Neuronal Electrical Activity Research Articles

From Local to Global Modeling for Characterizing Calcium Dynamics and Their Effects on Electrical Activity and Exocytosis in Excitable Cells.

Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca2+ concentration) of the channels, and local coupling in ion channel complexes (e.g., via local Ca2+ concentration surrounding Ca2+ channels (CaVs), the so-called Ca2+ nanodomains). We recently devised a model of large-conductance BKCa potassium currents, and hence BKCa–CaV complexes controlled locally by CaVs via Ca2+ nanodomains. We showed how different CaV types and BKCa–CaV stoichiometries affect whole-cell electrical behavior. Ca2+ nanodomains are also important for triggering exocytosis of hormone-containing granules, and in this regard, we implemented a strategy to characterize the local interactions between granules and CaVs. In this study, we coupled electrical and exocytosis models respecting the local effects via Ca2+ nanodomains. By simulating scenarios with BKCa–CaV complexes with different stoichiometries in pituitary cells, we achieved two main electrophysiological responses (continuous spiking or bursting) and investigated their effects on the downstream exocytosis process. By varying the number and distance of CaVs coupled with the granules, we found that bursting promotes exocytosis with faster rates than spiking. However, by normalizing to Ca2+ influx, we found that bursting is only slightly more efficient than spiking when CaVs are far away from granules, whereas no difference in efficiency between bursting and spiking is observed with close granule-CaV coupling.

Bayesian smooth‐and‐match inference for ordinary differential equations models linear in the parameters

Dynamic processes are crucial in many empirical fields, such as in oceanography, climate science, and engineering. Processes that evolve through time are often well described by systems of ordinary differential equations (ODEs). Fitting ODEs to data has long been a bottleneck because the analytical solution of general systems of ODEs is often not explicitly available. We focus on a class of inference techniques that uses smoothing to avoid direct integration. In particular, we develop a Bayesian smooth‐and‐match strategy that approximates the ODE solution while performing Bayesian inference on the model parameters. We incorporate in the strategy two main sources of uncertainty: the noise level of the measured observations and the model approximation error. We assess the performance of the proposed approach in an extensive simulation study and on a canonical data set of neuronal electrical activity.

In Vivo Melanoma Imaging on Living Mice Using Dynamic Nuclear Polarization Magnetic Resonance Imaging

Recording the electrical activity of multiple neurons simultaneously would greatly facilitate studies on the function of neuronal circuits. The combination of the fast scanning by random-access multiphoton microscopy (RAMP) and the latest two-photon-compatible high-performance fluorescent genetically encoded voltage indicators (GEVIs) has enabled action potential detection in deep layers in in vivo brain. However, neuron connectivity analysis on optically recorded action potentials from multiple neurons in brain tissue has yet to be achieved. With high expression of a two-photon-compatible GEVI, ASAP3, via in utero electroporation and RAMP, we achieved voltage recording of spontaneous activities from multiple neurons in brain slice. We provide evidence for the developmental changes in intralaminar horizontal connections in somatosensory cortex layer 2/3 with a greater sensitivity than calcium imaging. This method thus enables investigation of neuronal network connectivity at the cellular resolution in brain tissue.

Coding of odors in the anterior olfactory nucleus.

Odorant molecules stimulate olfactory receptor neurons, and axons of these neurons project into the main olfactory bulb where they synapse onto mitral and tufted cells. These project to the primary olfactory cortex including the anterior olfactory nucleus (AON), the piriform cortex, amygdala, and the entorhinal cortex. The properties of mitral cells have been investigated extensively, but how odor information is processed in subsequent brain regions is less well known. In the present study, we recorded the electrical activity of AON neurons in anesthetized rats. Most AON cells fired in bursts of 2–10 spikes separated by very short intervals (<20 ms), in a period linked to the respiratory rhythm. Simultaneous recordings from adjacent neurons revealed that the rhythms of adjacent cells, while locked to the same underlying rhythm, showed marked differences in phase. We studied the responses of AON cells to brief high‐frequency stimulation of the lateral olfactory tract, mimicking brief activation of mitral cells by odor. In different cells, such stimuli evoked transient or sustained bursts during stimulation or, more commonly, post‐stimulation bursts after inhibition during stimulation. This suggests that, in AON cells, phase shifts occur as a result of post‐inhibitory rebound firing, following inhibition by mitral cell input, and we discuss how this supports processing of odor information in the olfactory pathway. Cells were tested for their responsiveness to a social odor (the bedding of a strange male) among other simple and complex odors tested. In total, 11 cells responded strongly and repeatedly to bedding odor, and these responses were diverse, including excitation (transient or sustained), inhibition, and activation after odor presentation, indicating that AON neurons respond not only to the type of complex odor but also to temporal features of odor application.

Protonophoric and Photodynamic Effects of Fluorescein Decyl(triphenyl)phosphonium Ester on the Electrical Activity of Pond Snail Neurons.

Uncouplers of oxidative phosphorylation in mitochondria, which have been essential in elucidating the basic principles of cell bioenergetics, have recently attracted a considerable interest as compounds with therapeutic, e.g., neuroprotective, properties. Here, we report the effect of mitofluorescein (mitoFluo), a new protonophoric uncoupler representing a conjugate of fluorescein with decyl(triphenyl)phosphonium, on the electrical activity of neurons from Lymnaea stagnalis. Incubation with mitoFluo in the dark led to a decrease in the absolute value of the resting membrane potential of the neurons and alterations in their spike activity, such as spike broadening, spike amplitude reduction, and increase in the spike frequency. Prolonged incubation at high (tens micromoles) mitoFluo concentrations resulted in complete suppression of neuronal electrical activity. The effect of mitoFluo on the neurons was qualitatively similar to that of the classical mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) but manifested itself after much longer incubation and at higher concentrations. The distinctive feature of mitoFluo is its light-induced effect on the electrical activity of neurons. Changes in the parameters of the neuronal activity upon illumination in the presence of mitoFluo were similar to the light-induced effects of the well-known photosensitizer Rose Bengal, although less pronounced. It was suggested that the effects of mitoFluo on the electrical activity of neurons, both as a mitochondrial uncoupler and a photosensitizer, are mediated by the changes in the cytoplasmic calcium concentration.

Whole-cell patch clamp for monitoring low--energy focused ultrasound (LEFUS)-induced electrical activity in individual neurons

The objective of this project was to integrate a LEFUS-system to a patch-clamp platform for exploration of LEFUS-modulated and/or -stimulated electrophysiological responses from individual cultured neurons. Mouse primary neurons and human neural progenitor cells were cultured and plated onto 35-mm diameter Petri dishes. A whole-cell patch-clamp setup in current-clamp mode was used to record electrophysiological activity generated by the neurons. The LEFUS system consisted of a 2.2-MHz planar transducer (diameter: 10-mm), administering 0.5–10 ms pulses at pressures of 6–50 kPa. Neuromodulation studies consisted in measuring changes in the activation threshold to electrical stimulation (current density required to trigger an action potential: AP) in LEFUS-treated neurons. Neurostimulation experiments consisted in measuring electrophysiological responses to LEFUS exposures in the form of triggered APs or electrical discharges from the patched neuron. Neuromodulation results showed that the activation threshold required for triggering APs could be either elevated or lowered by approximately 25% following LEFUS treatment. In neurostimulation experiments, LEFUS pressures of 25 kPa and pulse durations of 10 ms were sufficient for either disturbing the membrane potential of the cell and, occasionally, depolarizing the neuron by approximately 70 mV. [This project was supported by the French National Research Agency (ANR-16-TERC-0017), LabEx DevWeCan, and Focused Ultrasound Foundation (Centers of Excellence).]

2310 A Mysterious Case of Non-Cirrhotic Recurrent Severe Hyperammonemia: What Urea-lly Need to Know

INTRODUCTION: Ammonia is a well-known toxin, mostly studied in Hepatic encephalopathy. While, it is related to severe liver disease in 90% cases, the remaining 10% is constituted by disturbances in its excretion or related to over production from other etiologies. [1] Awareness of hyperammonemia in absence of severe hepatic disease may lead to lifesaving prompt diagnosis and treatment. We present a mysterious case of recurrent severe hyperammonemia without known liver disease. CASE DESCRIPTION/METHODS: A 53 year old male with prior history of well controlled hypertension presented to the emergency department with unresponsiveness. On exam, he was unconscious with occasional spontaneous eye opening and a left gaze preference. CT head and CT angiogram of neck did not reveal any acute abnormalities. Liver enzymes and Bilirubin were normal. Blood alcohol level was 0.089gm/dl%. EEG showed diffuse encephalopathy. Serum ammonia was 705 umol/L. He was started on lactulose. His mentation improved in a day and repeat serum ammonia was 25umol/L. Ultrasound liver and CT abdomen ruled out cirrhosis and gall bladder disease. He was discharged home with a prescription of lactulose. He returned to the ED with another episode of unresponsiveness a month later and was found to have elevated serum ammonia of 213 umol/L. Levetiracetam was started empirically with suspicion of recurrent seizures causing this unresponsiveness. He continued to have similar episodes of hyperammonemic encephalopathy. Orotic acid in urine was high (&gt;200 mmol/mol creatinine ), clinching the diagnosis of ornithine transcarbamylase (OTC) deficiency. He was advised to consume a low protein diet and was prescribed L-carnitine along with lactulose. DISCUSSION: Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials. Secondary hyperammonemia occurs commonly in the presence of hepatic disorders leading to portosystemic encephalopathy. Less common causes include drugs like valproate, post-chemotherapy, gastric bypass surgery. Causes of primary hyperammonemia in adults include milder forms of urea cycle enzyme deficiencies like OTC, argininosuccinate lyase. Noncirrhotic hyperammonemia as a cause of altered mental status remains a diagnosis of exclusion and requires high index suspicion. Treatment options include lactulose, l-carnitine, and drugs to lower cerebral edema if patient has MRI findings. Liver transplantation is an important treatment modality in urea-cycle disorders.

Complexity Analysis in Focal Epilepsy Using Entropy Methods

Epilepsy is a neurological disorder characterized by abnormal electrical activity of neurons affecting a small or large area of the brain. Epilepsy is categorized into focal epilepsy and generalized epilepsy. Focal epilepsy is due to abnormal electrical activity that effects the smaller brain sections, whereas in generalized epilepsy the larger section of the brain is affected. Epilepsy affects the patient’s personality, behavior, and emotions, making daily routines difficult. Early detection is therefore essential. In this study, we use electroencephalogram (EEG) signals to detect the focal epilepsy. However, due to the random and non-stationary characteristics it is difficult to analyze the subtle changes in the EEG by visual inspection. Hence, in this study we proposed a system that classifies focal epileptic and normal signals accurately. In order to analyze the difference in the randomness of the focal epileptic and the normal signals we have used fuzzy approximation entropy and spectral entropy. The system first decomposes the signal, and then features are extracted using fuzzy approximation entropy and spectral entropy. We obtain classification accuracies of 95% and 85% using 4-nearest neighbor and support vector machine classifiers, respectively.

Firing dynamics in hybrid coupled populations of bistable neurons

We study the firing behavior of bistable neurons that are coupled by both electrical and chemical synapses, constituting a hybrid coupled population. We use stochastic Hodgkin–Huxley model neurons for the dynamics of individual bistable units within the population and the connectivity is implemented with a scale-free network topology which is a widely used network paradigm in theoretical studies of neural circuits. By analyzing the electrical activity of both whole population and individual neurons, it is shown that population mean firing rate exhibits a non-monotonic behavior in the space of electrical and chemical coupling strengths. We identify dynamical mechanisms that shape such non-monotonic spiking behavior and show that different types of population spiking patterns can emerge by fine-tuning the coupling strengths of electrical and chemical synapses. Furthermore, we map the transitions between observed dynamical states in the parameter space of interest depending on the level of individual neuron bistability, existence probability of a synapse type and intrinsic ion channel noise.

Pre-stimulus Brain Activity Is Associated With State-Anxiety Changes During Single-Session Transcranial Direct Current Stimulation.

Transcranial direct current stimulation is a promising neuromodulation method for treating depression. However, compared with pharmacological treatment, previous studies have reported that a relatively limited proportion of patients respond to tDCS treatment. In addition, the neurophysiological mechanisms underlying tDCS treatment remain unclear, making it difficult to identify response predictors for tDCS treatment based on neurophysiological function. Because treatment effects are achieved by repetitive application of tDCS, studying the immediate effects of tDCS in depressive patients could extend understanding of its treatment mechanisms. However, immediate changes in a single session of tDCS are not well documented. Thus, in the current study, we focused on the immediate impact of tDCS and its association with pre-stimulus brain activity. To address this question, we applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) or dorsomedial prefrontal cortex (DMPFC) in 14 patients with major depressive disorder (MDD) and 19 healthy controls (HCs), at an intensity of 1.0 mA for 20 min in a single session. To evaluate anxiety, the state trait anxiety inventory was completed before and after tDCS. We recorded resting electroencephalography before tDCS, and calculated electrical neuronal activity in the theta and alpha frequency bands using standardized low-resolution electromagnetic tomography. We found that, during application of left DLPFC tDCS to patients with MDD, the anxiety reduction effect of tDCS was related to higher baseline theta-band activity in the rostral anterior cingulate cortex (rACC) and no medication with benzodiazepine used as hypnotic. For DMPFC stimulation in MDD, the anxiety reduction effect was associated with lower baseline alpha-band activity in the left inferior parietal lobule. In contrast, in HCs, the anxiety reduction effect was associated with higher baseline alpha activity in the precuneus during DMPFC stimulation. The current results suggest that the association between pre-tDCS brain activity and the anxiety reduction effect of tDCS depends on psychopathology (depressed or non-depressed) as well as the site of stimulation (DMPFC or left DLPFC) and insomnia. Furthermore, the results suggest that tDCS response might be associated with baseline resting state electrophysiological neural activity.

Electric activities of time-delay memristive neuron disturbed by Gaussian white noise.

To study the effect of electromagnetic induction on the electric activities of neuron, memristive neuron models have been proposed by coupling membrane potential with magnetic flux. In this paper, on the basis of memristive Hindmarsh-Rose neuron model, time-delay memristive Hindmarsh-Rose neuron model is described and the responses of neuron in electrical activities are detected. The effect of time-delay on the dynamical behaviors of the neuron is discussed and the transition of electrical activities of the neuron is investigated with the change of noise intensity. It is found that, both the time-delay and the noise have effect on the electrical activities of the neuron. Especially, by selecting appropriate parameters, the noise not only can excite neuron from quiescent state to bursting state, but also can suppress the electrical activities in neuron during certain discharge period. Results mean that multiple modes and coherence resonance can be observed by changing the size of time-delay or the noise intensity, which could be associated with memory effect and self-adaption in neurons.

Correlation Transfer by Layer 5 Cortical Neurons Under Recreated Synaptic Inputs In Vitro.

Correlated electrical activity in neurons is a prominent characteristic of cortical microcircuits. Despite a growing amount of evidence concerning both spike-count and subthreshold membrane potential pairwise correlations, little is known about how different types of cortical neurons convert correlated inputs into correlated outputs. We studied pyramidal neurons and two classes of GABAergic interneurons of layer 5 in neocortical brain slices obtained from rats of both sexes, and we stimulated them with biophysically realistic correlated inputs, generated using dynamic clamp. We found that the physiological differences between cell types manifested unique features in their capacity to transfer correlated inputs. We used linear response theory and computational modeling to gain clear insights into how cellular properties determine both the gain and timescale of correlation transfer, thus tying single-cell features with network interactions. Our results provide further ground for the functionally distinct roles played by various types of neuronal cells in the cortical microcircuit.SIGNIFICANCE STATEMENT No matter how we probe the brain, we find correlated neuronal activity over a variety of spatial and temporal scales. For the cerebral cortex, significant evidence has accumulated on trial-to-trial covariability in synaptic inputs activation, subthreshold membrane potential fluctuations, and output spike trains. Although we do not yet fully understand their origin and whether they are detrimental or beneficial for information processing, we believe that clarifying how correlations emerge is pivotal for understanding large-scale neuronal network dynamics and computation. Here, we report quantitative differences between excitatory and inhibitory cells, as they relay input correlations into output correlations. We explain this heterogeneity by simple biophysical models and provide the most experimentally validated test of a theory for the emergence of correlations.

Elimination of spiral waves in a two-dimensional Hindmarsh–Rose neural network under long-range interaction effect and frequency excitation

The elimination of spiral waves is numerically studied in a network of Hindmarsh–Rose neurons in presence of long-range diffusive interactions and external frequency excitations. Some features of membrane potential, including time series, spatiotemporal and spatial diagrams are discussed. It is found that at low frequency excitations, weak and strong long-range couplings sustain target wave propagation and spiral wave formation. However, ultra-long-range connections fully suppress such patterns, especially in the case of a Kac–Baker-like long-range coupling. In addition, increase in the excitation frequency supports the transition from stable robust spiral waves to spiral turbulence at weak or strong long-range connections. The interplay between hyper-high-frequency excitation and Kac–Baker-like long-range interaction completely eliminates spiral waves and only regenerates target wave propagation. Our results suggest that both frequency excitation regimes and long-range interaction may efficiently regulate the electrical activity of thalamus neurons and effectively prevent some brain disorders such as epileptic seizures.

Prototyping a memristive-based device to analyze neuronal excitability

Many efforts have been spent in the last decade for the development of nanoscale synaptic devices integrated into neuromorphic circuits, trying to emulate the behavior of natural synapses. The study of brain properties with the standard approaches based on biocompatible electrodes coupled to conventional electronics, however, presents strong limitations, which in turn could be overcame by the in-situ growth of neuronal networks coupled to memristive devices. To meet this challenging task, here two different chips were designed and fabricated for culturing neuronal cells and sensing their electrophysiological activity. The first chip was designed to be connected to an external memristor, while the second chip was coated with TiO2 films owning memristive properties. The biocompatibility of chips was preliminary analyzed by culturing the hybrid motor-neuron cell line NSC-34 and by measuring the electrical activity of cells interfacing the chip with a standard patch-clamp setup. Next, neurons were seeded on chips and their activity measured with the same setup. For both cell types total current and voltage responses were evoked and recorded with optimal results with no breakdowns. In addition, an external stimulation was applied to cells through chip electrodes, being effective and causing no damage or pitfalls to the cells. Finally, the whole bio-hybrid system, i.e. the chip interconnected with a commercial memristor, was tested with promising results. Spontaneous electrical activity of neurons grown on the chip was indeed present and this signal was collected and sent to the memristor, changing its state. Taken together, we demonstrated the ability of memristor to work with a synaptic/plastic response together with natural systems, opening the way for the further implementation of basic computing elements able to perform both storage and processing of data, as in natural neurons.

Visualizing Protein Kinase A Activity In Head-fixed Behaving Mice Using In Vivo Two-photon Fluorescence Lifetime Imaging Microscopy.

Neuromodulation exerts powerful control over brain function. Dysfunction of neuromodulatory systems results in neurological and psychiatric disorders. Despite their importance, technologies for tracking neuromodulatory events with cellular resolution are just beginning to emerge. Neuromodulators, such as dopamine, norepinephrine, acetylcholine, and serotonin, trigger intracellular signaling events via their respective G protein-coupled receptors to modulate neuronal excitability, synaptic communications, and other neuronal functions, thereby regulating information processing in the neuronal network. The above mentioned neuromodulators converge onto the cAMP/protein kinase A (PKA) pathway. Therefore, in vivo PKA imaging with single-cell resolution was developed as a readout for neuromodulatory events in a manner analogous to calcium imaging for neuronal electrical activities. Herein, a method is presented to visualize PKA activity at the level of individual neurons in the cortex of head-fixed behaving mice. To do so, an improved A-kinase activity reporter (AKAR), called tAKARα, is used, which is based on Förster resonance energy transfer (FRET). This genetically-encoded PKA sensor is introduced into the motor cortex via in utero electroporation (IUE) of DNA plasmids, or stereotaxic injection of adeno-associated virus (AAV). FRET changes are imaged using two-photon fluorescence lifetime imaging microscopy (2pFLIM), which offers advantages over ratiometric FRET measurements for quantifying FRET signal in light-scattering brain tissue. To study PKA activities during enforced locomotion, tAKARα is imaged through a chronic cranial window above the cortex of awake, head-fixed mice, which run or rest on a speed-controlled motorized treadmill. This imaging approach will be applicable to many other brain regions to study corresponding behavior-induced PKA activities and to other FLIM-based sensors for in vivo imaging.

Oxygen-sensitive interneurons exhibit increased activity and GABA release during ROS scavenging in the cerebral cortex of the western painted turtle.

The western painted turtle (Chrysemys picta bellii) has the unique ability of surviving several months in the absence of oxygen, which is termed anoxia. One major protective strategy that the turtle employs during anoxia is a reduction in neuronal electrical activity, which may result from a natural reduction in reactive oxygen species (ROS). We previously linked a reduction in ROS levels to an increase in γ-amino butyric acid (GABA) receptor currents. The purpose of this study is to understand how fast-spiking, GABA-releasing neurons respond to reductions in ROS and how this affects GABA release. Using a fluorescence-coupled enzymatic microplate assay for GABA, we found that anoxia, the ROS scavenger N-(2-mercaptopriopionyl)glycine (MPG), or the mitochondria-specific ROS scavenger MitoTEMPO resulted in a 2.5-, 2.0-, and 2.5-fold increase in extracellular GABA concentration, respectively. This phenomenon could be blocked with TTX, indicating that it is activity dependent. Using whole cell patch-clamping techniques, we found that fast-spiking, burst-firing GABAergic turtle neurons increase the duration and number of action potentials per burst by 26% and 42%, respectively, in response to ROS scavenging via MPG. These results suggest that the reduction in mitochondrially produced ROS that occurs during anoxia leads to increased GABA release, which promotes postsynaptic inhibitory activity through activation of GABA receptors.NEW & NOTEWORTHY This is a novel study examining the response of cerebral cortical stellate interneurons to anoxia and mitochondrial reactive oxygen species (ROS) scavenging with MitoTEMPO. Under both conditions burst firing increases in these cells, and we show that extracellular GABA release increases in the presence of the ROS scavenger. We conclude that in the anoxia-tolerant painted turtle brain, a decrease in ROS levels is an important low oxygen signal.

Proteoglycans involved in bidirectional communication between mast cells and hippocampal neurons

BackgroundMast cells (MCs) in the brain can respond to environmental cues and relay signals to neurons that may directly influence neuronal electrical activity, calcium signaling, and neurotransmission. MCs also express receptors for neurotransmitters and consequently can be activated by them. Here, we developed a coculture model of peritoneal MCs, incubated together with dissociated hippocampal neurons for the study of cellular mechanisms involved in the mast cell-neuron interactions.MethodsCalcium imaging was used to simultaneously record changes in intracellular calcium [Ca2+]i in neurons and MCs. To provide insight into the contribution of MCs on neurotransmitter release in rat hippocampal neurons, we used analysis of FM dye release, evoked by a cocktail of mediators from MCs stimulated by heat.ResultsBidirectional communication is set up between MCs and hippocampal neurons. Neuronal depolarization caused intracellular calcium [Ca2+]i oscillations in MCs that produced a quick response in neurons. Furthermore, activation of MCs with antigen or the secretagogue compound 48/80 also resulted in a neuronal [Ca2+]i response. Moreover, local application onto neurons of the MC mediator cocktail elicited Ca2+ transients and a synaptic release associated with FM dye destaining. Neuronal response was partially blocked by D-APV, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and was inhibited when the cocktail was pre-digested with chondroitinase ABC, which induces enzymatic removal of proteoglycans of chondroitin sulfate (CS).ConclusionsMC-hippocampal neuron interaction affects neuronal [Ca2+]i and exocytosis signaling through a NMDAR-dependent mechanism.

Acute β-tetrabromoethylcyclohexane (β-TBECH) treatment inhibits the electrical activity of rat Purkinje neurons.

Brominated flame-retardants are environmentally pervasive and persistent synthetic chemicals, some of which have been demonstrated to disrupt neuroendocrine signaling and electrical activity of neurons. 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane (TBECH) lacks the toxicity of other classes of BFRs, however its safety is still questioned, as little is known of its neurological effects. Therefore, we sought to determine if TBECH could acutely alter the electrical activity of Purkinje neurons maintained in vitro. Briefly, cerebella from gestational day 20 rats were dissociated and maintained for up to three weeks in culture. Action potentials of Purkinje neurons were detected by cell-attached patch clamp before, during, and after application of β-TBECH. β-TBECH decreased action potential activity in a dose-dependent manner with an apparent EC50 of 396 nM. β-TBECH did not significantly alter the coefficient of variation, a measure of the regularity of firing, suggesting that the mechanism of β-TBECH's effects on firing frequency may be independent of Purkinje neuron intracellular calcium handling. Because levels of β-TBECH in exposed individuals may not approach the EC50, these data suggest that any abnormal neurodevelopment or behavior linked with β-TBECH exposure may result from endocrinological effects as opposed to direct disruption of electrical activity.

Experimentally-constrained biophysical models of tonic and burst firing modes in thalamocortical neurons.

Somatosensory thalamocortical (TC) neurons from the ventrobasal (VB) thalamus are central components in the flow of sensory information between the periphery and the cerebral cortex, and participate in the dynamic regulation of thalamocortical states including wakefulness and sleep. This property is reflected at the cellular level by the ability to generate action potentials in two distinct firing modes, called tonic firing and low-threshold bursting. Although the general properties of TC neurons are known, we still lack a detailed characterization of their morphological and electrical properties in the VB thalamus. The aim of this study was to build biophysically-detailed models of VB TC neurons explicitly constrained with experimental data from rats. We recorded the electrical activity of VB neurons (N = 49) and reconstructed morphologies in 3D (N = 50) by applying standardized protocols. After identifying distinct electrical types, we used a multi-objective optimization to fit single neuron electrical models (e-models), which yielded multiple solutions consistent with the experimental data. The models were tested for generalization using electrical stimuli and neuron morphologies not used during fitting. A local sensitivity analysis revealed that the e-models are robust to small parameter changes and that all the parameters were constrained by one or more features. The e-models, when tested in combination with different morphologies, showed that the electrical behavior is substantially preserved when changing dendritic structure and that the e-models were not overfit to a specific morphology. The models and their analysis show that automatic parameter search can be applied to capture complex firing behavior, such as co-existence of tonic firing and low-threshold bursting over a wide range of parameter sets and in combination with different neuron morphologies.

Early glioma is associated with abnormal electrical events in cortical cultures.

The prodromal stages of some neurological diseases have a distinct electrical profile which can potentially be leveraged for early diagnosis, predicting disease recurrence, monitoring of disease progression, and better understanding of the disease pathology. Gliomas are tumors that originate from glial cells present in the brain and spinal cord. Healthy glial cells support normal neuronal function and play an important role in modulating the regular electrical activity of neurons. However, gliomas can disrupt the normal electrical dynamics of the brain. Though experimental and clinical studies suggest that glioma and injury to glial cells disrupt electrical dynamics of the brain, whether these disruptions are present during the earliest stages of glioma and glial injury are unclear. The primary aim of this study is to investigate the effect of early in vitro glial pathology (glioma and glial injury in specific) on neuronal electrical activity. In particular, we investigated the effect of glial pathology on neural synchronization: an important phenomenon that underlies several central neurophysiological processes (ScienceDirect, 2018 ). We used two in vitro disease samples: (a) a sample in which cortical cultures were treated with anti-mitotic agents that deplete glial cells and (b) a glioma sample in which healthy cortical cells were cultured with CRL-2303 (an aggressive glioma cell line). Healthy cortical culture samples were used as controls. Cultures were established over a glass dish embedded with microelectrodes that permits simultaneous measurement of extracellular electrical activity from multiple sites of the culture. We observed that healthy cortical cultures produce spontaneous and synchronized oscillations which were attenuated in the absence of glial cells. The presence of glioma was associated with the emergence of two types of "abnormal electrical activity" each with distinct amplitude and frequency profile. Our results indicate that even early stages of glioma and glial injury are associated with distinct changes in neuronal electrical activity. Graphical abstract.