RESUMO
Objective.Commonly used cable equation approaches for simulating the effects of electromagnetic fields on excitable cells make several simplifying assumptions that could limit their predictive power. Bidomain or 'whole' finite element methods have been developed to fully couple cells and electric fields for more realistic neuron modeling. Here, we introduce a novel bidomain integral equation designed for determining the full electromagnetic coupling between stimulation devices and the intracellular, membrane, and extracellular regions of neurons.Approach.Our proposed boundary element formulation offers a solution to an integral equation that connects the device, tissue inhomogeneity, and cell membrane-induced E-fields. We solve this integral equation using first-order nodal elements and an unconditionally stable Crank-Nicholson time-stepping scheme. To validate and demonstrate our approach, we simulated cylindrical Hodgkin-Huxley axons and spherical cells in multiple brain stimulation scenarios.Main Results.Comparison studies show that a boundary element approach produces accurate results for both electric and magnetic stimulation. Unlike bidomain finite element methods, the bidomain boundary element method does not require volume meshes containing features at multiple scales. As a result, modeling cells, or tightly packed populations of cells, with microscale features embedded in a macroscale head model, is simplified, and the relative placement of devices and cells can be varied without the need to generate a new mesh.Significance.Device-induced electromagnetic fields are commonly used to modulate brain activity for research and therapeutic applications. Bidomain solvers allow for the full incorporation of realistic cell geometries, device E-fields, and neuron populations. Thus, multi-cell studies of advanced neuronal mechanisms would greatly benefit from the development of fast-bidomain solvers to ensure scalability and the practical execution of neural network simulations with realistic neuron morphologies.
Assuntos
Campos Eletromagnéticos , Análise de Elementos Finitos , Modelos Neurológicos , Neurônios , Neurônios/fisiologia , Neurônios/efeitos da radiação , Humanos , Simulação por Computador , Animais , Axônios/fisiologia , Axônios/efeitos da radiação , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Encéfalo/fisiologiaRESUMO
OBJECTIVE: This study aims to explore the potential of organic electrolytic photocapacitors (OEPCs), an innovative photovoltaic device, in mediating the activation of native voltage-gated Cav1.2 channels (ICa,L) in Guinea pig ventricular cardiomyocytes. METHODS: Whole-cell patch-clamp recordings were employed to examine light-triggered OEPC mediated ICa,L activation, integrating the channel's kinetic properties into a multicompartment cell model to take intracellular ion concentrations into account. A multidomain model was additionally incorporated to evaluate effects of OEPC-mediated stimulation. The final model combines external stimulation, multicompartmental cell simulation, and a patch-clamp amplifier equivalent circuit to assess the impact on achievable intracellular voltage changes. RESULTS: Light pulses activated ICa,L, with amplitudes similar to voltage-clamp activation and high sensitivity to the L-type Ca2+ channel blocker, nifedipine. Light-triggered ICa,L inactivation exhibited kinetic parameters comparable to voltage-induced inactivation. CONCLUSION: OEPC-mediated activation of ICa,L demonstrates their potential for nongenetic optical modulation of cellular physiology potentially paving the way for the development of innovative therapies in cardiovascular health. The integrated model proves the light-mediated activation of ICa,L and advances the understanding of the interplay between the patch-clamp amplifier and external stimulation devices. SIGNIFICANCE: Treating cardiac conduction disorders by minimal-invasive means without genetic modifications could advance therapeutic approaches increasing patients' quality of life compared with conventional methods employing electronic devices.
Assuntos
Canais de Cálcio Tipo L , Simulação por Computador , Miócitos Cardíacos , Animais , Cobaias , Miócitos Cardíacos/fisiologia , Canais de Cálcio Tipo L/metabolismo , Técnicas de Patch-Clamp , Modelos Cardiovasculares , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , LuzRESUMO
Optoelectronic biointerfaces have gained significant interest for wireless and electrical control of neurons. Three-dimentional (3D) pseudocapacitive nanomaterials with large surface areas and interconnected porous structures have great potential for optoelectronic biointerfaces that can fulfill the requirement of high electrode-electrolyte capacitance to effectively transduce light into stimulating ionic currents. In this study, the integration of 3D manganese dioxide (MnO2 ) nanoflowers into flexible optoelectronic biointerfaces for safe and efficient photostimulation of neurons is demonstrated. MnO2 nanoflowers are grown via chemical bath deposition on the return electrode, which has a MnO2 seed layer deposited via cyclic voltammetry. They facilitate a high interfacial capacitance (larger than 10 mF cm-2 ) and photogenerated charge density (over 20 µC cm-2 ) under low light intensity (1 mW mm-2 ). MnO2 nanoflowers induce safe capacitive currents with reversible Faradaic reactions and do not cause any toxicity on hippocampal neurons in vitro, making them a promising material for biointerfacing with electrogenic cells. Patch-clamp electrophysiology is recorded in the whole-cell configuration of hippocampal neurons, and the optoelectronic biointerfaces trigger repetitive and rapid firing of action potentials in response to light pulse trains. This study points out the potential of electrochemically-deposited 3D pseudocapacitive nanomaterials as a robust building block for optoelectronic control of neurons.
Assuntos
Eletroquímica , Luz , Compostos de Manganês , Nanoestruturas , Neurônios , Óxidos , Potenciais de Ação/efeitos da radiação , Capacitância Elétrica , Eletroquímica/métodos , Eletrodos , Eletrólitos/química , Eletrólitos/efeitos da radiação , Eletrofisiologia , Hipocampo/citologia , Compostos de Manganês/química , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Nanoestruturas/efeitos da radiação , Neurônios/metabolismo , Neurônios/efeitos da radiação , Óxidos/química , Técnicas de Patch-Clamp , Estimulação Luminosa , Tecnologia sem Fio , Humanos , Animais , RatosRESUMO
Optical stimulation technologies are gaining great consideration in cardiology, neuroscience studies, and drug discovery pathways by providing control over cell activity with high spatio-temporal resolution. However, this high precision requires manipulation of biological processes at genetic level concealing its development from broad scale application. Therefore, translating these technologies into tools for medical or pharmacological applications remains a challenge. Here, an all-optical nongenetic method for the modulation of electrogenic cells is introduced. It is demonstrated that plasmonic metamaterials can be used to elicit action potentials by converting near infrared laser pulses into stimulatory currents. The suggested approach allows for the stimulation of cardiomyocytes and neurons directly on commercial complementary metal-oxide semiconductor microelectrode arrays coupled with ultrafast pulsed laser, providing both stimulation and network-level recordings on the same device.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Raios Infravermelhos , Miócitos Cardíacos/fisiologia , Nanoestruturas/toxicidade , Neurônios/fisiologia , Potenciais de Ação/efeitos da radiação , Animais , Linhagem Celular , Humanos , Metais/química , Camundongos , Microeletrodos , Miócitos Cardíacos/citologia , Nanoestruturas/química , Neurônios/citologia , Porosidade , Ratos , Semicondutores , Dióxido de Silício/químicaRESUMO
Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.
Assuntos
Conexina 43/genética , Sistema de Condução Cardíaco/efeitos da radiação , Coração/efeitos da radiação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Taquicardia Ventricular/radioterapia , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Animais , Conexina 43/metabolismo , Relação Dose-Resposta à Radiação , Eletrocardiografia , Fibrose Endomiocárdica , Feminino , Regulação da Expressão Gênica , Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/fisiologia , Frequência Cardíaca/efeitos da radiação , Humanos , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Transdução de Sinais , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologiaRESUMO
Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of -C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input-output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.
Assuntos
Comportamento Animal/efeitos da radiação , Raios Infravermelhos , Neurônios/metabolismo , Transdução de Sinais/efeitos da radiação , Transmissão Sináptica/efeitos da radiação , Peixe-Zebra/metabolismo , Potenciais de Ação/efeitos da radiação , Animais , CamundongosRESUMO
Epiretinal prostheses aim at electrically stimulating the inner most surviving retinal cells-retinal ganglion cells (RGCs)-to restore partial sight to the blind. Recent tests in patients with epiretinal implants have revealed that electrical stimulation of the retina results in the percept of color of the elicited phosphenes, which depends on the frequency of stimulation. This paper presents computational results that are predictive of this finding and further support our understanding of the mechanisms of color encoding in electrical stimulation of retina, which could prove pivotal for the design of advanced retinal prosthetics that elicit both percept and color. This provides, for the first time, a directly applicable "amplitude-frequency" stimulation strategy to "encode color" in future retinal prosthetics through a predictive computational tool to selectively target small bistratified cells, which have been shown to contribute to "blue-yellow" color opponency in the retinal circuitry. The presented results are validated with experimental data reported in the literature and correlated with findings in blind patients with a retinal prosthetic implant collected by our group.
Assuntos
Cegueira/terapia , Neurônios/fisiologia , Retina/fisiopatologia , Células Ganglionares da Retina/fisiologia , Potenciais de Ação/efeitos da radiação , Cegueira/fisiopatologia , Simulação por Computador , Estimulação Elétrica , Terapia por Estimulação Elétrica , Membrana Epirretiniana/patologia , Humanos , Neurônios/patologia , Retina/diagnóstico por imagem , Células Ganglionares da Retina/patologia , Próteses VisuaisRESUMO
Probable mechanism behind the neuronal ephaptic coupling is investigated based on the introduction of "Brain"-triggered potential excitation signal smartly with a specific very low frequency (VLF) waves as a neuronal motor toolkit. Detection of this electric motor toolkit is attributed to in-vitro precise analyses of a neural network of snail, along to the disconnected snail's neuronal network as a control. This is achieved via rapid (real-time) electrical signals acquisition by blind patch-clamp method during micro-electrode implanting in the neurons at the gigaseal conditions by the surgery operations. This process is based on its waveform (potential excitation signal) detection by mathematical curve fitting process. The characterized waveform of this electrical signal is "Saw Tooth" that is smartly stimulated, alternatively, by the brain during triggering the action potential's (AP's) hyperpolarization zone at a certain time interval at the several µs levels. Triggering the neuron cells results in (1) observing a positive shift (10.0%, depending on the intensity of the triggering wave), and (2) major promotion in the electrical current from sub nano (n) to micro (µ) amper (nA, µA) levels. Direct tracing the time domain (i.e., electrical signal vs. time) and estimation of the frequency domain (diagram of electrical response vs. the applied electrical frequencies) by the "Discrete Fast Fourier Transform" algorithm approve the presence of bilateral and reversible electrical currents between axon and dendrite. This mechanism therefore opens a novel view about the neuronal motor toolkit mechanism, versus the general knowledge about the unilateral electrical current flow from axon to dendrite operations in as neural network. The reliability of this mechanism is evaluated via (1) sequential modulation and demodulation of the snail's neuron network by a simulation electrical functions and sequentially evaluation of the neuronal current sensitivity between pA and nA (during the promotion of the signal-to-noise ratio, via averaging of 30 ± 1 (n = 15) and recycling the electrical cycles before any neuronal response); and (2) operation of the process on the differentiated stem cells. The interstice behavior is attributed to the effective role of Ca2+ channels (besides Na+ and K+ ionic pumping), during hyper/hypo calcium processes, evidenced by inductively coupled plasma as the selected analytical method. This phenomenon is also modeled during proposing quadrupole well potential levels in the neuron systems. This mechanism therefore points to the microprocessor behavior of neuron networks. Stimulation of the neuronal system based on this mechanism, not only controls the sensitivity of neuron electrical stimulation, but also would open a light window for more efficient operating the neuronal connectivity during providing interruptions by phenomena such as neurolysis as well as an efficient treatment of neuron-based disorders.
Assuntos
Axônios/fisiologia , Encéfalo/fisiologia , Neurônios Motores/fisiologia , Neurônios Eferentes/fisiologia , Caramujos/fisiologia , Potenciais de Ação/efeitos da radiação , Animais , Axônios/efeitos da radiação , Encéfalo/efeitos da radiação , Ondas Encefálicas/fisiologia , Cálcio/metabolismo , Estimulação Elétrica/efeitos adversos , Potenciais da Membrana/efeitos da radiação , Neurônios Motores/efeitos da radiação , Rede Nervosa/fisiologia , Rede Nervosa/efeitos da radiação , Neurônios Eferentes/efeitos da radiação , Técnicas de Patch-Clamp , Caramujos/efeitos da radiaçãoRESUMO
Transcranial static magnetic stimulation is a novel noninvasive method of reduction of the cortical excitability in certain neurological diseases that makes use of static magnetic fields generated by permanent magnets. By contrast, ordinary transcranial magnetic stimulation makes use of pulsed magnetic fields generated by strong currents. Whereas the physical principle underlying ordinary transcranial magnetic stimulation is well known, that is, the Faraday´s law, the physical mechanism that explains the interaction between neurons and static magnetic fields in transcranial static magnetic stimulation remains unclear. In the present work, it is discussed the possibility that this mechanism might be the Lorentz force exerted on the ions flowing along the membrane channels of neurons. The overall effect of the static magnetic field would be to introduce an additional friction between the ions and the walls of the membrane channels, thus reducing its conductance. Calculations performed by using a Hodgkin-Huxley model demonstrate that even a slight reduction of the conductance of the membrane channels can lead to the suppression of the action potential, thus inhibiting neuronal activity.
Assuntos
Membrana Celular/metabolismo , Membrana Celular/efeitos da radiação , Fenômenos Eletromagnéticos , Canais Iônicos/metabolismo , Neurônios/citologia , Estimulação Magnética Transcraniana , Potenciais de Ação/efeitos da radiação , Fricção/efeitos da radiação , Modelos BiológicosRESUMO
The objective of the study was to investigate the efficacy of three energy densities 4, 10, and 50 J/cm2 of pulsed Nd:YAG laser for the treatment of crushed sciatic nerve in Wister rats by evaluating changes in the sciatic functional index and the electrophysiology.A total of 180 Wistar rats were involved in the study. Rats were randomly assigned to five groups. Rats were subjected to the sciatic nerve crushing. Control negative (CONT-ve), which received no crushing; control positive (CONT+ve), which received crushing with no laser; and HILT-4, HILT-10, and HILT-50 groups, which received pulsed Nd:YAG laser (10 Hz, 360 mJ/cm2) with energy densities 4, 10, and 50 J/cm2, respectively. The SFI, the amilitude of compound motor action potential (CMAP) and sciatic motor nerve conduction velocity (MNCV) were measured before and after seven, 14, and 21 days after crushing. For the SFI and electrophysiological analysis, repeated measures ANOVA is used, followed by Bonferroni's repeated-measures test. Statistical significance was set at p < 0.05. After one week, there was no significant difference in SFI, CMAP, and MNCV among the three laser groups with significant changes between them and CONT-ve and CONT+ve groups. There was a significant increase in either CMAP amplitude or MNCV after 14 days with significant decrease in the SFI after 21 days among all treatment groups. The pulsed Nd:YAG laser applied with energy densities 4, 10, and 50 J/cm2 significantly decreased the SFI and increased the CMAP and MNCV of the crushed sciatic nerve in Wister rats. Among laser doses, the difference in the rate of recovery in the electrophysiology was found after two weeks while in the SFI after three weeks. The improvement after the nerve injury was time and dose dependent.
Assuntos
Lasers de Estado Sólido/uso terapêutico , Compressão Nervosa , Nervo Isquiático/lesões , Nervo Isquiático/efeitos da radiação , Potenciais de Ação/efeitos da radiação , Animais , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Masculino , Regeneração Nervosa/fisiologia , Condução Nervosa/efeitos da radiação , Ratos Wistar , Nervo Isquiático/fisiopatologiaRESUMO
In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.
Assuntos
Neocórtex/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Animais , Feminino , Ritmo Gama/efeitos da radiação , Luz , Potenciação de Longa Duração/fisiologia , Potenciação de Longa Duração/efeitos da radiação , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Inibição Neural/efeitos da radiação , Plasticidade Neuronal/efeitos da radiação , Células Piramidais/fisiologia , Células Piramidais/efeitos da radiação , Sinapses/efeitos da radiação , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismoRESUMO
Optogenetics enables cell-type specific monitoring and actuation via light-activated proteins. In cardiac research, expressing light-activated depolarising ion channels in cardiomyocytes allows optical pacing and defibrillation. Previous studies largely relied on epicardial illumination. Light penetration through the myocardium is however problematic when moving to larger animals and humans. To overcome this limitation, we assessed the utility of an implantable multi light-emitting diode (LED) optical probe (IMLOP) for intramural pacing of mouse hearts expressing cardiac-specific channelrhodopsin-2 (ChR2). Here we demonstrated that IMLOP insertion needs approximately 20 mN of force, limiting possible damage from excessive loads applied during implantation. Histological sections confirmed the confined nature of tissue damage during acute use. The temperature change of the surrounding tissue was below 1 K during LED operation, rendering the probe safe for use in situ. This was confirmed in control experiments where no effect on cardiac action potential conduction was observed even when using stimulation parameters twenty-fold greater than required for pacing. In situ experiments on ChR2-expressing mouse hearts demonstrated that optical stimulation is possible with light intensities as low as 700 µW/mm2; although stable pacing requires higher intensities. When pacing with a single LED, rheobase and chronaxie values were 13.3 mW/mm2 ± 0.9 mW/mm2 and 3 ms ± 0.6 ms, respectively. When doubling the stimulated volume the rheobase decreased significantly (6.5 mW/mm2 ± 0.9 mW/mm2). We have demonstrated IMLOP-based intramural optical pacing of the heart. Probes cause locally constrained tissue damage in the acute setting and require low light intensities for pacing. Further development is necessary to assess effects of chronic implantation.
Assuntos
Channelrhodopsins/metabolismo , Regulação da Expressão Gênica , Audição/fisiologia , Dispositivos Ópticos , Potenciais de Ação/efeitos da radiação , Animais , Regulação da Expressão Gênica/efeitos da radiação , Audição/efeitos da radiação , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos da radiação , TemperaturaRESUMO
BACKGROUND AND OBJECTIVES: The objective of this study is to assess the hypothesis that the length of axon heated, defined here as block length (BL), affects the temperature required for thermal inhibition of action potential propagation applied using laser heating. The presence of such a phenomenon has implications for how this technique, called infrared neural inhibition (INI), may be applied in a clinically safe manner since it suggests that temperatures required for therapy may be reduced through the proper spatial application of light. Here, we validate the presence of this phenomenon by assessing how the peak temperatures during INI are reduced when two different BLs are applied using irradiation from either one or two adjacent optical fibers. STUDY DESIGN/MATERIALS AND METHODS: Assessment of the role of BL was carried out over two phases. First, a computational proof of concept was performed in the neural conduction simulation environment, NEURON, simulating the response of action potentials to increased temperatures applied at different full-width at half-maxima (FWHM) along axons. Second, ex vivo validation of these predictions was performed by measuring the radiant exposure, peak temperature rise, and FWHM of heat distributions associated with INI from one or two adjacent optical fibers. Electrophysiological assessment of radiant exposures at inhibition threshold were carried out in ex vivo Aplysia californica (sea slug) pleural abdominal nerves ( n = 6), an invertebrate with unmyelinated axons. Measurement of the maximum temperature rise required for induced heat block was performed in a water bath using a fine wire thermocouple. Finally, magnetic resonance thermometry (MRT) was performed on a nerve immersed in saline to assess the elevated temperature distribution at these radiant exposures. RESULTS: Computational modeling in NEURON provided a theoretical proof of concept that the BL is an important factor contributing to the peak temperature required during neural heat block, predicting a 11.7% reduction in temperature rise when the FWHM along an axon is increased by 42.9%. Experimental validation showed that, when using two adjacent fibers instead of one, a 38.5 ± 2.2% (mean ± standard error of the mean) reduction in radiant exposure per pulse per fiber threshold at the fiber output (P = 7.3E-6) is measured, resulting in a reduction in peak temperature rise under each fiber of 23.5 ± 2.1% ( P = 9.3E-5) and 15.0 ± 2.4% ( P = 1.4E-3) and an increase in the FWHM of heating by 37.7 ± 6.4% ( P = 1E-3), 68.4 ± 5.2% ( P = 2.4E-5), and 51.9 ± 9.9% ( P = 1.7E-3) in three MRT slices. CONCLUSIONS: This study provides the first experimental evidence for a phenomenon during the heat block in which the temperature for inhibition is dependent on the BL. While more work is needed to further reduce the temperature during INI, the results highlight that spatial application of the temperature rise during INI must be considered. Optimized implementation of INI may leverage this cellular response to provide optical modulation of neural signals with lower temperatures over greater time periods, which may increase the utility of the technique for laboratory and clinical use. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
Assuntos
Potenciais de Ação/efeitos da radiação , Lasers , Inibição Neural/efeitos da radiação , Animais , Aplysia , Desenho de Equipamento , Tecnologia de Fibra Óptica , Temperatura Alta , Raios Infravermelhos , Imageamento por Ressonância Magnética , Estudo de Prova de Conceito , Condutividade TérmicaRESUMO
Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
Assuntos
Axônios/fisiologia , Encefalopatias/fisiopatologia , Neurônios/efeitos da radiação , Esquizofrenia/fisiopatologia , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Animais , Axônios/efeitos da radiação , Corpo Estriado/fisiopatologia , Corpo Estriado/efeitos da radiação , Modelos Animais de Doenças , Estimulação Elétrica , Função Executiva/efeitos da radiação , Lobo Frontal/fisiopatologia , Lobo Frontal/efeitos da radiação , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Memória de Curto Prazo/efeitos da radiação , Neurônios/patologia , Optogenética/métodos , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/efeitos da radiação , Ratos , Tempo de Reação/fisiologia , Tempo de Reação/efeitos da radiação , Esquizofrenia/diagnóstico por imagemRESUMO
A key assumption of optogenetics is that light only affects opsin-expressing neurons. However, illumination invariably heats tissue, and many physiological processes are temperature-sensitive. Commonly used illumination protocols increased the temperature by 0.2-2 °C and suppressed spiking in multiple brain regions. In the striatum, light delivery activated an inwardly rectifying potassium conductance and biased rotational behavior. Thus, careful consideration of light-delivery parameters is required, as even modest intracranial heating can confound interpretation of optogenetic experiments.
Assuntos
Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Temperatura , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/efeitos da radiação , Animais , Compostos de Bário/farmacologia , Córtex Cerebral/citologia , Cloretos/farmacologia , Corpo Estriado/citologia , Hipocampo/citologia , Temperatura Alta , Transporte de Íons/efeitos dos fármacos , Transporte de Íons/efeitos da radiação , Luz , Camundongos , Atividade Motora/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Optogenética/métodos , Técnicas de Patch-Clamp , Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/efeitos da radiação , Projetos de PesquisaRESUMO
Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects.SIGNIFICANCE STATEMENT Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are unknown, making it difficult to optimize in any given application. We studied the physical mechanism by which ultrasound is converted into an effective energy form to cause neurostimulation in the retina and find that ultrasound acts via radiation force leading to a mechanical displacement of tissue. We further show that standing waves have a strong modulatory effect on activity. Our quantitative model by which ultrasound generates radiation force and leads to neural activity will be important in optimizing ultrasonic neurostimulation across a wide range of applications.
Assuntos
Retina/efeitos da radiação , Ondas Ultrassônicas , Acústica , Potenciais de Ação/efeitos da radiação , Ambystoma , Animais , Feminino , Corantes Fluorescentes/efeitos da radiação , Masculino , Camundongos , Microscopia Confocal , Modelos Neurológicos , Técnicas de Cultura de Órgãos , Fosfenos/fisiologia , Compostos de Piridínio/efeitos da radiação , Compostos de Amônio Quaternário/efeitos da radiação , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação , TemperaturaRESUMO
There is evidence that millimeter waves (MMWs) can have an impact on cellular function, including neurons. Earlier in vitro studies have shown that exposure levels well below the recommended safe limit of 1 mW/cm2 cause changes in the action potential (AP) firing rate, resting potential, and AP pulse shape of sensory neurons in leech preparations as well as alter neuronal properties in rat cortical brain slices; these effects differ from changes induced by direct heating. In this article, we compare the responses of thermosensitive primary nociceptors of the medicinal leech under thermal heating and MMW irradiation (80-170 mW/cm2 at 60 GHz). The results show that MMW exposure causes an almost twofold decrease in the threshold for activation of the AP compared with thermal heating (3.9 ± 0.4 vs. 8.3 ± 0.4 mV, respectively). Our analysis suggests that MMWs-mediated threshold alterations are not caused by the enhancement of voltage-gated sodium and potassium conductance. We propose that the reduction in AP threshold can be attributed to the sensitization of the transient receptor potential vanilloid 1-like receptor in the leech nociceptor. In silico modeling supported our experimental findings. Our results provide evidence that MMW exposure stimulates specific receptor responses that differ from direct thermal heating, fostering the need for additional studies.
Assuntos
Nociceptores/metabolismo , Nociceptores/efeitos da radiação , Ondas de Rádio/efeitos adversos , Canais de Cátion TRPV/metabolismo , Potenciais de Ação/efeitos da radiação , Animais , Sobrevivência Celular/efeitos da radiação , Nociceptores/citologia , TemperaturaRESUMO
In this study, we combine heat diffusion equation and modified Hodgkin-Huxley axonal model to investigate how an action potential is generated during infrared neural stimulation. The effects of temporal and spatial distribution of heat induced by infrared pulsed lasers on variation of electrical membrane capacitance are investigated. These variations can lead to depolarize the membrane and generate an action potential. We estimate the threshold values of laser light parameters such as energy density, pulse duration, and repetition rate are needed to trigger an action potential. In order to do it, we present an analytic solution to heat diffusion equation. Then, the analytic results are verified by experimental results. Furthermore, the modified Hodgkin-Huxley axonal model is applied to simulate the generation of action potential during infrared neural stimulation by taking into account the temperature dependence of electrical membrane capacitance. Results show that the threshold temperature increase induced by a train infrared pulse laser can be smaller if repetition rate is higher. These results also indicate that temperature rise time and axon diameter influence on threshold temperature increase. To verify threshold values estimated by the presented method, we use a train infrared pulsed laser (λ = 1450 nm with repetition rate of 3.8 Hz, pulse duration of 18 ms and energy density of 5 J/cm2) to optically pace an adult rat heart, and we are able to successfully pace the rat heart during an open-heart surgery. The presented method can be used to estimate threshold values of laser parameters required for generating an action potential, and it can provide an insight to how the temperature changes lead to neural stimulation during INS.
Assuntos
Raios Infravermelhos , Lasers , Sistema Nervoso/efeitos da radiação , Potenciais de Ação/efeitos da radiação , Animais , Axônios/efeitos da radiação , Membrana Celular/efeitos da radiação , Masculino , Imagens de Fantasmas , Ratos , Temperatura , Fatores de TempoRESUMO
OBJECTIVE: In this paper, a new method was established to monitor multichannel neural activity with microelectrode arrays (MEAs) under modulation of caged compounds in a rat model of seizures. METHODS: The 16-channel MEAs were fabricated and implanted into the hippocampus of normal rats and epileptic rats for neural spike and local field potential (LFP) recording. Using optical fibers with drug delivery tubing, two different caged compounds [ruthenium-bipyridine-trimethylphosphine glutamate (RuBi-Glu) and ruthenium-bipyridine-trimethylphosphine gamma aminobutyric acid (RuBi-GABA)] were applied, and blue light (465 nm) was used to modulate neural activity. RESULTS: In normal rats, RuBi-Glu excited neural activity, and RuBi-GABA inhibited neural activity. The amplitude of spikes increased 26% from 154 to 194 µV with RuBi-Glu modulation. During RuBi-GABA modulation, spikes recovered to 142 µV. The firing rate increased from 1.4 to 4.5 Hz with RuBi-Glu modulation and decreased to 0.8 Hz after RuBi-GABA modulation. The power of LFPs increased from 566 to 1128 µW with RuBi-Glu modulation and recovered to 710 µW with RuBi-GABA modulation. In epileptic rats, the neural activity during seizures was significantly inhibited by RuBi-GABA modulation. The amplitude of spikes was 242 µV during seizures and decreased to 112 µV with RuBi-GABA modulation. The firing rate decreased from 20.29 to 1.33 Hz with RuBi-GABA modulation. CONCLUSION: Using MEAs, the modulation of neural activity with caged compound photolysis was observed with high temporal-spatial resolution in normal and epileptic rats. SIGNIFICANCE: This new method is important for monitoring neural activity with photo-switchable modulation.
Assuntos
Potenciais de Ação , Eletrofisiologia/métodos , Hipocampo , Neurofisiologia/métodos , Convulsões/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/efeitos da radiação , Animais , Eletrofisiologia/instrumentação , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Microeletrodos , Neurofisiologia/instrumentação , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Estimulação Luminosa , Fotólise , Ratos , Compostos de Rutênio/metabolismo , Compostos de Rutênio/farmacologia , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here, we address these problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting soma-targeted GtACRs show improved photocurrents, reduced axonal excitation and high light sensitivity, allowing highly efficient inhibition of neuronal activity in the mammalian brain.