RESUMO
Currently, the nanofluidic synapse can only perform basic neuromorphic pulse patterns. One immediate problem that needs to be addressed to further its capability of brain-like computing is the realization of a nanofluidic spiking device. Here, we report the use of a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate membrane to achieve bionic ionic current-induced spiking. In addition to the simulation of various electrical pulse patterns, our synapse could produce transmembrane ionic current-induced spiking, which is highly analogous to biological action potentials with similar phases and excitability. Moreover, the spiking properties could be modulated by ions and neurochemicals. We expect that this work could contribute to biomimetic spiking computing in solution.
Assuntos
Potenciais de Ação , Poliestirenos , Sinapses , Potenciais de Ação/fisiologia , Sinapses/fisiologia , Poliestirenos/química , Nanotecnologia/métodos , Nanotecnologia/instrumentaçãoRESUMO
Temperature strongly influences the intensity of taste, but it remains understudied despite its physiological, hedonic, and commercial implications. The relative roles of the peripheral gustatory and somatosensory systems innervating the oral cavity in mediating thermal effects on taste sensation and perception are poorly understood. Type II taste-bud cells, responsible for sensing sweet, bitter umami, and appetitive NaCl, release neurotransmitters to gustatory neurons by the generation of action potentials, but the effects of temperature on action potentials and the underlying voltage-gated conductances are unknown. Here, we used patch-clamp electrophysiology to explore the effects of temperature on acutely isolated type II taste-bud cell electrical excitability and whole cell conductances. Our data reveal that temperature strongly affects action potential generation, properties, and frequency and suggest that thermal sensitivities of underlying voltage-gated Na+ and K+ channel conductances provide a mechanism for how and whether voltage-gated Na+ and K+ channels in the peripheral gustatory system contribute to the influence of temperature on taste sensitivity and perception.NEW & NOTEWORTHY The temperature of food affects how it tastes. Nevertheless, the mechanisms involved are not well understood, particularly whether the physiology of taste-bud cells in the mouth is involved. Here we show that the electrical activity of type II taste-bud cells that sense sweet, bitter, and umami substances is strongly influenced by temperature. These results suggest a mechanism for the influence of temperature on the intensity of taste perception that resides in taste buds themselves.
Assuntos
Papilas Gustativas , Papilas Gustativas/metabolismo , Paladar/fisiologia , Potenciais de Ação , Temperatura , NeurôniosRESUMO
Polysorbate 80 is a non-ionic detergent derived from polyethoxylated sorbitan and oleic acid. It is widely used in pharmaceuticals, foods, and cosmetics as an emulsifier. Nav1.7 is a peripheral sodium channel that is highly expressed in sympathetic and sensory neurons, and it plays a critical role in determining the threshold of action potentials (APs). We found that 10 µg/mL polysorbate 80 either abolished APs or increased the threshold of the APs of dorsal root ganglions. We thus investigated whether polysorbate 80 inhibits Nav1.7 sodium current using a whole-cell patch-clamp recording technique. Polysorbate 80 decreased the Nav1.7 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 250.4 µg/mL at a holding potential of -120 mV. However, the IC50 was 1.1 µg/mL at a holding potential of -90 mV and was estimated to be 0.9 µg/mL at the resting potentials of neurons, where most channels are inactivated. The activation rate and the voltage dependency of activation of Nav1.7 were not changed by polysorbate 80. However, polysorbate 80 caused hyperpolarizing shifts in the voltage dependency of the steady-state fast inactivation curve. The blocking of Nav1.7 currents by polysorbate 80 was not reversible at a holding potential of -90 mV but was completely reversible at -120 mV, where the channels were mostly in the closed state. Polysorbate 80 also slowed recovery from inactivation and induced robust use-dependent inhibition, indicating that it is likely to bind to and stabilize the inactivated state. Our results indicate that polysorbate 80 inhibits Nav1.7 current in concentration-, state-, and use-dependent manners when used even below commercial concentrations. This suggests that polysorbate 80 may be helpful in pain medicine as an excipient. In addition, in vitro experiments using polysorbate 80 with neurons should be conducted with caution.
Assuntos
Neurônios , Polissorbatos , Polissorbatos/farmacologia , Polissorbatos/metabolismo , Neurônios/metabolismo , Canais de Sódio/metabolismo , Potenciais da Membrana/fisiologia , Potenciais de Ação , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismoRESUMO
INTRODUCTION/AIMS: Measures for assessing cranial nerve vulnerability in spinal muscular atrophy (SMA) have not yet been determined. Motor unit number index (MUNIX) studies have shown correlations with disease severity but have been used only in limb muscles. In the present study, we explore facial nerve response, MUNIX, and motor unit size index (MUSIX) of the orbicularis oculi muscle in a cohort of patients with SMA. METHODS: Facial nerve response (measured as compound muscle action potential, CMAP), MUNIX, and MUSIX of the orbicularis oculi muscle were cross-sectionally recorded in patients with SMA and compared to healthy control subjects (HCs). Active maximum mouth opening (aMMO) was also measured at baseline in our SMA cohort. RESULTS: Thirty-seven patients with SMA (21 SMA II; 16 SMA III) and 27 HCs were recruited. CMAP of the facial nerve and MUNIX of orbicularis oculi proved to be feasible and well tolerated techniques. CMAP amplitude and MUNIX scores were significantly lower in patients with SMA compared to HCs (p < .0001). Both MUNIX and CMAP amplitude were significantly higher in patients with SMA III compared to SMA II. No significant difference emerged comparing CMAP amplitude, MUNIX and MUSIX scores between those with different functional status or nusinersen treatment. DISCUSSION: Our results provide neurophysiological evidence of facial nerve and muscle involvement in patients with SMA. CMAP of the facial nerve and MUNIX of orbicularis oculi showed high accuracy in discriminating between the various subtypes of SMA and in quantifying the motor unit loss of the facial nerve.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Humanos , Eletromiografia/métodos , Nervo Facial , Neurônios Motores/fisiologia , Músculo Esquelético , Atrofia Muscular Espinal/diagnóstico , Potenciais de Ação/fisiologiaRESUMO
Synaptic dysfunction is associated with several brain disorders, including Alzheimer's disease, Parkinson's disease (PD) and obsessive compulsive disorder (OCD). Utilizing synaptic plasticity, brain stimulation is capable of reshaping synaptic connectivity. This may pave the way for novel therapies that specifically counteract pathological synaptic connectivity. For instance, in PD, novel multichannel coordinated reset stimulation (CRS) was designed to counteract neuronal synchrony and down-regulate pathological synaptic connectivity. CRS was shown to entail long-lasting therapeutic aftereffects in PD patients and related animal models. This is in marked contrast to conventional deep brain stimulation (DBS) therapy, where PD symptoms return shortly after stimulation ceases. In the present paper, we study synaptic reshaping by periodic multichannel stimulation (PMCS) in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity (STDP). During PMCS, phase-shifted periodic stimulus trains are delivered to segregated neuronal subpopulations. Harnessing STDP, PMCS leads to changes of the synaptic network structure. We found that the PMCS-induced changes of the network structure depend on both the phase lags between stimuli and the shape of individual stimuli. Single-pulse stimuli and burst stimuli with low intraburst frequency down-regulate synapses between neurons receiving stimuli simultaneously. In contrast, burst stimuli with high intraburst frequency up-regulate these synapses. We derive theoretical approximations of the stimulation-induced network structure. This enables us to formulate stimulation strategies for inducing a variety of network structures. Our results provide testable hypotheses for future pre-clinical and clinical studies and suggest that periodic multichannel stimulation may be suitable for reshaping plastic neuronal networks to counteract pathological synaptic connectivity. Furthermore, we provide novel insight on how the stimulus type may affect the long-lasting outcome of conventional DBS. This may strongly impact parameter adjustment procedures for clinical DBS, which, so far, primarily focused on acute effects of stimulation.
Assuntos
Modelos Neurológicos , Doença de Parkinson , Animais , Plásticos , Neurônios/fisiologia , Sinapses/fisiologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação/fisiologiaRESUMO
Mammalian nervous systems, as natural ionic circuitries, stand out in environmental perception and sophisticated information transmission, relying on protein ionic channels and additional necessary structures. Prosperously emerged ionic regulated biomimetic nanochannels exhibit great potentialities in various application scenarios, especially signal transduction. Most reported direct current systems possess deficiencies in informational density and variability, which are superiorities of alternating current (AC) systems and necessities in bioinspired nervous signal transmission. Here, inspired by myelinated saltatory conduction, alternating electrostatic potential controlled nanofluidics are constructed with a noncontact application pattern and MXene nanosheets. Under time-variant external stimuli, ions confined in the interlaminar space obtain the capability of carriers for the AC ionic circuit. The transmitted information is accessible from typical sine to a frequency-modulated binary signal. This work demonstrates the potentiality of the bioinspired nervous signal transmission between electronics and ionic nanofluidics, which might push one step forward to the avenue of AC ionics.
Assuntos
Potenciais de Ação , Materiais Biomiméticos/química , Condutividade Elétrica , Microfluídica/métodos , Modelos Neurológicos , Nanoestruturas/química , Dimetilpolisiloxanos/química , Equipamentos e Provisões Elétricas , Transporte de Íons , Microfluídica/instrumentaçãoRESUMO
Understanding how a network of interconnected neurons receives, stores, and processes information in the human brain is one of the outstanding scientific challenges of our time. The ability to reliably detect neuroelectric activities is essential to addressing this challenge. Optical recording using voltage-sensitive fluorescent probes has provided unprecedented flexibility for choosing regions of interest in recording neuronal activities. However, when recording at a high frame rate such as 500 to 1,000 Hz, fluorescence-based voltage sensors often suffer from photobleaching and phototoxicity, which limit the recording duration. Here, we report an approach called electrochromic optical recording (ECORE) that achieves label-free optical recording of spontaneous neuroelectrical activities. ECORE utilizes the electrochromism of poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) thin films, whose optical absorption can be modulated by an applied voltage. Being based on optical reflection instead of fluorescence, ECORE offers the flexibility of an optical probe without suffering from photobleaching or phototoxicity. Using ECORE, we optically recorded spontaneous action potentials in cardiomyocytes, cultured hippocampal and dorsal root ganglion neurons, and brain slices. With minimal perturbation to cells, ECORE allows long-term optical recording over multiple days.
Assuntos
Eletrofisiologia/métodos , Neurônios/fisiologia , Poliestirenos , Tiofenos , Potenciais de Ação/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Técnicas Eletroquímicas/métodos , Fenômenos Eletrofisiológicos , Corantes Fluorescentes , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Humanos , Imagem Óptica , Óptica e Fotônica/métodosRESUMO
New strategies for intracellular electrophysiology break the spatiotemporal limitation of the action potential and lead a notable advance in the investigation of electrically excitable cells and their network. Although successful applications of intracellular recording have been achieved by 3D micro/nanodevices, complex micro/nanofabrication processes preclude the progress of extensive applications. We address this challenge by introducing porous polyethylene terephthalate (PET) membrane to develop a new type of nanotemplate electrode. This nanotemplate electrode is manufactured following a fabrication process on a porous PET membrane by atomic layer deposition. The 3D nanotemplate electrodes afford intracellular access to cardiomyocytes to report intracellular-like action potentials. These controllable nanotemplate electrodes exhibit sensitive and prolonged intracellular recordings of action potentials compared with free-growing 3D nanoelectrodes. This study indicates that the optimized structure of the nanoelectrode significantly promotes the performance of intracellular recording to assess electrophysiology in the fields of cardiology and neuroscience at an action potential level.
Assuntos
Fenômenos Eletrofisiológicos , Polietilenotereftalatos , Potenciais de Ação/fisiologia , Eletrodos , PorosidadeRESUMO
Optical recording based on voltage-sensitive fluorescent reporters allows for spatial flexibility of measuring from desired cells, but photobleaching and phototoxicity of the fluorescent labels often limit their sensitivity and recording duration. Voltage-dependent optical absorption, rather than fluorescence, of electrochromic materials, would overcome these limitations to achieve long-term optical recording of bioelectrical signals. Electrochromic materials such as PEDOT:PSS possess the property that an applied voltage can either increase or decrease the light absorption depending on the wavelength. In this work, we harness this anticorrelated light absorption at two different wavelengths to significantly improve the signal detection. With dual-color detection, electrical activity from cells produces signals of opposite polarity, while artifacts, mechanical motions, and technical noises are uncorrelated or positively correlated. Using this technique, we are able to optically record cardiac action potentials with a high signal-to-noise ratio, 10 kHz sampling rate, >15 min recording duration, and no time-dependent degradation of the signal. Furthermore, we can reliably perform multiple recording sessions from the same culture for over 25 days.
Assuntos
Neurônios , Polímeros , Potenciais de Ação/fisiologia , Fenômenos Eletrofisiológicos , Razão Sinal-RuídoRESUMO
Fluctuations of synaptic weights, among many other physical, biological, and ecological quantities, are driven by coincident events of two "parent" processes. We propose a multiplicative shot-noise model that can capture the behaviors of a broad range of such natural phenomena, and analytically derive an approximation that accurately predicts its statistics. We apply our results to study the effects of a multiplicative synaptic plasticity rule that was recently extracted from measurements in physiological conditions. Using mean-field theory analysis and network simulations, we investigate how this rule shapes the connectivity and dynamics of recurrent spiking neural networks. The multiplicative plasticity rule is shown to support efficient learning of input stimuli, and it gives a stable, unimodal synaptic-weight distribution with a large fraction of strong synapses. The strong synapses remain stable over long times but do not "run away." Our results suggest that the multiplicative shot-noise offers a new route to understand the tradeoff between flexibility and stability in neural circuits and other dynamic networks.
Assuntos
Modelos Neurológicos , Plásticos , Potenciais de Ação , Plasticidade Neuronal , SinapsesRESUMO
The application of electric field stimulation (EFS) can reduce the cation influx after spinal cord injury. However, regenerated cation influx and reestablished injury potential are observed after EFS. Polyethylene glycol (PEG) is popular as an effective cell membrane fusion agent. This study aims to determine the effects of the combination therapy of EFS and PEG in the ex vivo spinal cord after compression. The ex vivo spinal cords of female rats with compression injury were incubated in a double sucrose gap recording chamber (DSGRC) and randomly divided into the following four groups: (1) compression group: compression only, (2) EFS group: EFS for 15 min, (3) PEG group: PEG treatment for 4 min, and (4) EFS + PEG group: EFS for 15 min and PEG treatment for 4 min. The hematoxylin-eosin staining was performed to measure the necrotic area of the spinal cords. The gap potential was detected, and the area under the curve of the gap potential was calculated. The intracellular cation concentration, membrane permeability, and compound action potential were measured and quantified. Results revealed no significant difference in the necrotic areas among different groups, and the compression model of the ex vivo spinal cord in the DSGRC had high consistency and stability. The combination therapy could attenuate cation inflow, promote cell membrane restoration, and promote the functional recovery of the spinal cord conduction after compression in ex vivo spinal cords.
Assuntos
Estimulação Elétrica/métodos , Polietilenoglicóis/farmacologia , Compressão da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Terapia Combinada/métodos , Feminino , Condução Nervosa/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacosRESUMO
Cardiac sympathetic overactivation is involved in arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1ß in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of ventricular electrical activities, but also decreased the incidence and duration of ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.
Assuntos
Anti-Inflamatórios/farmacologia , Ácido Clodrônico/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Coração/inervação , Macrófagos/efeitos dos fármacos , Doenças Neuroinflamatórias/prevenção & controle , Gânglio Estrelado/efeitos dos fármacos , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/prevenção & controle , Potenciais de Ação , Animais , Canais de Cálcio Tipo N/metabolismo , Sinalização do Cálcio , Modelos Animais de Doenças , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipossomos , Macrófagos/metabolismo , Masculino , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/fisiopatologia , Ratos Sprague-Dawley , Gânglio Estrelado/metabolismo , Gânglio Estrelado/fisiopatologia , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fator de Necrose Tumoral alfa/metabolismo , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1G93A mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na+ channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age-matched SOD1G93A mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects, such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.SIGNIFICANCE STATEMENT Neurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1G93A mouse model for neurodegenerative motor neuron disease, amyotrophic lateral sclerosis. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na+ channel deficiency, which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects, such as muscle fasciculations in amyotrophic lateral sclerosis, as suggested by our computational model.
Assuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Propriocepção/fisiologia , Células Receptoras Sensoriais/fisiologia , Tegmento Mesencefálico/fisiologia , Potenciais de Ação , Animais , Modelos Animais de Doenças , Feminino , Arcada Osseodentária/inervação , Arcada Osseodentária/fisiopatologia , Masculino , Mecanorreceptores/fisiologia , Camundongos Transgênicos , Modelos Neurológicos , Nociceptividade/fisiologia , Superóxido Dismutase-1/genéticaRESUMO
Neuropeptide Y (NPY) is one of a number of neuropeptides with powerful orexigenic effects. Intracerebroventricular administration of NPY induces increases in food intake and alters feeding rate. Besides it role in feeding behavior, NPY also has significant effects on neuronal systems related to other spontaneous behaviors such as rearing and grooming. In the present study, we examined the direct effects of NPY on mesencephalic V neurons (Mes V), which are important sensory neurons involved in oral motor reflexes and rhythmical jaw movements, as well as masticatory proprioception. Coronal brain slices were prepared from neonatal Sprague-Dawley rats (P3-17) and whole-cell patch clamp recordings were obtained from Mes V neurons. Bath application of NPY depolarized the membrane potential and induced inward current in most neurons. Application of NPY shortened the duration of the afterhyperpolarization following an action potential, and increased the mean spike frequency during repetitive discharge. In those neurons which exhibited rhythmical burst discharge in response to maintained current injection, the bursting frequency was also increased. These effects were mediated predominately by both Y1 and Y5 receptors.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Animais , Animais Recém-Nascidos , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-DawleyRESUMO
Cell-to-cell communication via a local current caused by ion transport is elucidated using a model-cell system. To imitate tissues such as smooth muscles and cardiac muscles, liquid-membrane cells mimicking the function of K+ and Na+ channels were made. Connecting these channel-mimicking cells (K+ channel and voltage-gated Na+ channel) in parallel, model cells imitating living cell functions were constructed. Action-potential propagation within the cell aggregate model constructed by multiple model cells was investigated. When an action potential was generated at one cell, the cell behaved as an electric power source. Since a circulating current flowed around the cell, it flowed through neighboring model cells. Influx and efflux currents caused negative and positive shifts of the membrane potential, respectively, on the surface of neighboring model cells. The action potential was generated at the depolarized domain when the membrane potential exceeded the threshold of the voltage-gated Na+ channels. Thus, the action potential spread all over the cell system. When an external electric stimulus was applied to the layered cell-aggregate model system, propagation of the action potential was facilitated as if they were synchronized.
Assuntos
Células Artificiais , Comunicação Celular , Modelos Biológicos , Potenciais de Ação , Eletricidade , Eletrônica , Potenciais da Membrana , Potássio/química , Canais de Potássio/química , Sódio/química , Canais de Sódio/químicaRESUMO
The enhanced electrochemical activity of nanostructured materials is readily exploited in energy devices, but their utility in scalable and human-compatible implantable neural interfaces can significantly advance the performance of clinical and research electrodes. We utilize low-temperature selective dealloying to develop scalable and biocompatible one-dimensional platinum nanorod (PtNR) arrays that exhibit superb electrochemical properties at various length scales, stability, and biocompatibility for high performance neurotechnologies. PtNR arrays record brain activity with cellular resolution from the cortical surfaces in birds and nonhuman primates. Significantly, strong modulation of surface recorded single unit activity by auditory stimuli is demonstrated in European Starling birds as well as the modulation of local field potentials in the visual cortex by light stimuli in a nonhuman primate and responses to electrical stimulation in mice. PtNRs record behaviorally and physiologically relevant neuronal dynamics from the surface of the brain with high spatiotemporal resolution, which paves the way for less invasive brain-machine interfaces.
Assuntos
Potenciais de Ação , Materiais Biocompatíveis , Interfaces Cérebro-Computador , Nanotubos , Neurônios/metabolismo , Platina , Córtex Visual/fisiologia , Animais , Estimulação Elétrica , Eletrodos , Macaca mulatta , Masculino , Camundongos , Aves CanorasRESUMO
Despite the key role of beat-to-beat action potential (AP) variability in the onset of ventricular arrhythmias at high pacing rate, the knowledge of the involved dynamics and of effective prognostic parameters is largely incomplete. Electrical restitution (ER), the way AP duration (APD) senses changes in preceding cycle length (CL), has been used to monitor transition to arrhythmias. The use of standard ER (sER), though, is controversial, not always suitable for in vivo and only rarely for clinical applications. By means of simulations on a human ventricular AP model, I investigate the dynamics of APD at high pacing rate under sinusoidally, saw-tooth, and randomly variable pacing CLs. AP sequences were compared in terms of beat-to-beat restitution (btb-ER) and of the collections of sER curves generated from each beat. A definition of APD stability is also proposed, based on successive APD changes introduced in an AP sequence by a premature beat. The explored CL range includes values leading to APD alternans under constant pacing. Three different types of response to CL variability were found, corresponding to progressively higher rate of beat-to-beat CL changes. Low rates (â¼1 ms/beat) generate a btb-ER dominated by steady-state rate dependence of APD (type 1), intermediate rates (â¼5 ms/beat) lead to a btb-ER similar to a single sER (type 2), and high rates (â¼20 ms/beat) to hysteretic btb-ER under periodic pacing and to a vertically spread btb-ER in the case of random pacing (type 3). Stability of AP repolarization always increases with the rate of CL changes. Thus, rather than looking at sER slope, which requires additional interventions during the recording of cardiac electrical activity, this study provides rationale for the use of btb-ER representations as predictors of repolarization stability under extreme pacing conditions, known to be critical for the arrhythmia development.
Assuntos
Potenciais de Ação , Relógios Biológicos , Ventrículos do Coração/citologia , Modelos Cardiovasculares , Função Ventricular , Humanos , CinéticaRESUMO
The development of effective and safe therapies for scar-related ventricular tachycardias requires a detailed understanding of the mechanisms underlying the conduction block that initiates electrical re-entries associated with these arrhythmias. Conduction block has been often associated with electrophysiological changes that prolong action potential duration (APD) within the border zone (BZ) of chronically infarcted hearts. However, experimental evidence suggests that remodeling processes promoting conduction slowing as opposed to APD prolongation mark the chronic phase. In this context, the substrate for the initial block at the mouth of an isthmus/diastolic channel leading to ventricular tachycardia is unclear. The goal of this study was to determine whether electrophysiological parameters associated with conduction slowing can cause block and re-entry in the BZ. In silico experiments were conducted on two-dimensional idealized infarct tissue as well as on a cohort of postinfarction porcine left ventricular models constructed from ex vivo magnetic resonance imaging scans. Functional conduction slowing in the BZ was modeled by reducing sodium current density, whereas structural conduction slowing was represented by decreasing tissue conductivity and including fibrosis. The arrhythmogenic potential of APD prolongation was also tested as a basis for comparison. Within all models, the combination of reduced sodium current with structural remodeling more often degenerated into re-entry and, if so, was more likely to be sustained for more cycles. Although re-entries were also detected in experiments with prolonged APD, they were often not sustained because of the subsequent block caused by long-lasting repolarization. Functional and structural conditions associated with slow conduction rather than APD prolongation form a potent substrate for arrhythmogenesis at the isthmus/BZ of chronically infarcted hearts. Reduced excitability led to block while slow conduction shortened the wavelength of propagation, facilitating the sustenance of re-entries. These findings provide important insights for models of patient-specific risk stratification and therapy planning.
Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Infarto do Miocárdio/fisiopatologia , Potenciais de Ação , Animais , Fibrose , Cinética , Imageamento por Ressonância Magnética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Suínos , Taquicardia Ventricular/complicaçõesRESUMO
Although homeoproteins Msx1 and Msx2, the cell-specific transcription regulators, have been proven to play multiple roles in the embryogenesis of bone, muscle and tooth, the functions and mechanisms of Msx1 and Msx2 in the development of the central nervous system of mice after birth are not clear because of the death of Msx1 and Msx1/2 germline-deleted embryo at late gestation of mouse. In current research, Nestin-Cre mice was introduced to generate the central nervous system-specific knockout mice (Nestin-Cre;Msx1,Msx2fl/fl). We found that besides the falling of the body mass and the brain volume, the cortical tissue sections and staining showed the decreasing thickness of layer II-IV and declining number of vertebral cells in layer V resulting from Msx1/2 deletion. In addition, electrophysiological tests revealed the aberrant action potential parameters of deep pyramidal neurons in Nestin-Cre;Msx1,2â¯fl/fl mice, which may be related with the ethology impairment displayed in further experiments. We discovered Nestin-Cre;Msx1,2â¯fl/fl mice had severe impairment in their athletic ability and kinematic learning ability in rotate test, and exhibited hyperactivity in open-field test. Above all, our results revealed that deletion of homeoproteins Msx1 and Msx2 could lead to behavioral disorders and suggested that Msx1 and Msx2 played a crucial role in regulating the development and function of the neocortex. In addition, our current research provided a new mouse model for understanding the pathogenesis of human central nervous system disease.
Assuntos
Deleção de Genes , Proteínas de Homeodomínio/genética , Fator de Transcrição MSX1/genética , Neocórtex/patologia , Neurônios/patologia , Potenciais de Ação , Animais , Fenômenos Biomecânicos , Camundongos , Camundongos Knockout , Neocórtex/anormalidades , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurônios/metabolismo , Condicionamento Físico AnimalRESUMO
OBJECTIVE: Charcot-Marie-Tooth type 4J (CMT4J) is a rare autosomal recessive neuropathy caused by mutations in FIG4 that result in loss of FIG4 protein. This study investigates the natural history and mechanisms of segmental demyelination in CMT4J. METHODS: Over the past 9 years, we have enrolled and studied a cohort of 12 CMT4J patients, including 6 novel FIG4 mutations. We evaluated these patients and related mouse models using morphological, electrophysiological, and biochemical approaches. RESULTS: We found sensory motor demyelinating polyneuropathy consistently in all patients. This underlying myelin pathology was associated with nonuniform slowing of conduction velocities, conduction block, and temporal dispersion on nerve conduction studies, which resemble those features in acquired demyelinating peripheral nerve diseases. Segmental demyelination was also confirmed in mice without Fig4 (Fig4-/- ). The demyelination was associated with an increase of Schwann cell dedifferentiation and macrophages in spinal roots where nerve-blood barriers are weak. Schwann cell dedifferentiation was induced by the increasing intracellular Ca2+ . Suppression of Ca2+ level by a chelator reduced dedifferentiation and demyelination of Schwann cells in vitro and in vivo. Interestingly, cell-specific knockout of Fig4 in mouse Schwann cells or neurons failed to cause segmental demyelination. INTERPRETATION: Myelin change in CMT4J recapitulates the features of acquired demyelinating neuropathies. This pathology is not Schwann cell autonomous. Instead, it relates to systemic processes involving interactions of multiple cell types and abnormally elevated intracellular Ca2+ . Injection of a Ca2+ chelator into Fig4-/- mice improved segmental demyelination, thereby providing a therapeutic strategy against demyelination. Ann Neurol 2018;83:756-770.