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1.
Cardiovasc Ther ; 2020: 3480276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565909

RESUMO

Wenxin Keli (WXKL) is a traditional Chinese medicine drug approved for the treatment of cardiovascular diseases. This study aimed to identify WXKL-targeting genes involved in antiarrhythmic efficacy of WXKL. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) technology platform was used to screen active compounds of WXKL and WXKL-targeting arrhythmia-related genes. A pig model of myocardial ischemia (MI) was established by balloon-expanding the endothelium of the left coronary artery. Pigs were divided into the model group and WXKL group (n = 6). MI, QT interval, heart rate, and arrhythmia were recorded, and the mRNA expression of target genes in myocardial tissues was detected by PCR. Eleven active ingredients of WXKL and eight WXKL-targeting arrhythmia-related genes were screened. Five pathways were enriched, and an "ingredient-gene-path" network was constructed. WXKL markedly decreased the incidence of arrhythmia in the MI pig model (P < 0.05). The QT interval was significantly shortened, and the heart rate was slowed down in the WXKL group compared with the model group (P < 0.05). In addition, the expression of sodium channel protein type 5 subunit alpha (SCN5A) and beta-2 adrenergic receptor (ADRB2) was downregulated, while muscarinic acetylcholine receptor M2 (CHRM2) was upregulated in the WXKL group (P < 0.05). In conclusion, WXKL may shorten the QT interval and slow down the heart rate by downregulating SCN5A and ADRB2 and upregulating CHRM2 during MI. These findings provide novel insight into molecular mechanisms of WXKL in reducing the incidence of ventricular arrhythmia.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Frequência Cardíaca/genética , Masculino , Medicina Tradicional Chinesa , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Mapas de Interação de Proteínas , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Suínos , Porco Miniatura , Fatores de Tempo
2.
J Oral Sci ; 62(3): 265-270, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32493863

RESUMO

Orexins (Oxs) are multifunctional neuropeptides, secreted from the lateral hypothalamus, that stimulate feeding behavior and energy expenditure. In this study, the direct effects of Oxs on the membrane properties of trigeminal motoneurons (TMNs) were examined, which critically participate in the genesis of rhythmical oral motor activities underlying suckling and mastication. Sprague-Dawley rats (3-6 day-old) were used to obtain whole-cell patch-clamp recordings from TMNs. Bath application of Ox-A depolarized the membrane potential and induced inward current, wherein Na+ and Ca2+ were charge carriers. Transient receptor potential channel activation potentially contributed to current and voltage responses by way of Ox-A. Ox-A increased the peak amplitude and duration at half-amplitude of the medium-duration after hyperpolarization following the action potential. The interspike frequency of steady-state firings during repetitive discharge was increased, along with a shift in the frequency-current relationship occurring toward the left. Extracellular and intracellular Ca2+ were involved in regulating modulatory effects, but a requisite level of intracellular Ca2+ was not essential for Ox-induced upregulation of the interspike frequency. Ox-A also enhanced conditional bursting induced by N-methyl-d-aspartate and 5-HT, suggesting it participates in modulating TMNs' discharge patterns during various oral motor activities.


Assuntos
Neurônios Motores , Potenciais de Ação , Animais , Potenciais da Membrana , Orexinas , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley
3.
PLoS One ; 15(5): e0231695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392258

RESUMO

We present a novel modification of genetic algorithm (GA) which determines personalized parameters of cardiomyocyte electrophysiology model based on set of experimental human action potential (AP) recorded at different heart rates. In order to find the steady state solution, the optimized algorithm performs simultaneous search in the parametric and slow variables spaces. We demonstrate that several GA modifications are required for effective convergence. Firstly, we used Cauchy mutation along a random direction in the parametric space. Secondly, relatively large number of elite organisms (6-10% of the population passed on to new generation) was required for effective convergence. Test runs with synthetic AP as input data indicate that algorithm error is low for high amplitude ionic currents (1.6±1.6% for IKr, 3.2±3.5% for IK1, 3.9±3.5% for INa, 8.2±6.3% for ICaL). Experimental signal-to-noise ratio above 28 dB was required for high quality GA performance. GA was validated against optical mapping recordings of human ventricular AP and mRNA expression profile of donor hearts. In particular, GA output parameters were rescaled proportionally to mRNA levels ratio between patients. We have demonstrated that mRNA-based models predict the AP waveform dependence on heart rate with high precision. The latter also provides a novel technique of model personalization that makes it possible to map gene expression profile to cardiac function.


Assuntos
Potenciais de Ação , Coração/fisiologia , Miócitos Cardíacos/fisiologia , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Expressão Gênica , Transplante de Coração , Ventrículos do Coração/metabolismo , Humanos , Modelos Biológicos , Técnicas de Patch-Clamp , RNA-Seq , Doadores de Tecidos
4.
Am J Physiol Heart Circ Physiol ; 318(6): H1387-H1400, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357112

RESUMO

Plasticity is a fundamental property of neurons in both the central and peripheral nervous systems, enabling rapid changes in neural network function. The intracardiac nervous system (ICNS) is an extensive network of neurons clustered into ganglionated plexi (GP) on the surface of the heart. GP neurons are the final site of neuronal control of heart rhythm, and pathophysiological remodeling of the ICNS is proposed to feature in multiple cardiovascular diseases, including heart failure and atrial fibrillation. To examine the potential role of GP neuron plasticity in atrial arrhythmia and hypertension, we developed whole cell patch clamp recording techniques from GP neurons in isolated ICNS preparations from aged control (Wistar-Kyoto) and spontaneously hypertensive rats (SHRs). Anesthetized SHRs showed frequent premature ventricular contractions and episodes of atrial arrhythmia following carbachol injection, and isolated SHR atrial preparations were susceptible to pacing induced atrial arrhythmia. Whole cell recordings revealed elevated spontaneous postsynaptic current frequency in SHR GP neurons, as well as remodeled electrophysiology, with significant decreases in action potential amplitude and half-width. SHRs also showed a parallel increase in the number of cholinergic neurons and adrenergic glomus cells in cardiac ganglia, a higher proportion of synaptic α7-subunit but not ß2-containing nicotinic receptors, and an elevation in the number of synaptic terminals onto GP neurons. Our data show that significant structural and functional plasticity occurs in the intracardiac nervous system and suggest that enhanced excitability through synaptic plasticity, together with remodeling of cardiac neuron electrophysiology, contributes to the substrate for atrial arrhythmia in hypertensive heart disease.NEW & NOTEWORTHY We have developed intracardiac neuron whole cell recording techniques in atrial preparations from control and spontaneous hypertensive rats. This has enabled the identification of significant synaptic plasticity in the intracardiac nervous system, including enhanced postsynaptic current frequency, increased synaptic terminal density, and altered postsynaptic receptors. This increased synaptic drive together with altered cardiac neuron electrophysiology could increase intracardiac nervous system excitability and contribute to the substrate for atrial arrhythmia in hypertensive heart disease.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Coração/inervação , Hipertensão/fisiopatologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação , Animais , Átrios do Coração/fisiopatologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(2): 262-267, 2020 Feb 29.
Artigo em Chinês | MEDLINE | ID: mdl-32376530

RESUMO

OBJECTIVE: To investigate effect of upregulated touch sensation induced by olfactory deprivation on action potentials and ankyrin-G expression in the glutamatergic neurons in the barrel cortex of mice. METHODS: Chloroform (40 µL) was dropped into the unilateral nasal cavity to induce olfactory deprivation in 40 C57 mice (12 days old), whose glutamatergic neurons were genetically labeled with yellow fluorescent protein (YFP). Behavioral experiments were carried out to assess the effects of olfactory deprivation on whisker tactile of the mice. The action potentials of the glutamatergic neurons in the barrel cortex on the side with or without chloroform treatment (olfactory deprivation group and control group, respectively) were recorded by patch-clamp electrophysiological recording, and ankyrin-G expression in the proximal axonal segment of the neurons was detected with immunohistochemistry. RESULTS: Compared with those on the control side, the inter-spike intervals of the barrel glutamatergic neurons were significantly decreased and the absolute refractory periods were significantly shortened on the side with olfactory deprivation (P < 0.01); the expression of ankyrin-G was also significantly increased in the proximal axonal segment of the glutamatergic neurons in the barrel cortex on the side with olfactory deprivation (P < 0.01). CONCLUSIONS: Olfaction deprivation induces up-regulation of touch sensation in mice possibly as a result of functional enhancement of the glutamatergic neurons and increased ankyrin-G expression in the barrel cortex.


Assuntos
Olfato , Córtex Somatossensorial , Potenciais de Ação , Animais , Anquirinas , Camundongos , Plasticidade Neuronal , Neurônios , Privação Sensorial
6.
Am J Physiol Heart Circ Physiol ; 318(6): H1436-H1440, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32383994

RESUMO

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a degenerative muscle disease triggered by mutations in the gene encoding for the intracellular protein dystrophin. A major source for the arrhythmias in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant mechanisms. The reason for ventricular conduction impairments and the associated arrhythmias in the dystrophic heart has remained unidentified. In the present study, we explored the hypothesis that dystrophin-deficient cardiac Purkinje fibers have reduced Na+ currents (INa), which would represent a potential mechanism underlying slowed ventricular conduction in the dystrophic heart. Therefore, by using a Langendorff perfusion system, we isolated Purkinje fibers from the hearts of adult wild-type control and dystrophin-deficient mdx mice. Enhanced green fluorescent protein (eGFP) expression under control of the connexin 40 gene allowed us to discriminate Purkinje fibers from eGFP-negative ventricular working cardiomyocytes after cell isolation. Finally, we recorded INa from wild-type and dystrophic mdx Purkinje fibers for comparison by means of the whole cell patch clamp technique. We found substantially reduced INa densities in mdx compared with wild-type Purkinje fibers, suggesting that dystrophin deficiency diminishes INa. Because Na+ channels in the Purkinje fiber membrane represent key determinants of ventricular conduction velocity, we propose that reduced INa in Purkinje fibers at least partly explains impaired ventricular conduction and the associated arrhythmias in the dystrophic heart.NEW & NOTEWORTHY Dystrophic cardiac Purkinje fibers have abnormally reduced Na+ current densities. This explains impaired ventricular conduction in the dystrophic heart.


Assuntos
Arritmias Cardíacas/metabolismo , Doença do Sistema de Condução Cardíaco/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Ramos Subendocárdicos/metabolismo , Canais de Sódio/metabolismo , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/fisiopatologia , Doença do Sistema de Condução Cardíaco/complicações , Doença do Sistema de Condução Cardíaco/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/fisiopatologia , Sódio/metabolismo
7.
Nat Commun ; 11(1): 2217, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371879

RESUMO

Theta oscillations play a major role in temporarily defining the hippocampal rate code by translating behavioral sequences into neuronal representations. However, mechanisms constraining phase timing and cell-type-specific phase preference are unknown. Here, we employ computational models tuned with evolutionary algorithms to evaluate phase preference of individual CA1 pyramidal cells recorded in mice and rats not engaged in any particular memory task. We applied unbiased and hypothesis-free approaches to identify effects of intrinsic and synaptic factors, as well as cell morphology, in determining phase preference. We found that perisomatic inhibition delivered by complementary populations of basket cells interacts with input pathways to shape phase-locked specificity of deep and superficial pyramidal cells. Somatodendritic integration of fluctuating glutamatergic inputs defined cycle-by-cycle by unsupervised methods demonstrated that firing selection is tuneable across sublayers. Our data identify different mechanisms of phase-locking selectivity that are instrumental for flexible dynamical representations of theta sequences.


Assuntos
Região CA1 Hipocampal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Ritmo Teta/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Animais , Região CA1 Hipocampal/citologia , Simulação por Computador , Feminino , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Técnicas de Patch-Clamp , Células Piramidais/fisiologia , Ratos Wistar
8.
PLoS One ; 15(4): e0232451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353050

RESUMO

Numerous neuronal properties including the synaptic vesicle release process, neurotransmitter receptor complement, and postsynaptic ion channels are involved in transforming synaptic inputs into postsynaptic spiking. Temperature is a significant influencer of neuronal function and synaptic integration. Changing temperature can affect neuronal physiology in a diversity of ways depending on how it affects different members of the cell's ion channel complement. Temperature's effects on neuronal function are critical for pathological states such as fever, which can trigger seizure activity, but are also important in interpreting and comparing results of experiments conducted at room vs physiological temperature. The goal of this study was to examine the influence of temperature on synaptic properties and ion channel function in thalamocortical (TC) relay neurons in acute brain slices of the dorsal lateral geniculate nucleus, a key synaptic target of retinal ganglion cells in the thalamus. Warming the superfusate in patch clamp experiments with acutely-prepared brain slices led to an overall inhibition of synaptically-driven spiking behavior in TC neurons in response to a retinal ganglion cell spike train. Further study revealed that this was associated with an increase in presynaptic synaptic vesicle release probability and synaptic depression and altered passive and active membrane properties. Additionally, warming the superfusate triggered activation of an inwardly rectifying potassium current and altered the voltage-dependence of voltage-gated Na+ currents and T-type calcium currents. This study highlights the importance of careful temperature control in ex vivo physiological experiments and illustrates how numerous properties such as synaptic inputs, active conductances, and passive membrane properties converge to determine spike output.


Assuntos
Corpos Geniculados/fisiologia , Temperatura Alta/efeitos adversos , Optogenética/métodos , Terminações Pré-Sinápticas/fisiologia , Células Ganglionares da Retina/fisiologia , Potenciais de Ação/fisiologia , Animais , Canais de Cálcio Tipo T/metabolismo , Feminino , Corpos Geniculados/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Transmissão Sináptica/fisiologia , Canais de Sódio Disparados por Voltagem/metabolismo
9.
PLoS Comput Biol ; 16(5): e1007834, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453727

RESUMO

Neurons form complex networks that evolve over multiple time scales. In order to thoroughly characterize these networks, time dependencies must be explicitly modeled. Here, we present a statistical model that captures both the underlying structural and temporal dynamics of neuronal networks. Our model combines the class of Stochastic Block Models for community formation with Gaussian processes to model changes in the community structure as a smooth function of time. We validate our model on synthetic data and demonstrate its utility on three different studies using in vitro cultures of dissociated neurons.


Assuntos
Potenciais de Ação , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Células Cultivadas , Córtex Cerebral/citologia , Eletrodos , Hipocampo/citologia , Cadeias de Markov , Camundongos , Neuroglia/citologia , Distribuição Normal , Probabilidade , Ratos , Processos Estocásticos , Fatores de Tempo
10.
PLoS Comput Biol ; 16(5): e1007932, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453795

RESUMO

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.


Assuntos
Cloretos/química , Dendritos/fisiologia , Neurônios/fisiologia , Receptores de GABA/fisiologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Encéfalo/fisiologia , Simulação por Computador , Hipocampo/fisiologia , Humanos , Cinética , Masculino , Modelos Neurológicos , Técnicas de Cultura de Órgãos , Ligação Proteica , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia
11.
Nat Commun ; 11(1): 2101, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355170

RESUMO

Neural computation relies on the integration of synaptic inputs across a neuron's dendritic arbour. However, it is far from understood how different cell types tune this process to establish cell-type specific computations. Here, using two-photon imaging of dendritic Ca2+ signals, electrical recordings of somatic voltage and biophysical modelling, we demonstrate that four morphologically distinct types of mouse retinal ganglion cells with overlapping excitatory synaptic input (transient Off alpha, transient Off mini, sustained Off, and F-mini Off) exhibit type-specific dendritic integration profiles: in contrast to the other types, dendrites of transient Off alpha cells were spatially independent, with little receptive field overlap. The temporal correlation of dendritic signals varied also extensively, with the highest and lowest correlation in transient Off mini and transient Off alpha cells, respectively. We show that differences between cell types can likely be explained by differences in backpropagation efficiency, arising from the specific combinations of dendritic morphology and ion channel densities.


Assuntos
Dendritos/fisiologia , Células Ganglionares da Retina/citologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Sinalização do Cálcio , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Fótons , Retina/fisiologia
12.
Life Sci ; 254: 117797, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417371

RESUMO

AIMS: Atrial remodeling, including structural and electrical remodeling, is considered as the substrate in the development of atrial fibrillation (AF). Structural remodeling mainly involves atrial fibrosis, and electrical remodeling is closely related to the changes of ion channels in atrial myocytes. In this study, we aimed to investigate the changes of ion channels in atrial remodeling induced by CIH in rats, which provide the explication for the mechanisms of AF. MATERIALS AND METHODS: 80 male Sprague-Dawley rats were randomized into two groups: Control and CIH group (n = 40). CIH rats were subjected to CIH 8 h/d for 30 days. Atrial epicardial conduction velocity, conduction inhomogeneity and AF inducibility were examined. Masson's trichrome staining was used to evaluate the extent of atrial fibrosis, and the expression levels of ion channel subunits were measured by RT-qPCR, Western blot, and IHC, respectively. The remaining 40 rats were used for whole-cell patch clamp experiments. Action potential, INa, ICa-L, Ito were recorded and compared between two groups. KEY FINDINGS: CIH rats showed increased AF inducibility, atrial interstitial collagen deposition, APD, expression levels of RyR2, p-RyR2, CaMKII, p-CaMKII, and decreased atrial epicardial conduction velocity, expression levels of Nav1.5, Cav1.2, Kv1.5, Kv4.2, Kv4.3 compared to the Control rats, and the current density of INa, ICa-L, Ito were significantly decreased in CIH group. SIGNIFICANCE: We observed significant atrial remodeling induced by CIH in our rat model, which was characterized by changes in ion channels. These changes may be the mechanisms of CIH promoting AF.


Assuntos
Remodelamento Atrial/fisiologia , Hipóxia/fisiopatologia , Canais Iônicos/fisiologia , Potenciais de Ação/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Doença Crônica , Fibrose/complicações , Fibrose/patologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Hipóxia/complicações , Hipóxia/metabolismo , Canais Iônicos/biossíntese , Masculino , Potenciais da Membrana/fisiologia , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese
13.
Proc Natl Acad Sci U S A ; 117(16): 9094-9100, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253308

RESUMO

Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. Using rabies virus-based transsynaptic tracing, we find that at 6 mo after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons. We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side. Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.


Assuntos
Células-Tronco Pluripotentes Induzidas/fisiologia , Infarto da Artéria Cerebral Média/terapia , Atividade Motora/fisiologia , Neurônios/transplante , Córtex Somatossensorial/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Neurônios/fisiologia , Optogenética , Técnicas de Patch-Clamp , Ratos , Recuperação de Função Fisiológica , Córtex Somatossensorial/citologia , Córtex Somatossensorial/patologia
14.
Medicine (Baltimore) ; 99(17): e19558, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332604

RESUMO

This 2-group study was carried out to determine the inter-practitioner difference of nerve conduction studies with standardized techniques.56 normal subjects of 19 to 49 year-old were recruited, 29, and 27 in the 2 labs respectively. Tests were carried out unilaterally on: 5 motor nerve distal latency, conduction velocities (MNCV) and minimum latency of F wave, 3 sensory nerves with negative amplitude, onset, and peak distal latency, sensory nerve distal latency.T-test disclosed 4(15.4%) attributes with statistical significance (P < .05). They were 2 of 4 (50%) compound motor action potentials, which were ulnar and tibial nerve, and 2 of 6 (33.3%) MNCVs, which were elbow-to-wrist MNCV of median nerve and cross-fibula MNCV of peroneal nerve. No differences were disclosed in motor nerve distal latencys, minimum latency of F waves and all sensory attributes.Inconsistency pattern of certain attributes were found. This could be explained with the insufficient definition of related techniques.


Assuntos
Condução Nervosa/fisiologia , Exame Neurológico/métodos , Padrões de Prática Médica , Potenciais de Ação , Adulto , Fatores Etários , Pesos e Medidas Corporais , Feminino , Humanos , Masculino , Nervo Mediano/fisiologia , Pessoa de Meia-Idade , Nervo Fibular/fisiologia , Fatores Sexuais , Nervo Tibial/fisiologia , Nervo Ulnar/fisiologia , Adulto Jovem
15.
PLoS One ; 15(4): e0231056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302318

RESUMO

Transverse and axial tubules (TATS) are an essential ingredient of the excitation-contraction machinery that allow the effective coupling of L-type Calcium Channels (LCC) and ryanodine receptors (RyR2). They form a regular network in ventricular cells, while their presence in atrial myocytes is variable regionally and among animal species We have studied the effect of variations in the TAT network using a bidomain computational model of an atrial myocyte with variable density of tubules. At each z-line the t-tubule length is obtained from an exponential distribution, with a given mean penetration length. This gives rise to a distribution of t-tubules in the cell that is characterized by the fractional area (F.A.) occupied by the t-tubules. To obtain consistent results, we average over different realizations of the same mean penetration length. To this, in some simulations we add the effect of a network of axial tubules. Then we study global properties of calcium signaling, as well as regional heterogeneities and local properties of sparks and RyR2 openings. In agreement with recent experiments in detubulated ventricular and atrial cells, we find that detubulation reduces the calcium transient and synchronization in release. However, it does not affect sarcoplasmic reticulum (SR) load, so the decrease in SR calcium release is due to regional differences in Ca2+ release, that is restricted to the cell periphery in detubulated cells. Despite the decrease in release, the release gain is larger in detubulated cells, due to recruitment of orphaned RyR2s, i.e, those that are not confronting a cluster of LCCs. This probably provides a safeguard mechanism, allowing physiological values to be maintained upon small changes in the t-tubule density. Finally, we do not find any relevant change in spark properties between tubulated and detubulated cells, suggesting that the differences found in experiments could be due to differential properties of the RyR2s in the membrane and in the t-tubules, not incorporated in the present model. This work will help understand the effect of detubulation, that has been shown to occur in disease conditions such as heart failure (HF) in ventricular cells, or atrial fibrillation (AF) in atrial cells.


Assuntos
Canais de Cálcio Tipo L/genética , Sinalização do Cálcio/genética , Miócitos Cardíacos/fisiologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Cálcio/metabolismo , Acoplamento Excitação-Contração/fisiologia , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Humanos , Mamíferos , Sarcolema/genética , Sarcolema/fisiologia , Retículo Sarcoplasmático/genética , Retículo Sarcoplasmático/fisiologia , Ovinos
16.
Am J Physiol Heart Circ Physiol ; 318(5): H1198-H1207, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32243771

RESUMO

Posttraumatic stress disorder (PTSD) is more prevalent in women and associated with greater risk of major forms of cardiovascular disease, but physiological mechanisms underlying this association remain unknown. We hypothesized that abnormal sympathetic responses to sympathoexcitatory stimuli might predispose PTSD patients to a greater risk of cardiovascular disease. We examined changes in integrated muscle sympathetic nerve activity (MSNA) burst and multiunit action potential (AP) recruitment patterns as well as hemodynamic responses during cold pressor test (CPT) in 14 women with PTSD and 14 healthy control subjects. Data were collected during 1-min baseline, 2-min CPT, and 3-min recovery. At baseline, blood pressure (BP) was not different between groups; however, heart rate and sympathetic neural activity were greater in women with PTSD [MSNA burst frequency (BF): 27 ± 13 vs. 18 ± 14 bursts/min (P = 0.04); AP frequency: 272 ± 152 vs. 174 ± 146 spikes/min (P = 0.03)]. In response to CPT, BP responses exhibited a significant group × time interaction (P = 0.01) highlighted by a significant diastolic BP main group effect (P = 0.048) despite the finding that increases in integrated MSNA burst responses were not different between groups (P > 0.05). However, compared with control subjects, AP firing frequency (group × time interaction P = 0.0001, group P = 0.02) and AP per burst (group × time interaction P = 0.03, group P = 0.03) were augmented in women with PTSD. Collectively, women with PTSD exhibited a greater pressor response and an exaggerated sympathetic neural recruitment pattern during sympathoexcitatory stimuli that may, in part, explain the propensity toward developing hypertension and cardiovascular disease later in life.NEW & NOTEWORTHY The novel findings of the present study are that women with posttraumatic stress disorder (PTSD) have an augmented pressor response to the sympathoexcitatory stimulus of a cold pressor test (CPT) compared with healthy control subjects. Although integrated muscle sympathetic nerve activity burst responses were not significantly different between groups, total sympathetic action potential discharge in response to the CPT was markedly elevated in women with PTSD exhibiting increased firing of low-threshold axons as well as the recruitment of latent subpopulations of larger-sized axons that are otherwise silent at baseline. Aberrant autonomic circulatory control in response to sympathoexcitatory stimulus may in part explain the propensity toward developing hypertension and cardiovascular disease in this population.


Assuntos
Pressão Sanguínea , Recrutamento Neurofisiológico , Reflexo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Potenciais de Ação , Adulto , Temperatura Baixa , Feminino , Humanos , Pessoa de Meia-Idade
17.
Nat Commun ; 11(1): 1687, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245941

RESUMO

Crowding is a profound loss of discriminability of visual features, when a target stimulus is surrounded by distractors. Numerous studies of human perception have characterized how crowding depends on the properties of a visual display. Yet, there is limited understanding of how and where stimulus information is lost in the visual system under crowding. Here, we show that macaque monkeys exhibit perceptual crowding for target orientation that is similar to humans. We then record from neuronal populations in monkey primary visual cortex (V1). These populations show an appreciable loss of information about target orientation in the presence of distractors, due both to divisive and additive modulation of responses to targets by distractors. Our results show that spatial contextual effects in V1 limit the discriminability of visual features and can contribute substantively to crowding.


Assuntos
Aglomeração/psicologia , Discriminação Psicológica/fisiologia , Orientação Espacial/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação/fisiologia , Adulto , Animais , Eletrodos Implantados , Humanos , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Psicometria , Técnicas Estereotáxicas/instrumentação
18.
Proc Natl Acad Sci U S A ; 117(19): 10278-10285, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32341158

RESUMO

Neurons undergo nanometer-scale deformations during action potentials, and the underlying mechanism has been actively debated for decades. Previous observations were limited to a single spot or the cell boundary, while movement across the entire neuron during the action potential remained unclear. Here we report full-field imaging of cellular deformations accompanying the action potential in mammalian neuron somas (-1.8 to 1.4 nm) and neurites (-0.7 to 0.9 nm), using high-speed quantitative phase imaging with a temporal resolution of 0.1 ms and an optical path length sensitivity of <4 pm per pixel. The spike-triggered average, synchronized to electrical recording, demonstrates that the time course of the optical phase changes closely matches the dynamics of the electrical signal. Utilizing the spatial and temporal correlations of the phase signals across the cell, we enhance the detection and segmentation of spiking cells compared to the shot-noise-limited performance of single pixels. Using three-dimensional (3D) cellular morphology extracted via confocal microscopy, we demonstrate that the voltage-dependent changes in the membrane tension induced by ionic repulsion can explain the magnitude, time course, and spatial features of the phase imaging. Our full-field observations of the spike-induced deformations shed light upon the electromechanical coupling mechanism in electrogenic cells and open the door to noninvasive label-free imaging of neural signaling.


Assuntos
Potenciais de Ação , Membrana Celular/fisiologia , Interferometria/métodos , Neurônios/citologia , Neurônios/fisiologia , Animais , Imagem Molecular , Optogenética
19.
Mol Pharmacol ; 97(6): 355-364, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32241959

RESUMO

Voltage-gated potassium 11.1 (Kv11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-Kv11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 µM dofetilide or 10 µM dofetilide + 5 µM LUF7244. In trafficking defective G601S-Kv11.1 cells, dofetilide (10 µM) or dofetilide + LUF7244 (10 + 5 µM) also restored Kv11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 µM) increased IKv 11.1 despite the presence of dofetilide (1 µM) in WT Kv11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 µM) and dofetilide (1 µM) increased IKv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1 Thus, combined administration of LUF7244 and an IKv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional Kv11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of Kv11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired Kv11.1 trafficking defects, resulting in functional Kv11.1 current.


Assuntos
Antiarrítmicos/farmacologia , Canal de Potássio ERG1/efeitos dos fármacos , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/química , Western Blotting , Simulação por Computador , Sinergismo Farmacológico , Canal de Potássio ERG1/fisiologia , Células HEK293 , Humanos , Microscopia de Fluorescência , Modelos Moleculares , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Fenetilaminas/química , Bloqueadores dos Canais de Potássio/química , Sulfonamidas/química
20.
J Med Life ; 13(1): 98-101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341709

RESUMO

Here we present a case of a 70-year-old man with acute myocardial infarction caused by left anterior descending artery occlusion presenting as ST elevation in the inferior leads that suggested an occlusion of the right coronary artery. In contrast, coronary angiography results indicated a complete occlusion of the proximal left anterior descending coronary artery. We reported our observation in electrocardiographic data and coronary angiography and its changes after a percutaneous coronary intervention, and then we discuss its pathophysiologic mechanism.


Assuntos
Arteriopatias Oclusivas/complicações , Vasos Coronários/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Potenciais de Ação , Idoso , Arteriopatias Oclusivas/diagnóstico por imagem , Arteriopatias Oclusivas/fisiopatologia , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Eletrocardiografia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia
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