auditiva/genética , Mecanorreceptores/fisiologia , Neurônios/fisiologia , Sinapses/genética , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Animais Geneticamente Modificados , Antenas de Artrópodes/fisiologia , Vias Auditivas/fisiologia , Percepção Auditiva/fisiologia , Toxina Diftérica/farmacologia , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Masculino , Mecanorreceptores/metabolismo , Células Receptoras Sensoriais/fisiologia , Som , Sinapses/fisiologia
6.
Am J Physiol Heart Circ Physiol ; 318(2): H391-H400, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922881

RESUMO

Ventricular fibrillation (VF) during acute myocardial infarction (AMI) is an important contributor to sudden cardiac death. Large animal models are widely used to study AMI-induced arrhythmia, but the mode of AMI induction ranges from thoracotomy and surgical ligation of a coronary vessel (open chest) to minimally invasive techniques, including balloon occlusion (closed chest). How the choice of induction affects arrhythmia development is unclear. The aim of this study was to compare an open-chest and a closed-chest model with regard to hemodynamics, electrophysiology, and arrhythmia development. Forty-two female Danish Landrace pigs (20 open chest, 22 closed chest) were anesthetized, and occlusion of the mid-left anterior descending coronary artery was performed for 60 min. Opening the chest reduced blood pressure and cardiac output (Δ -22 mmHg, Δ -1.5 L/min from baseline, both P < 0.001 intragroup). Heart rate decreased with opening of the chest but increased with balloon placement (P < 0.001). AMI-induced ST elevation was lower in the open-chest group (P < 0.001). Premature ventricular contractions occurred in two distinct phases (0-15 and 15-40 min), the latter of which was delayed in the open-chest group (P = 0.005). VF occurred in 7 out of 20 and 12 out of 22 pigs in the open-chest and closed-chest groups, respectively (P = 0.337), with longer time-to-VF in the open-chest group (23.4 ± 1.2 min in open chest and 17.8 ± 1.4 min in closed chest; P = 0.007). In summary, opening the chest altered hemodynamic parameters and delayed the onset of ventricular arrhythmias. Hence, in the search for mechanisms and novel treatments of AMI-induced arrhythmia, caution should be taken when choosing between or comparing the results from these two models.NEW & NOTEWORTHY We demonstrated pronounced differences in hemodynamic parameters and time course of ventricular arrhythmias in regard to mode of infarct induction. Inducing myocardial infarction by thoracotomy and subsequent ligation decreased blood pressure and cardiac output and delayed the onset of ventricular arrhythmia, whereas balloon occlusion resulted in higher heart rates during infarct.


Assuntos
Arritmias Cardíacas/fisiopatologia , Eletrocardiografia , Coração/fisiopatologia , Hemodinâmica , Infarto do Miocárdio/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas , Feminino , Contração Miocárdica , Suínos , Taquicardia Ventricular/fisiopatologia , Complexos Ventriculares Prematuros/fisiopatologia
7.
Proc Natl Acad Sci U S A ; 117(6): 3192-3202, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974304

RESUMO

The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential-a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.


Assuntos
Córtex Cerebral , Interneurônios , Inibição Neural/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Interneurônios/citologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Cinética , Camundongos , Modelos Neurológicos , Técnicas de Patch-Clamp
8.
Proc Natl Acad Sci U S A ; 117(6): 3232-3238, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31988119

RESUMO

Theories of cerebellar functions posit that the cerebellum implements internal models for online correction of motor actions and sensory estimation. As an example of such computations, an internal model resolves a sensory ambiguity where the peripheral otolith organs in the inner ear sense both head tilts and translations. Here we exploit the response dynamics of two functionally coupled Purkinje cell types in the vestibular part of the caudal vermis (lobules IX and X) to understand their role in this computation. We find that one population encodes tilt velocity, whereas the other, translation-selective, population encodes linear acceleration. We predict that an intermediate neuronal type should temporally integrate the output of tilt-selective cells into a tilt position signal.


Assuntos
Potenciais de Ação/fisiologia , Vermis Cerebelar , Movimento/fisiologia , Células de Purkinje/fisiologia , Animais , Vermis Cerebelar/citologia , Vermis Cerebelar/fisiologia , Macaca , Masculino , Postura/fisiologia , Rotação , Vestíbulo do Labirinto/fisiologia
9.
PLoS Comput Biol ; 16(1): e1007606, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961853

RESUMO

Learning to produce spatiotemporal sequences is a common task that the brain has to solve. The same neurons may be used to produce different sequential behaviours. The way the brain learns and encodes such tasks remains unknown as current computational models do not typically use realistic biologically-plausible learning. Here, we propose a model where a spiking recurrent network of excitatory and inhibitory spiking neurons drives a read-out layer: the dynamics of the driver recurrent network is trained to encode time which is then mapped through the read-out neurons to encode another dimension, such as space or a phase. Different spatiotemporal patterns can be learned and encoded through the synaptic weights to the read-out neurons that follow common Hebbian learning rules. We demonstrate that the model is able to learn spatiotemporal dynamics on time scales that are behaviourally relevant and we show that the learned sequences are robustly replayed during a regime of spontaneous activity.


Assuntos
Potenciais de Ação/fisiologia , Aprendizagem/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Biologia Computacional , Simulação por Computador , Fatores de Tempo
10.
Am J Physiol Heart Circ Physiol ; 318(3): H534-H546, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951472

RESUMO

Computational modeling based on experimental data remains an important component in cardiac electrophysiological research, especially because clinical data such as human action potential (AP) dynamics are scarce or limited by practical or ethical concerns. Such modeling has been used to develop and test a variety of mechanistic hypotheses, with the majority of these studies involving the rate dependence of AP duration (APD) including APD restitution and conduction velocity (CV). However, there is very little information regarding the complex dynamics at the boundary of repolarization (or refractoriness) and reexcitability. Here, we developed a "minimal" ionic model of the human AP, based on in vivo human monophasic AP (MAP) recordings obtained during clinical programmed electrical stimulation (PES) to address the progressive decrease in AP take-off potential (TOP) and associated CV slowing seen during three tightly spaced extrastimuli. Recent voltage-clamp data demonstrating the effect of intracellular calcium on sodium current availability were incorporated and were required to reproduce large (>15 mV) elevations in take-off potential and progressive encroachment. Introducing clinically observed APD gradients into the model enabled us to replicate the dynamic response to PES in patients leading to conduction block and reentry formation for the positive, but not the negative, APD gradient. Finally, we modeled the dynamics of reentry and show that spiral waves follow a meandering trajectory with a period of ~180 ms. We conclude that our model reproduces a variety of electrophysiological behavior including the response to sequential premature stimuli and provides a basis for studies of the initiation of reentry in human ventricular tissue.NEW & NOTEWORTHY This work presents a new model of the action potential of the human which reproduces the complex dynamics during premature stimulation in patients.


Assuntos
Potenciais de Ação/fisiologia , Simulação por Computador , Modelos Cardiovasculares , Miócitos Cardíacos/fisiologia , Função Ventricular/fisiologia , Arritmias Cardíacas/fisiopatologia , Estimulação Elétrica , Frequência Cardíaca/fisiologia , Ventrículos do Coração/fisiopatologia , Humanos
11.
Am J Physiol Heart Circ Physiol ; 318(3): H485-H507, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951471

RESUMO

Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and ß-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to ß-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the ß-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.


Assuntos
Potenciais de Ação/fisiologia , Função Atrial/fisiologia , Simulação por Computador , Átrios do Coração/citologia , Modelos Cardiovasculares , Miócitos Cardíacos/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Camundongos , Miócitos Cardíacos/citologia
12.
Am J Physiol Heart Circ Physiol ; 318(3): H558-H565, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31975627

RESUMO

Cardiac sympathetic nerves undergo cholinergic transdifferentiation following reperfused myocardial infarction (MI), whereby the sympathetic nerves release both norepinephrine (NE) and acetylcholine (ACh). The functional electrophysiological consequences of post-MI transdifferentiation have never been explored. We performed MI or sham surgery in wild-type (WT) mice and mice in which choline acetyltransferase was deleted from adult noradrenergic neurons [knockout (KO)]. Electrophysiological activity was assessed with optical mapping of action potentials (AP) and intracellular Ca2+ transients (CaT) in innervated Langendorff-perfused hearts. KO MI hearts had similar NE content but reduced ACh content compared with WT MI hearts (0.360 ± 0.074 vs. 0.493 ± 0.087 pmol/mg; KO, n = 6; WT, n = 4; P < 0.05). KO MI hearts also had higher basal ex vivo heart rates versus WT MI hearts (328.5 ± 35.3 vs. 247.4 ± 62.4 beats/min; KO, n = 8; WT, n = 6; P < 0.05). AP duration at 80% repolarization was significantly shorter in the remote and border zones of KO MI versus WT MI hearts, whereas AP durations (APDs) were similar in infarct regions. This APD heterogeneity resulted in increased APD dispersion in the KO MI versus WT MI hearts (11.9 ± 2.7 vs. 8.2 ± 2.3 ms; KO, n = 8; WT, n = 6; P < 0.05), which was eliminated with atropine. CaT duration at 80% and CaT alternans magnitude were similar between groups both with and without sympathetic nerve stimulation. These results indicate that cholinergic transdifferentiation following MI prolongs APD in the remote and border zone and reduces APD heterogeneity.NEW & NOTEWORTHY Cardiac sympathetic neurons undergo cholinergic transdifferentiation following myocardial infarction; however, the electrophysiological effects of corelease of norepinephrine and acetylcholine (ACh) have never been assessed. Using a mouse model in which choline acetyltransferase was deleted from adult noradrenergic neurons and optical mapping of innervated hearts, we found that corelease of ACh reduces dispersion of action potential duration, which may be antiarrhythmic.


Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Transdiferenciação Celular/fisiologia , Neurônios Colinérgicos/metabolismo , Infarto do Miocárdio/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Neurônios Adrenérgicos/metabolismo , Animais , Colina O-Acetiltransferase/genética , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Coração/inervação , Camundongos , Camundongos Knockout , Infarto do Miocárdio/metabolismo
13.
Muscle Nerve ; 61(4): 491-495, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31944327

RESUMO

INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.


Assuntos
Potenciais de Ação/fisiologia , Eletrodiagnóstico/métodos , Músculo Esquelético/fisiopatologia , Miotonia Congênita/diagnóstico , Nervo Ulnar/fisiopatologia , Estimulação Elétrica , Eletromiografia , Teste de Esforço , Feminino , Humanos , Masculino , Mutação , Miotonia Congênita/genética , Miotonia Congênita/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
14.
Nat Commun ; 11(1): 512, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980605

RESUMO

Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that INa is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Neurônios/metabolismo , Nó Sinoatrial/fisiopatologia , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Adulto , Idoso , Alcoolismo/genética , Arritmias Cardíacas/genética , Doença Crônica , Simulação por Computador , Feminino , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/metabolismo , Insuficiência Cardíaca/genética , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Imagem Óptica , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Nó Sinoatrial/metabolismo , Canais de Sódio/genética , Estresse Fisiológico , Adulto Jovem
15.
Nat Commun ; 11(1): 505, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980628

RESUMO

Internal brain states strongly modulate sensory processing during behaviour. Studies of visual processing in primates show that attention to space selectively improves behavioural and neural responses to stimuli at the attended locations. Here we develop a visual spatial task for mice that elicits behavioural improvements consistent with the effects of spatial attention, and simultaneously measure network, cellular, and subthreshold activity in primary visual cortex. During trial-by-trial behavioural improvements, local field potential (LFP) responses to stimuli detected inside the receptive field (RF) strengthen. Moreover, detection inside the RF selectively enhances excitatory and inhibitory neuron responses to task-irrelevant stimuli and suppresses noise correlations and low frequency LFP fluctuations. Whole-cell patch-clamp recordings reveal that detection inside the RF increases synaptic activity that depolarizes membrane potential responses at the behaviorally relevant location. Our study establishes that mice display fundamental signatures of visual spatial attention spanning behavioral, network, cellular, and synaptic levels, providing new insight into rapid cognitive enhancement of sensory signals in visual cortex.


Assuntos
Atenção/fisiologia , Limiar Sensorial/fisiologia , Percepção Espacial/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação/fisiologia , Animais , Nível de Alerta/fisiologia , Comportamento Animal/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Motivação , Neurônios/fisiologia , Estimulação Luminosa , Pupila/fisiologia , Análise e Desempenho de Tarefas , Campos Visuais/fisiologia
16.
DNA Cell Biol ; 39(2): 289-298, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916853

RESUMO

TBX3 reprograms cardiac myocytes into cells that possess sinoatrial node phenotype, but no specific funny current (If) was detected. We explore whether overexpression of TBX3 alone or combined with HCN2 can reprogram human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) into pacemaker-like cells. HiPSC-CMs were transfected with TBX3 and/or HCN2 in this study. Expression analysis showed that overexpression of TBX3 induces a reduced reduction expression profile of working cardiomyocytes into that of pacemaker cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and electrophysiological analyses showed a reduced expression of connexins subunits (CX40, CX43), the sodium current (SCN5A, INa), the inward rectified potassium channels (Kir2.1, IK1), and an increased expression of connexins subunits (CX30.2, CX45). No If was detected. The reduction of IK1 resulted in a more depolarized maximum diastolic potential together with an expression of If (generated by HCN2), which they work in synergy to generate spontaneous diastolic depolarization that was the most typical characteristic of pacemaker cells. In conclusion, overexpression of TBX3 and HCN2 could reprogram hiPSC-CMs into pacemaker-like cells. The ability to enable diastolic depolarization formation provides a new strategy for the construction of a biological pacemaker.


Assuntos
Diferenciação Celular/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Canais de Potássio/genética , Proteínas com Domínio T/genética , Potenciais de Ação/fisiologia , Relógios Biológicos/genética , Humanos , Miócitos Cardíacos/metabolismo
17.
Neural Netw ; 121: 88-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31536902

RESUMO

Applications that generate huge amounts of data in the form of fast streams are becoming increasingly prevalent, being therefore necessary to learn in an online manner. These conditions usually impose memory and processing time restrictions, and they often turn into evolving environments where a change may affect the input data distribution. Such a change causes that predictive models trained over these stream data become obsolete and do not adapt suitably to new distributions. Specially in these non-stationary scenarios, there is a pressing need for new algorithms that adapt to these changes as fast as possible, while maintaining good performance scores. Unfortunately, most off-the-shelf classification models need to be retrained if they are used in changing environments, and fail to scale properly. Spiking Neural Networks have revealed themselves as one of the most successful approaches to model the behavior and learning potential of the brain, and exploit them to undertake practical online learning tasks. Besides, some specific flavors of Spiking Neural Networks can overcome the necessity of retraining after a drift occurs. This work intends to merge both fields by serving as a comprehensive overview, motivating further developments that embrace Spiking Neural Networks for online learning scenarios, and being a friendly entry point for non-experts.


Assuntos
Potenciais de Ação/fisiologia , Educação a Distância/métodos , Redes Neurais de Computação , Neurônios/fisiologia , Algoritmos , Encéfalo/citologia , Encéfalo/fisiologia , Humanos , Modelos Neurológicos
18.
Neural Netw ; 121: 169-185, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31568895

RESUMO

OBJECTIVE: This paper argues that Brain-Inspired Spiking Neural Network (BI-SNN) architectures can learn and reveal deep in time-space functional and structural patterns from spatio-temporal data. These patterns can be represented as deep knowledge, in a partial case in the form of deep spatio-temporal rules. This is a promising direction for building new types of Brain-Computer Interfaces called Brain-Inspired Brain-Computer Interfaces (BI-BCI). A theoretical framework and its experimental validation on deep knowledge extraction and representation using SNN are presented. RESULTS: The proposed methodology was applied in a case study to extract deep knowledge of the functional and structural organisation of the brain's neural network during the execution of a Grasp and Lift task. The BI-BCI successfully extracted the neural trajectories that represent the dorsal and ventral visual information processing streams as well as its connection to the motor cortex in the brain. Deep spatiotemporal rules on functional and structural interaction of distinct brain areas were then used for event prediction in BI-BCI. SIGNIFICANCE: The computational framework can be used for unveiling the topological patterns of the brain and such knowledge can be effectively used to enhance the state-of-the-art in BCI.


Assuntos
Potenciais de Ação/fisiologia , Interfaces Cérebro-Computador , Encéfalo/fisiologia , Aprendizado Profundo , Redes Neurais de Computação , Interfaces Cérebro-Computador/tendências , Cognição/fisiologia , Aprendizado Profundo/tendências , Eletroencefalografia/métodos , Humanos
19.
Neural Netw ; 121: 242-258, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31581065

RESUMO

We present a framework based on iterative free-energy optimization with spiking neural networks for modeling the fronto-striatal system (PFC-BG) for the generation and recall of audio memory sequences. In line with neuroimaging studies carried out in the PFC, we propose a genuine coding strategy using the gain-modulation mechanism to represent abstract sequences based solely on the rank and location of items within them. Based on this mechanism, we show that we can construct a repertoire of neurons sensitive to the temporal structure in sequences from which we can represent any novel sequences. Free-energy optimization is then used to explore and to retrieve the missing indices of the items in the correct order for executive control and compositionality. We show that the gain-modulation mechanism permits the network to be robust to variabilities and to have long-term dependencies as it implements a gated recurrent neural network. This model, called Inferno Gate, is an extension of the neural architecture Inferno standing for Iterative Free-Energy Optimization of Recurrent Neural Networks with Gating or Gain-modulation. In experiments performed with an audio database of ten thousand MFCC vectors, Inferno Gate is capable of encoding efficiently and retrieving chunks of fifty items length. We then discuss the potential of our network to model the features of working memory in the PFC-BG loop for structural learning, goal-direction and hierarchical reinforcement learning.


Assuntos
Potenciais de Ação/fisiologia , Aprendizagem/fisiologia , Memória de Curto Prazo/fisiologia , Redes Neurais de Computação , Córtex Pré-Frontal/fisiologia , Humanos , Rememoração Mental/fisiologia , Neurônios/fisiologia , Reforço Psicológico
20.
Neural Netw ; 121: 294-307, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31586857

RESUMO

Artificial neural networks (ANNs), a popular path towards artificial intelligence, have experienced remarkable success via mature models, various benchmarks, open-source datasets, and powerful computing platforms. Spiking neural networks (SNNs), a category of promising models to mimic the neuronal dynamics of the brain, have gained much attention for brain inspired computing and been widely deployed on neuromorphic devices. However, for a long time, there are ongoing debates and skepticisms about the value of SNNs in practical applications. Except for the low power attribute benefit from the spike-driven processing, SNNs usually perform worse than ANNs especially in terms of the application accuracy. Recently, researchers attempt to address this issue by borrowing learning methodologies from ANNs, such as backpropagation, to train high-accuracy SNN models. The rapid progress in this domain continuously produces amazing results with ever-increasing network size, whose growing path seems similar to the development of deep learning. Although these ways endow SNNs the capability to approach the accuracy of ANNs, the natural superiorities of SNNs and the way to outperform ANNs are potentially lost due to the use of ANN-oriented workloads and simplistic evaluation metrics. In this paper, we take the visual recognition task as a case study to answer the questions of "what workloads are ideal for SNNs and how to evaluate SNNs makes sense". We design a series of contrast tests using different types of datasets (ANN-oriented and SNN-oriented), diverse processing models, signal conversion methods, and learning algorithms. We propose comprehensive metrics on the application accuracy and the cost of memory & compute to evaluate these models, and conduct extensive experiments. We evidence the fact that on ANN-oriented workloads, SNNs fail to beat their ANN counterparts; while on SNN-oriented workloads, SNNs can fully perform better. We further demonstrate that in SNNs there exists a trade-off between the application accuracy and the execution cost, which will be affected by the simulation time window and firing threshold. Based on these abundant analyses, we recommend the most suitable model for each scenario. To the best of our knowledge, this is the first work using systematical comparisons to explicitly reveal that the straightforward workload porting from ANNs to SNNs is unwise although many works are doing so and a comprehensive evaluation indeed matters. Finally, we highlight the urgent need to build a benchmarking framework for SNNs with broader tasks, datasets, and metrics.


Assuntos
Potenciais de Ação/fisiologia , Inteligência Artificial , Redes Neurais de Computação , Reconhecimento Automatizado de Padrão/métodos , Algoritmos , Encéfalo/fisiologia , Humanos , Memória/fisiologia , Neurônios/fisiologia
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