Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation.

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.

Radiation Force as a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina.

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.

Identifying the Role of Block Length in Neural Heat Block to Reduce Temperatures During Infrared Neural Inhibition.

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.

Dose-dependent effect of the pulsed Nd:YAG laser in the treatment of crushed sciatic nerve in Wister rats: an experimental model.

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.

The Lorentz force on ions in membrane channels of neurons as a mechanism for transcranial static magnetic stimulation.

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.

Millimeter Wave Radiation Activates Leech Nociceptors via TRPV1-Like Receptor Sensitization.

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.

Optogenetic Activation of Colon Epithelium of the Mouse Produces High-Frequency Bursting in Extrinsic Colon Afferents and Engages Visceromotor Responses.

Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial-neuronal signaling at this interface, we analyzed mice in which channelrhodopsin (ChR2) was targeted to either TRPV1-positive afferents or to villin-expressing colon epithelial cells. Expression of a ChR2-EYFP fusion protein was directed to either primary sensory neurons or to colon epithelial cells by crossing Ai32 mice with TRPV1-Cre or villin-Cre mice, respectively. An ex vivo preparation of the colon was used for single-fiber analysis of colon sensory afferents of the pelvic nerve. Afferents were characterized using previously described criteria as mucosal, muscular, muscular-mucosal, or serosal and then tested for blue light-induced activation. Light activation of colon epithelial cells produced robust firing of action potentials, similar to that elicited by physiologic stimulation (e.g., circumferential stretch), in 50.5% of colon afferents of mice homozygous for ChR2 expression. Light-induced activity could be reduced or abolished in most fibers using a cocktail of purinergic receptor blockers suggesting ATP release by the epithelium contributed to generation of sensory neuron action potentials. Using electromyographic recording of visceromotor responses we found that light stimulation of the colon epithelium evoked behavioral responses in Vil-ChR2 mice that was similar to that seen with balloon distension of the colon. These ex vivo and in vivo data indicate that light stimulation of colon epithelial cells alone, without added mechanical or chemical stimuli, can directly activate colon afferents and elicit behavioral responses.SIGNIFICANCE STATEMENT Abdominal pain that accompanies inflammatory diseases of the bowel is particularly vexing because it can occur without obvious changes in the structure or inflammatory condition of the colon. Pain reflects abnormal sensory neuron activity that may be controlled in part by release of substances from lining epithelial cells. In support of this mechanism we determined that blue-light stimulation of channelrhodopsin-expressing colon epithelial cells could evoke action potential firing in sensory neurons and produce changes in measures of behavioral sensitivity. Thus, activity of colon epithelial cells alone, without added mechanical or chemical stimuli, is sufficient to activate pain-sensing neurons.

Anatomical Correlates of Local, Translaminar, and Transcolumnar Inhibition by Layer 6 GABAergic Interneurons in Somatosensory Cortex.

In the vibrissal area of rodent somatosensory cortex, information on whisker stimulation is processed by neuronal networks in a corresponding cortical column. To understand how sensory stimuli are represented in a column, it is essential to identify cell types constituting these networks. Layer 6 (L6) comprises 25% of all neurons in a column. In rats, 430 of these are inhibitory interneurons (INs). Little is known about the axon projection of L6 INs with reference to columnar and laminar organization. We quantified axonal projections of L6 INs (n = 68) with reference to columns and layers in somatosensory cortex of rats. We found distinct projection types differentially targeting layers of a cortical column. The majority of L6 INs did not show a column-specific innervation, densely projecting to neighboring columns as well as the home column. However, a small fraction targeted granular and supragranular layers, where axon projections were confined to the home column. We also quantified putative innervation of pyramidal cells as a functional correlate of axonal distribution. Electrophysiological properties were not correlated to axon projection. The quantitative data on axonal projections and electrophysiological properties of L6 INs can guide future studies investigating cortical processing of sensory information at the single cell level.

Luminopsins integrate opto- and chemogenetics by using physical and biological light sources for opsin activation.

Luminopsins are fusion proteins of luciferase and opsin that allow interrogation of neuronal circuits at different temporal and spatial resolutions by choosing either extrinsic physical or intrinsic biological light for its activation. Building on previous development of fusions of wild-type Gaussia luciferase with channelrhodopsin, here we expanded the utility of luminopsins by fusing bright Gaussia luciferase variants with either channelrhodopsin to excite neurons (luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO, iLMO). These improved LMOs could reliably activate or silence neurons in vitro and in vivo. Expression of the improved LMO in hippocampal circuits not only enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal resolution but also could drive rhythmic circuit excitation over a large spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or iLMO in the substantia nigra in vivo produced not only the expected bidirectional control of single unit activity but also opposing effects on circling behavior in response to systemic injection of a luciferase substrate. Thus, although preserving the ability to be activated by external light sources, LMOs expand the use of optogenetics by making the same opsins accessible to noninvasive, chemogenetic control, thereby allowing the same probe to manipulate neuronal activity over a range of spatial and temporal scales.

Influence of radiant exposure and repetition rate in infrared neural stimulation with near-infrared lasers.

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.

Decreased spontaneous electrical activity in neuronal networks exposed to radiofrequency 1,800 MHz signals.

The rapid development of wireless communications has raised questions about their potential health risks. So far, the only identified biological effects of radiofrequency fields (RF) are known to be caused by heating, but the issue of potential nonthermal biological effects, especially on the central nervous system (CNS), remains open. We previously reported a decrease in the firing and bursting rates of neuronal cultures exposed to a Global System for Mobile (GSM) RF field at 1,800 MHz for 3 min (Moretti D, Garenne A, Haro E, Poulleier de Gannes F, Lagroye I, Lévêque P, Veyret B, Lewis N. Bioelectromagnetics 34: 571-578, 2013). The aim of the present work was to assess the dose-response relationship for this effect and also to identify a potential differential response elicited by pulse-modulated GSM and continuous-wave (CW) RF fields. Spontaneous bursting activity of neuronal cultures from rat embryonic cortices was recorded using 60-electrode multielectrode arrays (MEAs). At 17-28 days in vitro, the neuronal cultures were subjected to 15-min RF exposures, at specific absorption rates (SAR) ranging from 0.01 to 9.2 W/kg. Both GSM and CW signals elicited a clear decrease in bursting rate during the RF exposure phase. This effect became more marked with increasing SAR and lasted even beyond the end of exposure for the highest SAR levels. Moreover, the amplitude of the effect was greater with the GSM signal. Altogether, our experimental findings provide evidence for dose-dependent effects of RF signals on the bursting rate of neuronal cultures and suggest that part of the mechanism is nonthermal. NEW & NOTEWORTHY In this study, we investigated the effects of some radiofrequency (RF) exposure parameters on the electrical activity of neuronal cultures. We detected a clear decrease in bursting activity, dependent on exposure duration. The amplitude of this effect increased with the specific absorption rate (SAR) level and was greater with Global System for Mobile signal than with continuous-wave signal, at the same average SAR. Our experiment provides unique evidence of a decrease in electrical activity of cortical neuronal cultures during RF exposure.

Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output.

The axon initial segment (AIS) is a structure at the start of the axon with a high density of sodium and potassium channels that defines the site of action potential generation. It has recently been shown that this structure is plastic and can change its position along the axon, as well as its length, in a homeostatic manner. Chronic activity-deprivation paradigms in a chick auditory nucleus lead to a lengthening of the AIS and an increase in neuronal excitability. On the other hand, a long-term increase in activity in dissociated rat hippocampal neurons results in an outward movement of the AIS and a decrease in the cell's excitability. Here, we investigated whether the AIS is capable of undergoing structural plasticity in rat hippocampal organotypic slices, which retain the diversity of neuronal cell types present at postnatal ages, including chandelier cells. These interneurons exclusively target the AIS of pyramidal neurons and form rows of presynaptic boutons along them. Stimulating individual CA1 pyramidal neurons that express channelrhodopsin-2 for 48 h leads to an outward shift of the AIS. Intriguingly, both the pre- and postsynaptic components of the axo-axonic synapses did not change position after AIS relocation. We used computational modeling to explore the functional consequences of this partial mismatch and found that it allows the GABAergic synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability. We propose that this spatial arrangement is the optimal configuration for a homeostatic response to long-term stimulation.

Elevated intraocular pressure decreases response sensitivity of inner retinal neurons in experimental glaucoma mice.

Glaucoma is the second leading cause of blindness in the United States and the world, characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGCs). Glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs in sectored patterns. Recent evidence has suggested that this early sensitivity loss may be associated with dysfunctions in the inner retina, but detailed cellular and synaptic mechanisms underlying such sensitivity changes are largely unknown. In this study, we use whole-cell voltage-clamp techniques to analyze light responses of individual bipolar cells (BCs), AII amacrine cells (AIIACs), and ON and sustained OFF alpha-ganglion cells (ONαGCs and sOFFαGCs) in dark-adapted mouse retinas with elevated intraocular pressure (IOP). We present evidence showing that elevated IOP suppresses the rod ON BC inputs to AIIACs, resulting in less sensitive AIIACs, which alter AIIAC inputs to ONαGCs via the AIIAC→cone ON BC→ONαGC pathway, resulting in lower ONαGC sensitivity. The altered AIIAC response also reduces sOFFαGC sensitivity via the AIIAC→sOFFαGC chemical synapses. These sensitivity decreases in αGCs and AIIACs were found in mice with elevated IOP for 3-7 wk, a stage when little RGC or optic nerve degeneration was observed. Our finding that elevated IOP alters neuronal function in the inner retina before irreversible structural damage occurs provides useful information for developing new diagnostic tools and treatments for glaucoma in human patients.

Left-right asymmetry in firing rate of extra-retinal photosensitive neurons in the crayfish.

The purpose of this paper is to explore the firing rate of the caudal photoreceptors (CPRs) from the sixth abdominal ganglion of the crayfish Cherax quadricarinatus. We use simultaneous extracellular recordings on left and right CPR in the isolated ganglion (n = 10). The CPRs showed an asymmetry in the spontaneous activity and light-induced response. In darkness, we observed one subgroup (70%) in which the left CPR (CPR-L) and right CPR (CPR-R) had spontaneous firing rates with a median of 18 impulses/s and 6 impulses/s, respectively. In another subgroup (20%), the CPR-R had a median of 15 impulses/s and the CPR-L had 8 impulses/s. In both groups, the differences were significant. Furthermore, the CPRs showed an asymmetrical photoresponse induced by a pulse of white light (700 Lux, 4 s). In one subgroup (30%), the CPR-L showed light-induced activity with a median of 73%, (interquartile range, IQR = 51), while the CPR-R had a median of 41%, (IQR = 47). In another subgroup (70%), the CPR-R showed a median of 56%, (IQR = 51) and the CPR-L had a median of 42%, (IQR = 46). In both groups, the differences were significant. Moreover, we observed a differential effect of temperature on CPR activity. These results suggest a functional asymmetry in both activities from left and right CPRs. These CPR activity fluctuations may modulate the processing of information by the nervous system.

Magnetic Fields Modulate Blue-Light-Dependent Regulation of Neuronal Firing by Cryptochrome.

Many animals are able to sense the Earth's geomagnetic field to enable behaviors such as migration. It is proposed that the magnitude and direction of the geomagnetic field modulates the activity of cryptochrome (CRY) by influencing photochemical radical pair intermediates within the protein. However, this proposal will remain theoretical until a CRY-dependent effect on a receptor neuron is shown to be modified by an external magnetic field (MF). It is established that blue-light (BL) photoactivation of CRY is sufficient to depolarize and activate Drosophila neurons. Here, we show that this CRY-dependent effect is significantly potentiated in the presence of an applied MF (100 mT). We use electrophysiological recordings from larval identified motoneurons, in which CRY is ectopically expressed, to show that BL-dependent depolarization of membrane potential and increased input resistance are markedly potentiated by an MF. Analysis of membrane excitability shows that these effects of MF exposure evoke increased action potential firing. Almost nothing is known about the mechanism by which a magnetically induced change in CRY activity might produce a behavioral response. We further report that specific structural changes to the protein alter the impact of the MF in ways that are strikingly similar to those from recent behavioral studies into the magnetic sense of Drosophila These observations provide the first direct experimental evidence to support the hypothesis that MF modulation of CRY activity is capable of influencing neuron activity to allow animal magnetoreception. SIGNIFICANCE STATEMENT: The biophysical mechanism of animal magnetoreception is still unclear. The photoreceptor protein cryptochrome has risen to prominence as a candidate magnetoreceptor molecule based on multiple reports derived from behavioral studies. However, the role of cryptochrome as a magnetoreceptor remains controversial primarily because of a lack of direct experimental evidence linking magnetic field (MF) exposure to a change in neuronal activity. Here, we show that exposure to an MF (100 mT) is sufficient to potentiate the ability of light-activated cryptochrome to increase neuronal action potential firing. Our results provide critical missing evidence to show that the activity of cryptochrome is sensitive to an external MF that is capable of modifying animal behavior.

Extending Integrate-and-Fire Model Neurons to Account for the Effects of Weak Electric Fields and Input Filtering Mediated by the Dendrite.

Transcranial brain stimulation and evidence of ephaptic coupling have recently sparked strong interests in understanding the effects of weak electric fields on the dynamics of brain networks and of coupled populations of neurons. The collective dynamics of large neuronal populations can be efficiently studied using single-compartment (point) model neurons of the integrate-and-fire (IF) type as their elements. These models, however, lack the dendritic morphology required to biophysically describe the effect of an extracellular electric field on the neuronal membrane voltage. Here, we extend the IF point neuron models to accurately reflect morphology dependent electric field effects extracted from a canonical spatial "ball-and-stick" (BS) neuron model. Even in the absence of an extracellular field, neuronal morphology by itself strongly affects the cellular response properties. We, therefore, derive additional components for leaky and nonlinear IF neuron models to reproduce the subthreshold voltage and spiking dynamics of the BS model exposed to both fluctuating somatic and dendritic inputs and an extracellular electric field. We show that an oscillatory electric field causes spike rate resonance, or equivalently, pronounced spike to field coherence. Its resonance frequency depends on the location of the synaptic background inputs. For somatic inputs the resonance appears in the beta and gamma frequency range, whereas for distal dendritic inputs it is shifted to even higher frequencies. Irrespective of an external electric field, the presence of a dendritic cable attenuates the subthreshold response at the soma to slowly-varying somatic inputs while implementing a low-pass filter for distal dendritic inputs. Our point neuron model extension is straightforward to implement and is computationally much more efficient compared to the original BS model. It is well suited for studying the dynamics of large populations of neurons with heterogeneous dendritic morphology with (and without) the influence of weak external electric fields.

Modulation of voltage-gated conductances of retinal horizontal cells by UV-excited TiO2 nanoparticles.

This study examines the ability of optically-excited titanium dioxide nanoparticles to influence voltage-gated ion channels in retinal horizontal cells. Voltage clamp recordings were obtained in the presence and absence of TiO2 and ultraviolet laser excitation. Significant current changes were observed in response to UV light, particularly in the -40 mV to +40 mV region where voltage-gated Na+ and K+ channels have the highest conductance. Cells in proximity to UV-excited TiO2 exhibited a left-shift in the current-voltage relation of around 10 mV in the activation of Na+ currents. These trends were not observed in control experiments where cells were excited with UV light without being exposed to TiO2. Electrostatic force microscopy confirmed that electric fields can be induced in TiO2 with UV light. Simulations using the Hodgkin-Huxley model yielded results which agreed with the experimental data and showed the I-V characteristics of individual ion channels in the presence of UV-excited TiO2.

Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice.

Serotonin 2c receptors (5-HT2c-Rs) are drug targets for certain mental disorders, including schizophrenia, depression, and anxiety. 5-HT2c-Rs are expressed throughout the brain, making it difficult to link behavioral changes to circuit specific receptor expression. Various 5-HT-Rs, including 5-HT2c-Rs, are found in the dorsal raphe nucleus (DRN); however, the function of 5-HT2c-Rs and their influence on the serotonergic signals mediating mood disorders remain unclear. To investigate the role of 5-HT2c-Rs in the DRN in mice, we developed a melanopsin-based optogenetic probe for activation of Gq signals in cellular domains, where 5-HT2c-Rs are localized. Our results demonstrate that precise temporal control of Gq signals in 5-HT2c-R domains in GABAergic neurons upstream of 5-HT neurons provides negative feedback regulation of serotonergic firing to modulate anxiety-like behavior in mice.

Model study of combined electrical and near-infrared neural stimulation on the bullfrog sciatic nerve.

This paper implemented a model study of combined electrical and near-infrared (808 nm) neural stimulation (NINS) on the bullfrog sciatic nerve. The model includes a COMSOL model to calculate the electric-field distribution of the surrounding area of the nerve, a Monte Carlo model to simulate light transport and absorption in the bullfrog sciatic nerve during NINS, and a NEURON model to simulate the neural electrophysiology changes under electrical stimulus and laser irradiation. The optical thermal effect is considered the main mechanism during NINS. Therefore, thermal change during laser irradiation was calculated by the Monte Carlo method, and the temperature distribution was then transferred to the NEURON model to stimulate the sciatic nerve. The effects on thermal response by adjusting the laser spot size, energy of the beam, and the absorption coefficient of the nerve are analyzed. The effect of the ambient temperature on the electrical stimulation or laser stimulation and the interaction between laser irradiation and electrical stimulation are also studied. The results indicate that the needed stimulus threshold for neural activation or inhibition is reduced by laser irradiation. Additionally, the needed laser energy for blocking the action potential is reduced by electrical stimulus. Both electrical and laser stimulation are affected by the ambient temperature. These results provide references for subsequent animal experiments and could be of great help to future basic and applied studies of infrared neural stimulation (INS).

Heat pulse excitability of vestibular hair cells and afferent neurons.

In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (ΔT ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (dT/dt) and an inward conduction current driven by ΔT An iberiotoxin-sensitive inhibitory conduction current was also evoked by ΔT, rising in <3 ms and decaying with a time constant of ∼24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68 mV and in 67% of hair cells at -60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability.