Multichannel Electrophysiology Research Articles

Abstract Mo066: A Bifunctional Actuator Reverses Na V 1.5 Dysfunction Linked To Cardiac Arrhythmias

Cardiac voltage-gated sodium channels (Na V 1.5) are critical for the initiation of action potentials within the heart. Alterations in Na V 1.5 function significantly contribute to diverse inherited and acquired arrhythmias, such as Long QT syndrome (LQT), Brugada syndrome (BrS), mixed-syndrome, and heart failure. These pathologies are closely associated with two distinct modifications in Na V 1.5 function: (1) a gain-of-function phenotype, characterized by incomplete inactivation of Na V 1.5 leading to a sustained Na + current ( I NaL ), and (2) a loss-of-function phenotype resulting in diminished peak Na + current ( I NaP ). Despite the broad understanding of Na V 1.5 implication in cardiac pathophysiology, the development of effective therapeutic strategies to reverse these dysfunctions remains challenging. Here, we introduce a novel bifunctional actuator that inhibits I NaL and upregulates I NaP , as a common molecular strategy to reverse pathophysiological changes in Nav-linked cardiac arrhythmias. To do so, we use a genetically encoded approach by engineering a selective nanobody (nb82) targeting Na V 1.5, linked to (1) a peptide inhibitor targeting I NaL (FixR), and (2) the catalytic domain of a deubiquitinase (DUB) to enhance Na V 1.5 membrane expression. Changes in I NaP and I NaL were assessed using whole-cell and multichannel electrophysiology techniques in both wild-type and channelopathic mutant channels. Our results demonstrate that NbFixR-DUB effectively reduces I NaL while concurrently increasing I NaP for multiple channelopathic mutations. Overall, this approach holds considerable promise for rectifying both loss-of-function and gain-of-function phenotypes in Nav channelopathies.

Emerging trends in the development of flexible optrode arrays for electrophysiology.

Optical-electrode (optrode) arrays use light to modulate excitable biological tissues and/or transduce bioelectrical signals into the optical domain. Light offers several advantages over electrical wiring, including the ability to encode multiple data channels within a single beam. This approach is at the forefront of innovation aimed at increasing spatial resolution and channel count in multichannel electrophysiology systems. This review presents an overview of devices and material systems that utilize light for electrophysiology recording and stimulation. The work focuses on the current and emerging methods and their applications, and provides a detailed discussion of the design and fabrication of flexible arrayed devices. Optrode arrays feature components non-existent in conventional multi-electrode arrays, such as waveguides, optical circuitry, light-emitting diodes, and optoelectronic and light-sensitive functional materials, packaged in planar, penetrating, or endoscopic forms. Often these are combined with dielectric and conductive structures and, less frequently, with multi-functional sensors. While creating flexible optrode arrays is feasible and necessary to minimize tissue-device mechanical mismatch, key factors must be considered for regulatory approval and clinical use. These include the biocompatibility of optical and photonic components. Additionally, material selection should match the operating wavelength of the specific electrophysiology application, minimizing light scattering and optical losses under physiologically induced stresses and strains. Flexible and soft variants of traditionally rigid photonic circuitry for passive optical multiplexing should be developed to advance the field. We evaluate fabrication techniques against these requirements. We foresee a future whereby established telecommunications techniques are engineered into flexible optrode arrays to enable unprecedented large-scale high-resolution electrophysiology systems.

Enhancement of EFL-inactivation gate interaction by truncation of Nav1.5 carboxy-terminal domain.

The voltage-gated sodium channel 1.5 (NaV1.5) participates in the initiation of the cardiac action potential by undergoing rapid activation which, within milliseconds, is followed by inactivation. Human channelopathic mutations in NaV1.5 are linked to various cardiac maladies, including cardiac arrythmia, atrial fibrillation, and dilated cardiomyopathies. The carboxy-terminal domain (CTD) of NaV1.5 is a well-recognized hotspot for channelopathic mutations. This domain harbors an EF-hand-like domain (EFL) and an IQ motif, which tune channel function via binding of auxiliary proteins, including the fibroblast growth factor homologous factors and calmodulin. In addition, the isolated NaV1.5 EFL has been reported to bind the channel inactivation gate (IG) via a partially buried hydrophobic pocket. However, whether this binding occurs in the full-length human channel and how it tunes NaV1.5 function are not well understood. Here, we have used high-resolution multi-channel electrophysiology recordings of disease-associated truncations and engineered NaV1.5 mutants to probe this interaction. We show that truncation of the NaV1.5 CTD increases late Na current, with a maximal increase observed for a truncation that includes helix V of the EFL (NaV1.5E[1864]∗), while further truncation resulted in reduced late Na current. Deletion of helix V increases the exposure of the EFL hydrophobic pocket, suggesting the large late Na current observed for NaV1.5E[1864]∗ may stem from a tighter interaction between the IG and the mutant EFL. Consistent with this, co-expression of NaV1.5E[1864]∗ with the WT NaV1.5 CTD or IG reduced late Na current, while expression with IG mutants designed to disrupt binding with either the pore-domain (IFM/QQQ) or EFL (K1504E/K1505E) showed only a partial reduction. These findings suggest that as NaV1.5 cycles between its functional states, the IG shuttles between the EFL and the pore domain shedding new light onto how these regions tune channel function.

Abstract P1086: Lrrc10 Is A Multifaceted Modulator Of Cardiac Calcium And Sodium Channels

L-type calcium channels (LTCC) are vital for heart physiology as they allow entry of calcium to the cardiomyocyte, ultimately leading to contraction. These channels are exquisitely modulated by auxiliary subunits and a vast array of regulatory proteins. Heart-specific leucine-rich repeat-containing protein 10 (Lrrc10) plays a key role as a regulator of LTCC. Previous work has shown that Lrrc10 knockdown in zebrafish disrupts development of the cardiac tube, while ablation of Lrrc10 in mice results in heart dysfunction and maladaptation to increased cardiac afterload. Moreover, human mutations in Lrrc10 gene have been linked to dilated cardiomyopathy, and sudden unexplained nocturnal death syndrome (SUNDS). Still, the molecular mechanisms underlying Lrrc10 regulation of LTCC is not fully established. Beyond this, it is unknown whether Lrrc10 modulates other cardiac ion channels. Here, we hypothesized that Lrrc10 serves as a versatile regulator of four-domain voltage-gated ion channels, while mutations in Lrrc10 differentially disrupt channel regulation. Using whole-cell and single-channel electrophysiology, we found that Lrrc10: 1) upregulates LTCC currents by increasing peak open probability; 2) accelerates calcium-dependent inactivation; and 3) evokes a hyperpolarizing-shift in voltage-dependence of activation. Flow cytometric FRET 2-hybrid assay showed that Lrrc10 interacts with LTCC cytoplasmic subunits, specifically the N- and C-termini. We further used FRET 2-hybrid analysis to evaluate the interaction of Lrrc10 with related cardiac ion channels. We observed robust Lrrc10 interaction with Na V 1.5 channels. Multi-channel electrophysiology recordings revealed increased late sodium currents, suggesting that Lrrc10 also modulates Na V 1.5 activity. Additionally, electrophysiological studies showed that Lrrc10 variants linked to dilated cardiomyopathy and SUNDS disparately alter modulation of calcium and sodium channels. In conclusion, Lrrc10 is a multifaceted regulator of four-domain, voltage-gated cardiac ion channels, a finding that will lend critical insights into heart function and disease.

A comparative study of microwire electrode array with built-in and external reference electrodes

Objective: To compare the difference between the built-in and external reference electrode of microwire electrode array in the process of recording rat brain neuron firings, optimizing the production and embedding of the microwire electrode array, and providing a more affordable and excellent media tool for multi-channel electrophysiological real-time recording system. Methods: A 16 channel microwire electrode array was made by using nickel chromium alloy wires, circuit board, electrode pin and ground wires (silver wires). The reference electrode of the microwire electrode array was built-in (the reference electrode and electrode array were arranged in parallel) or external (the reference electrode and ground wire were welded at both ends of one side of the electrode), and the difference between the two electrodes was observed and compared in recording neuronal discharges in ACC brain area of rats. Experimental rats were divided into built-in group and external group, n=8-9. The test indicators included signal-to-noise ratio (n=8), discharge amplitude (n=380) and discharge frequency (n=54). Results: The microwire electrode array with both built-in and external reference electrodes successfully recorded the electrical signals of neurons in the ACC brain region of rats. Compared with the external group, the electrical signals of neurons in built-in group had the advantages of a higher signal-to-noise ratio (P＜0.05), a smaller amplitude of background signals and less noise interference, and a larger discharge amplitude(P＜0.05); there was no significant difference in spike discharge frequency recorded by these two types of electrodes (P＞0.05). Conclusion: When recording the electrical activity of neurons in the ACC brain region of rats, the microwire electrode array with built-in reference electrode recorded electrical signals with higher signal-to-noise ratio and larger discharge amplitude, providing a more reliable tool for multi-channel electrophysiology technology.

A tutorial on generalized eigendecomposition for denoising, contrast enhancement, and dimension reduction in multichannel electrophysiology

The goal of this paper is to present a theoretical and practical introduction to generalized eigendecomposition (GED), which is a robust and flexible framework used for dimension reduction and source separation in multichannel signal processing. In cognitive electrophysiology, GED is used to create spatial filters that maximize a researcher-specified contrast. For example, one may wish to exploit an assumption that different sources have different frequency content, or that sources vary in magnitude across experimental conditions. GED is fast and easy to compute, performs well in simulated and real data, and is easily adaptable to a variety of specific research goals. This paper introduces GED in a way that ties together myriad individual publications and applications of GED in electrophysiology, and provides sample MATLAB and Python code that can be tested and adapted. Practical considerations and issues that often arise in applications are discussed.

Daily changes in neuronal activities of the dorsal motor nucleus of the vagus under standard and high‐fat diet

Recently, we found that the dorsal vagal complex displays autonomous circadian timekeeping properties The dorsal motor nucleus of the vagus (DMV) is an executory part of this complex - a source of parasympathetic innervation of the gastrointestinal tract Here, we reveal daily changes in the neuronal activities of the rat DMV, including firing rate, intrinsic excitability and synaptic input - all of these peaking in the late day Additionally, we establish that short term high-fat diet disrupts these daily rhythms, boosting the variability in the firing rate, but blunting the DMV responsiveness to ingestive cues These results help us better understand daily control over parasympathetic outflow and provide evidence on its dependence on the high-fat diet ABSTRACT: The suprachiasmatic nuclei (SCN) of the hypothalamus function as the brain's primary circadian clock, but circadian clock genes are also rhythmically expressed in several extra-SCN brain sites where they can exert local temporal control over physiology and behaviour. Recently, we found that the hindbrain dorsal vagal complex possesses strong daily timekeeping capabilities, with the area postrema and nucleus of the solitary tract exhibiting the most robust clock properties. The possibility that the executory part of this complex - the dorsal motor nucleus of the vagus (DMV) - also exhibits daily changes has not been extensively studied. The DMV is the source of vagal efferent motoneurons that regulate gastric motility and emptying and consequently influence meal size and energy homeostasis. We used a combination of multi-channel electrophysiology and patch clamp recordings to gain insight into effects of time of day and diet on these DMV cells. We found that DMV neurons increase their spontaneous activity, excitability and responsiveness to metabolic neuromodulators at late day and this was paralleled with an enhanced synaptic input to these neurons. A high-fat diet typically damps circadian rhythms, but we found that consumption of a high-fat diet paradoxically amplified daily variation of DMV neuronal activity, while blunting the neurons responsiveness to metabolic neuromodulators. In summary, we show for the first time that DMV neural activity changes with time of day, with this temporal variation modulated by diet. These findings have clear implications for our understanding of the daily control of vagal efferents and parasympathetic outflow.

Rapid fabrication of teflon apertures by controlled high voltage pulses for formation of free standing planar lipid bilayer membrane.

Free standing artificial lipid bilayers are widely used in the study of biological pores. In these types of studies, the free standing planar lipid bilayer is formed over a micron-sized aperture consisting of either polymer such as Polytetrafluoroethylene (PTFE, Teflon) or glass. Teflon is chemically inert, has a low dielectric constant, and has a high electrical resistance which combined allow for obtaining low noise recordings. This study investigates the reproducible generation of micropores in the range of 50-100 microns in diameter in a Teflon film using a high energy discharge set-up. The discharger set-up consists of a microprocessor, a transformer, a voltage regulator, and is controlled by a computer. We compared two approaches for pore creation: single and multi-pulse methods. The results showed that the multi-pulse method produced narrower aperture size distributions and is more convenient for lipid bilayer formation, and thus would have a higher success rate than the single-pulse method. The bilayer stability experiments showed that the lipid bilayer lasts for more than 33h. Finally, as a proof-of-concept, we show that the single and multi-channel electrophysiology experiments were successfully performed with the apertures created by using the mentioned discharger. In conclusion, the described discharger provides reproducible Teflon-pores in a cheap and easy-to-operate manner.

A data-driven method to identify frequency boundaries in multichannel electrophysiology data

BackgroundElectrophysiological recordings of the brain often exhibit neural oscillations, defined as narrowband bumps that deviate from the background power spectrum. These narrowband dynamics are grouped into frequency ranges, and the study of how activities in these ranges are related to cognition and disease is a major part of the neuroscience corpus. Frequency ranges are nearly always defined according to integer boundaries, such as 4−8 Hz for the theta band and 8−12 Hz for the alpha band. New methodA data-driven multivariate method is presented to identify empirical frequency boundaries based on clustering of spatiotemporal similarities across a range of frequencies. The method, termed gedBounds, identifies patterns in covariance matrices that maximally separate narrowband from broadband activity, and then identifies clusters in the correlation matrix of those spatial patterns over all frequencies, using the dbscan clustering algorithm. Those clusters are empirically derived frequency bands, from which boundaries can be extracted. ResultsgedBounds recovers ground truth results in simulated data with high accuracy. The method was tested on EEG resting-state data from Parkinson’s patients and control, and several features of the frequency components differed between patients and controls. Comparison with existing methodsThe proposed method offers higher precision in defining subject-specific frequency boundaries compared to the current standard approach. ConclusionsgedBounds can increase the precision and feature extraction of spectral dynamics in electrophysiology data.

Smart Autonomous Electro-Optic Platforms Enabling Innovative Brain Therapies

The future of brain research lies in the application of new technologies drawing from the latest developments in biology, physics and engineering to advance our understanding of how this complex organ processes, integrates and transfers information. Among these, optogenetics is a groundbreaking technology that allows using light to selectively activate neurons in the cortex of transgenic animals, usually mice, to observe its effect in large biological networks. A new research paradigm drawing from these advances consists of synchronizing optogenetic stimulation with electrophysiology recordings, to close the loop and to regulate the neural microcircuits, or to repair them. Such an approach holds promise to accelerate the development of new therapeutics against brain diseases by enabling entirely new experimental research scenarios with freely behaving animal models. As a result, the development of advanced wireless microelectronic implantable systems to elicit, extract and process brain data in real time has become a source of significant interest. This paper reviews the design challenges and the state-of-the-art technology in this field. We present the design of a complete electro-optic device for preforming optogenetics and multichannel electrophysiology in a closed-loop (CL) system with live neurons. We cover the design of the different CMOS integrated building blocks involved in this system to perform photostimulation and multichannel neural recording in parallel. We describe advanced hardware strategies to perform action potential (AP) detection, neural data compression and AP sorting in real-time, over several parallel recording channels for enabling real-time CL neural control. Finally, we present CL experimental results obtained <;i>in vivo<;/i> with an electro-optic prototype.

CONCEPT AND REALIZATION OF BACKPACK-TYPE SYSTEM FOR MULTICHANNEL ELECTROPHYSIOLOGY IN FREELY BEHAVING RODENTS

Technologies for multichannel electrophysiology are experiencing astounding growth. Numbers of channels reach thousands of recording sites, systems are often combined with electrostimulations and optic stimulations. However, the task of design the cheap, flexible system for freely behaving animals without tethered cable are not solved completely. We propose the system for multichannel electrophysiology for both rats and mice. The system allows to record unit activity and local field potential (LFP) up to 32 channels with different types of electrodes. The system was constructed using Intan technologies RHD 2132 chip. Data acquisition and recordings take place on the DAQ-card, which is placed as a back-pack on the animal. The signal is amplified with amplifier cascade and digitalized with 16-bit ADC. Instrumental filters allow to filter the signal in 0.1–20000 Hz bandwidth. The system is powered from the mini-battery with capacity 340 mA/hr. The system was validated with generated signals, in anaesthetized rat and showed a high quality of recordings.

Optimizing optogenetic stimulation protocols in auditory corticofugal neurons based on closed-loop spike feedback

Objective. Optogenetics provides a means to probe functional connections between brain areas. By activating a set of presynaptic neurons and recording the activity from a downstream brain area, one can establish the sign and strength of a feedforward connection. One challenge is that there are virtually limitless patterns that can be used to stimulate a presynaptic brain area. Functional influences on downstream brain areas can depend not just on whether presynaptic neurons were activated, but how they were activated. Corticofugal axons from the auditory cortex (ACtx) heavily innervate the auditory tectum, the inferior colliculus (IC). Here, we sought to determine whether different modes of corticocollicular activation could titrate the strength of feedforward modulation of sound processing in IC neurons. Approach. We used multi-channel electrophysiology and optogenetics to record from multiple regions of the IC in awake head-fixed mice while optogenetically stimulating ACtx neurons expressing Chronos, an ultra-fast channelrhodopsin. To identify cortical activation patterns associated with the strongest effects on IC firing rates, we employed a closed-loop evolutionary optimization procedure that tailored the voltage command signal sent to the laser based on spike feedback from single IC neurons. Main results. Within minutes, our evolutionary search procedure converged on ACtx stimulation configurations that produced more effective and widespread enhancement of IC unit activity than generic activation parameters. Cortical modulation of midbrain spiking was bi-directional, as the evolutionary search procedure could be programmed to converge on activation patterns that either suppressed or enhanced sound-evoked IC firing rate. Significance. This study introduces a closed-loop optimization procedure to probe functional connections between brain areas. Our findings demonstrate that the influence of descending feedback projections on subcortical sensory processing can vary both in sign and degree depending on how cortical neurons are activated in time.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Effect of sepsis on the action potential and cardiac serotonin response in rats.

The current study aimed to investigate the effect of sepsis on rat serotonin (5-HT) responses and cardiac action potentials. A total of 20 rats were randomly divided into a sepsis and control group (each, n=10). Rat hearts were harvested and perfused using the Langendorff method 18-h after the induction of sepsis, which was assessed using cecal puncture. Cardiac action potential was subsequently measured using a multichannel electrophysiology instrument. Immunohistochemistry and quantitative analysis were performed to identify the effect of sepsis on myocardial 5-HT expression. The results revealed that mitochondrial changes were present in septic rat hearts. Heart rate (361.10±12.29 bpm vs. 348.60±12.38 bpm; P<0.05) was significantly higher, atrial action potential duration (106.40±2.95 ms vs. 86.60±4.12 ms; P<0.01) was significantly longer and the area (0.62±0.06 µm2 vs. 0.39±0.05 µm2; P<0.05) and number (0.92±0.02/field vs. 0.46±0.01/field; P<0.01) of myocardial cells were significantly higher in the septic compared with the control group. These results demonstrated that 5-HT prolongs the atrial action potential, increases heart rate and aggravates myocardial injury, indicating that it may therefore be one of the factors that leads to cardiac dysfunction in sepsis.

A Common Neuroendocrine Substrate for Diverse General Anesthetics and Sleep

How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, exvivo brain slice recording, and invivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states. VIDEO ABSTRACT.

A Head-Mounted Camera System Integrates Detailed Behavioral Monitoring with Multichannel Electrophysiology in Freely Moving Mice

SummaryBreakthroughs in understanding the neural basis of natural behavior require neural recording and intervention to be paired with high-fidelity multimodal behavioral monitoring. An extensive genetic toolkit for neural circuit dissection, and well-developed neural recording technology, make the mouse a powerful model organism for systems neuroscience. However, most methods for high-bandwidth acquisition of behavioral data in mice rely upon fixed-position cameras and other off-animal devices, complicating the monitoring of animals freely engaged in natural behaviors. Here, we report the development of a lightweight head-mounted camera system combined with head-movement sensors to simultaneously monitor eye position, pupil dilation, whisking, and pinna movements along with head motion in unrestrained, freely behaving mice. The power of the combined technology is demonstrated by observations linking eye position to head orientation; whisking to non-tactile stimulation; and, in electrophysiological experiments, visual cortical activity to volitional head movements.

Open Ephys: an open-source, plugin-based platform for multichannel electrophysiology

Objective. Closed-loop experiments, in which causal interventions are conditioned on the state of the system under investigation, have become increasingly common in neuroscience. Such experiments can have a high degree of explanatory power, but they require a precise implementation that can be difficult to replicate across laboratories. We sought to overcome this limitation by building open-source software that makes it easier to develop and share algorithms for closed-loop control. Approach. We created the Open Ephys GUI, an open-source platform for multichannel electrophysiology experiments. In addition to the standard ‘open-loop’ visualization and recording functionality, the GUI also includes modules for delivering feedback in response to events detected in the incoming data stream. Importantly, these modules can be built and shared as plugins, which makes it possible for users to extend the functionality of the GUI through a simple API, without having to understand the inner workings of the entire application. Main results. In combination with low-cost, open-source hardware for amplifying and digitizing neural signals, the GUI has been used for closed-loop experiments that perturb the hippocampal theta rhythm in a phase-specific manner. Significance. The Open Ephys GUI is the first widely used application for multichannel electrophysiology that leverages a plugin-based workflow. We hope that it will lower the barrier to entry for electrophysiologists who wish to incorporate real-time feedback into their research.

Theta-gamma coupling in hippocampus during working memory deficits induced by low frequency electromagnetic field exposure

The dramatically increased use of electricity is raising major concerns as to the consequences of the interaction between electromagnetic field (EMF) and neurobiology. The aim of this study is to investigate the effects of magnetic field on working memory in the hippocampal region by analyzing local field potentials (LFPs) and spikes pattern in vivo.In present study, mice were exposed to EMF (50Hz, 1mT), static magnetic field (SMF, 1mT), or placed in the exposure tube but without EMF exposure (SHAM), respectively. During the exposure for 7 consecutive days, mice were subjected to perform working memory (WM) tasks in Y-maze, and multichannel electrophysiology signals from hippocampus of mice were recorded during the test, from which LFPs, spike firing rates, band power at different frequencies, and theta-gamma modulation index (MI) were analyzed in details.From our results, correct choice rate during WM task was found significantly decreased in EMF group after 3-day exposure, which was consistent with noticeable decline in firing rate. Starting from Day 3 after EMF exposure, the power of theta (4–12Hz) and gamma (LG, 30–60Hz) before reference point (RP) in Y-maze were also found to be descending, together with decrease of oscillatory activities of theta and gamma frequencies.The results indicated that MI between theta and gamma could play a significant role in modulating the spikes discharge and encoding WM. Therefore, the analysis of theta-gamma coupling and its oscillation strength may provide a new perspective for mechanistic investigation of EMF-induced WM deficits.

Magnitude and behavior of cross-talk effects in multichannel electrophysiology experiments

Modern neurophysiological experiments frequently involve multiple channels separated by very small distances. A unique methodological concern for multiple-electrode experiments is that of capacitive coupling (cross-talk) between channels. Yet the nature of the cross-talk recording circuit is not well known in the field, and the extent to which it practically affects neurophysiology experiments has never been fully investigated. Here we describe a simple electrical circuit model of simultaneous recording and stimulation with two or more channels and experimentally verify the model using ex vivo brain slice and in vivo whole-brain preparations. In agreement with the model, we find that cross-talk amplitudes increase nearly linearly with the impedance of a recording electrode and are larger for higher frequencies. We demonstrate cross-talk contamination of action potential waveforms from intracellular to extracellular channels, which is observable in part because of the different orders of magnitude between the channels. This contamination is electrode impedance-dependent and matches predictions from the model. We use recently published parameters to simulate cross-talk in high-density multichannel extracellular recordings. Cross-talk effectively spatially smooths current source density (CSD) estimates in these recordings and induces artefactual phase shifts where underlying voltage gradients occur; however, these effects are modest. We show that the effects of cross-talk are unlikely to affect most conclusions inferred from neurophysiology experiments when both originating and receiving electrode record signals of similar magnitudes. We discuss other types of experiments and analyses that may be susceptible to cross-talk, techniques for detecting and experimentally reducing cross-talk, and implications for high-density probe design.NEW & NOTEWORTHY We develop and experimentally verify an electrical circuit model describing cross-talk that necessarily occurs between two channels. Recorded cross-talk increased with electrode impedance and signal frequency. We recorded cross-talk contamination of spike waveforms from intracellular to extracellular channels. We simulated high-density multichannel extracellular recordings and demonstrate spatial smoothing and phase shifts that cross-talk enacts on CSD measurements. However, when channels record similar-magnitude signals, effects are modest and unlikely to affect most conclusions.

Increasing GABA reverses age-related alterations in excitatory receptive fields and intensity coding of auditory midbrain neurons in aged mice

A key feature of age-related hearing loss is a reduction in the expression of inhibitory neurotransmitters in the central auditory system. This loss is partially responsible for changes in central auditory processing, as inhibitory receptive fields play a critical role in shaping neural responses to sound stimuli. Vigabatrin (VGB), an antiepileptic agent that irreversibly inhibits γ-amino butyric acid (GABA) transaminase, leads to increased availability of GABA throughout the brain. This study used multi-channel electrophysiology measurements to assess the excitatory frequency response areas in old CBA mice to which VGB had been administered. We found a significant post-VGB reduction in the proportion of V-type shapes, and an increase in primary-like excitatory frequency response areas. There was also a significant increase in the mean maximum driven spike rates across the tonotopic frequency range of all treated animals, consistent with observations that GABA buildup within the central auditory system increases spike counts of neural receptive fields. This increased spiking is also seen in the rate-level functions and seems to explain the improved low-frequency thresholds.