Endogenous Electrical Activity Research Articles

Self-Assembling Hydrogel Structures for Neural Tissue Repair.

Hydrogel materials have been employed as biological scaffolds for tissue regeneration across a wide range of applications. Their versatility and biomimetic properties make them an optimal choice for treating the complex and delicate milieu of neural tissue damage. Aside from finely tailored hydrogel properties, which aim to mimic healthy physiological tissue, a minimally invasive delivery method is essential to prevent off-target and surgery-related complications. The specific class of injectable hydrogels termed self-assembling peptides (SAPs), provide an ideal combination of in situ polymerization combined with versatility for biofunctionlization, tunable physicochemical properties, and high cytocompatibility. This review identifies design criteria for neural scaffolds based upon key cellular interactions with the neural extracellular matrix (ECM), with emphasis on aspects that are reproducible in a biomaterial environment. Examples of the most recent SAPs and modification methods are presented, with a focus on biological, mechanical, and topographical cues. Furthermore, SAP electrical properties and methods to provide appropriate electrical and electrochemical cues are widely discussed, in light of the endogenous electrical activity of neural tissue as well as the clinical effectiveness of stimulation treatments. Recent applications of SAP materials in neural repair and electrical stimulation therapies are highlighted, identifying research gaps in the field of hydrogels for neural regeneration.

Towards the Translation of Electroconductive Organic Materials for Regeneration of Neural Tissues

Electroconductive materials, such as conductive polymers and carbon-nanomaterials, have been studied since the 1970s for use in a broad range of applications. These materials showcase electrical properties that are similar to those of commonly used metals, while providing other benefits such as processing flexibility, ability to modify, and ease of synthesis. Conductive polymers (e.g., polypyrrole, polythiophene, polyaniline) as well as carbon-based nanomaterials (e.g., graphene, fullerenes) are organic in nature. This makes them ideal candidates to be augmented to create biocompatible materials while maintaining electroactive properties at functional levels that match endogenous electrical tissue activity. In this review, we focus on the uses of these electroconductive materials in the context of the nervous system, specifically recent studies in the brain, eye, ear, spinal cord, and peripheral nerve. We also highlight in vivo studies and clinical trials, as well as provide a brief look at emerging electroconductive materials.

Classification of First-Episode Schizophrenia, Chronic Schizophrenia and Healthy Control Based on Brain Network of Mismatch Negativity by Graph Neural Network.

Mismatch negativity (MMN) has been consistently found deficit in schizophrenia, which was considered as a promising biomarker for assessing the impairments in pre-attentive auditory processing. However, the functional connectivity between brain regions based on MMN is not clear. This study provides an in-depth investigation in brain functional connectivity during MMN process among patients with first-episode schizophrenia (FESZ), chronic schizophrenia (CSZ) and healthy control (HC). Electroencephalography (EEG) data of 128 channels is recorded during frequency and duration MMN in 40 FESZ, 40 CSZ patients and 40 matched HC subjects. We reconstruct the cortical endogenous electrical activity from EEG recordings using exact low-resolution electromagnetic tomography and build functional brain networks based on source-level EEG data. Then, graph-theoretic features are extracted from the brain networks with the support vector machine (SVM) to classify FESZ, CSZ and HC groups, since the SVM has good generalization ability and robustness as a universally applicable nonlinear classifier. Furthermore, we introduce the graph neural network (GNN) model to directly learn for the network topology of brain network. Compared to HC, the damaged brain areas of CSZ are more extensive than FESZ, and the damaged area involved the auditory cortex. These results demonstrate the heterogeneity of the impacts of schizophrenia for different disease courses and the association between MMN and the auditory cortex. More importantly, the GNN classification results are significantly better than those of SVM, and hence the EEG-based GNN model of brain networks provides an effective method for discriminating among FESZ, CSZ and HC groups.

Neuronal excitability and sensory responsiveness in the thalamo-cortical network in a novel rat model of isoelectric brain state.

The neuronal and network properties that persist during an isoelectric coma remain largely unknown. We developed a new in vivo rat model to assess cell excitability and sensory responsiveness in the thalamo-cortical pathway during an isoflurane-induced isoelectric brain state. The isoelectric electrocorticogram reflected a complete interruption of spontaneous synaptic and firing activities in cortical and thalamic neurons. Cell excitability and sensory responses in the thalamo-cortical network persisted at a reduced level in the isoelectric condition and returned to control values after resumption of background brain activity. These findings could lead to a reassessment of the functional status of the drug-induced isoelectric state: a latent state in which individual neurons and networks retain to some extent the ability of being activated by external inputs. The neuronal and network properties that persist in an isoelectric brain completely deprived of spontaneous electrical activity remain largely unexplored. Here, we developed a new in vivo rat model to examine cell excitability and sensory responsiveness in somatosensory thalamo-cortical networks during the interruption of endogenous brain activity induced by high doses of isoflurane. Electrocorticograms (ECoGs) from the barrel cortex were captured simultaneously with either intracellular recordings of subjacent cortical pyramidal neurons or extracellular records of the related thalamo-cortical neurons. Isoelectric ECoG periods reflected the disappearance of spontaneous synaptic and firing activities in cortical and thalamic neurons. This was associated with a sustained membrane hyperpolarization and a reduced intrinsic excitability in deep-layer cortical neurons, without significant changes in their membrane input resistance. Concomitantly, we found that whisker-evoked potentials in the ECoG and synaptic responses in cortical neurons were attenuated in amplitude and increased in latency. Impaired responsiveness in the barrel cortex paralleled with a lowering of the sensory-induced firing in thalamic cells. The return of endogenous brain electrical activities, after reinstatement of a control isoflurane concentration, led to the recovery of cortical neurons excitability and sensory responsiveness. These findings demonstrate the persistence of a certain level of cell excitability and sensory integration in the isoelectric state and the full recovery of cortico-thalamic functions after restoration of internal cerebral activities.

TACS entrains neural activity while somatosensory input is blocked.

Transcranial alternating current stimulation (tACS) modulates brain activity by passing electrical current through electrodes that are attached to the scalp. Because it is safe and noninvasive, tACS holds great promise as a tool for basic research and clinical treatment. However, little is known about how tACS ultimately influences neural activity. One hypothesis is that tACS affects neural responses directly, by producing electrical fields that interact with the brain's endogenous electrical activity. By controlling the shape and location of these electric fields, one could target brain regions associated with particular behaviors or symptoms. However, an alternative hypothesis is that tACS affects neural activity indirectly, via peripheral sensory afferents. In particular, it has often been hypothesized that tACS acts on sensory fibers in the skin, which in turn provide rhythmic input to central neurons. In this case, there would be little possibility of targeted brain stimulation, as the regions modulated by tACS would depend entirely on the somatosensory pathways originating in the skin around the stimulating electrodes. Here, we directly test these competing hypotheses by recording single-unit activity in the hippocampus and visual cortex of alert monkeys receiving tACS. We find that tACS entrains neuronal activity in both regions, so that cells fire synchronously with the stimulation. Blocking somatosensory input with a topical anesthetic does not significantly alter these neural entrainment effects. These data are therefore consistent with the direct stimulation hypothesis and suggest that peripheral somatosensory stimulation is not required for tACS to entrain neurons.

Profiles of women in science: Prof. Lisa Marshall of the University of Lübeck, Lübeck, Germany.

Profiles of women in science: Prof. Lisa Marshall of the University of Lübeck, Lübeck, Germany.

Nonvectorial responses in photoreceptor cells stimulated by electrical fields

The eye possesses various different types of electrical properties, and ocular cells are exposed to endogenous electrical fields (EFs) under natural conditions. Cellular behaviors that are regulated by EFs include vectorial (migration, orientation, and elongation) and nonvectorial responses (apoptosis and proliferation). The aim of this study was to investigate the nonvectorial responses of photoreceptor cells stimulated by EFs and to decipher the underlying molecular mechanisms. To investigate the effects of endogenous EFs on the cell behavior, we designed a customized electrical instrument that was mimetic of endogenous electrical activity. We observed that 60 and 90 mV/mm voltage gradients dramatically enhanced cell proliferation. Gene expression profiling, together with signaling pathway and gene ontology analyses, collectively demonstrated that the Ca2+-dependent extracellular signal-regulated kinase pathway is involved in cellular responses to EFs. Moreover, the results of our study clearly demonstrated that EFs promote photoreceptor cell proliferation via increased Ca2+ influx, which subsequently activates the ERK pathway. EF stimulation affects ionic fluxes in photoreceptor cells and is an important regulator of some important aspects of photoreceptor cell behavior. In conclusion, the findings of our study offer new insights on how EFs affect intracellular Ca2+, which further influences intracellular signal transduction and cell behavior.

Mapping the mechanisms of transcranial alternating current stimulation: a pathway from network effects to cognition.

In recent decades, our appreciation of the complexity of the brain has deepened immensely, as has our understanding of how it performs key functions. In the face of such complexity, and given the rising cost of neuropsychiatric illness (1), an intriguing question is whether we can promote further understanding, and in some cases enhancement, of the typical and atypical brain by targeted modulation of its activity. Notably, transcranial alternating current stimulation (tACS) – which involves transcranial application of weak sinusoidal electrical currents (2) – seems ideally suited to address this question, as it has been demonstrated to modulate endogenous oscillatory electrical activity (3), enhance cognitive functions (4–7), and provide support in neurological disease (8, 9). However, a complete mechanistic pathway between the neuronal and cognitive effects of tACS remains in need of explication, precluding both significant theoretical contribution by tACS studies, and the development of more adaptive neuroenhancement regimes. Therefore, in this Opinion article, we briefly review the role of oscillatory neuronal activity in cognition, before outlining one potential pathway by which the interaction between tACS and endogenous oscillations at a network level may be reconciled with its effects on broader cognitive functions.

The effects of direct current stimulation on isolated chondrocytes seeded in 3D agarose constructs

Endogenous electrical activity has been detected in articular cartilage. It has previously been suggested that the associated electrical currents and potentials are important to the mechanotransduction processes in cartilage. The present study investigates the effects of direct current on cell proliferation and matrix synthesis, using the well established 3D chondrocyte--agarose model system. Bovine chondrocytes isolated from metacarpalphalangeal joints were seeded in agarose constructs and exposed to a current density of 4 mA/cm2 for 6 h, a magnitude and period which was shown to maintain cell viability. The influence of the optimized electric stimulus was assessed by protein incorporation and mRNA measurements, using radiolabels and real-time QPCR, respectively. Results indicated no systematic influences of electrical current on protein synthesis, cell proliferation and mRNA expression levels. These data suggest that both the mode of stimulation and the model system are critical for the in vitro modulation of chondrocyte metabolism.

MHC class I in activity-dependent structural and functional plasticity

Members of the major histocompatibility complex (MHC) class I family of proteins are well known for their central role in the adaptive immune system, where they present self and non-self peptides for immune surveillance. Although the brain has been long considered immune privileged, in part because of an apparent lack of neuronal MHC class I, it has since been shown that MHC class I proteins are expressed by normal, uninfected neurons. Moreover, expression of MHC class I is unusually dynamic in the developing and adult brain, and MHC class I levels in neurons can be regulated by endogenous and exogenous electrical activity. Unexpectedly, several recent studies find that MHC class I is required for distinct activity-dependent events during brain development, adult plasticity, and in response to injury. Together, these studies indicate a novel role for MHC class I proteins in translating electrical activity into changes in synaptic strength and neuronal connectivity in vivo.

A targeted extracellular approach for recording long-term firing patterns of excitable cells: a practical guide.

Excitable cells in many endocrine and neuronal systems display rhythms with periodicities on the order of many minutes. To observe firing patterns that represent the output of these rhythms requires a recording technique that can monitor electrophysiological activity for several hours without affecting cell behavior. A targeted extracellular approach (also known as loose-patch) accomplishes this objective. Because low resistance seals (<20 MΩ) do not influence the cell membrane and because the normal intracellular milieu is maintained, this approach is the least invasive method for monitoring the endogenous electrical activity of single cells. In this report, we detail our use of this technique to record the firing patterns of gonadotropin-releasing hormone (GnRH) neurons in brain slices continuously for several hours.

Current thinking about risks from currents

The production, transmission, distribution, and use of electricity generate electromagnetic fields having a frequency of 50–60 Hz, sometimes called power frequency. This range falls within the extremely low-frequency band (ELF-EMF). The hypothesis that exposure to such fields increases the risk of cancer has been controversial ever since a link was reported more than two decades ago. 1 Wertheimer N Leeper E Electrical wiring configurations and childhood cancer. Am J Epidemiol. 1979; 109: 273-384 Crossref PubMed Scopus (1372) Google Scholar The main reason for scepticism has been the low amount of energy that these fields transfer because of their low frequency; the wave-length corresponding to 50 Hz is similar to the radius of the earth. The only established mechanism for biological effects of ELF-EMF is induction of electrical currents in the tissue, but the fields to which a person is normally exposed in the environment are generally orders of magnitude too low to be of any significance in this context, in view of the endogenous electrical activity in nerve and muscle cells. These considerations have led physicists to claim that ELF-EMF cannot produce biological effects at the low levels of environmental exposure.

Do electromagnetic fields interact directly with DNA?

The mechanisms whereby electromagnetic (EM) fields stimulate changes in biosynthesis in cells are not known. It has has generally been assumed that EM fields first interact with cell membranes, but this pathway may not be only one. Interactions with membranes are well documented, but recent studies of EM signal transduction in the membrane Na,K-ATPase are best explained by direct interaction of electric and magnetic fields with mobile charges within the enzyme. Interaction with moving charges may be a mechanism that is operative in other biopolymers. Recent studies on DNA have shown that large electron flows are possible within the stacked base pairs of the double helix. Therefore, gene activation by magnetic fields could be due to direct interaction with moving electrons within DNA. Electric fields as well as magnetic fields stimulate transcription, and both fields could interact with DNA directly. The mechanism of EM field-stimulated transcription may be related to the process in striated muscles, where endogenous electrical activity induces the synthesis of new proteins.

Phosphorylation of presynaptic and postsynaptic calcium channels by cAMP-dependent protein kinase in hippocampal neurons.

Phosphorylation by cAMP-dependent protein kinase (PKA) and other second messenger-activated protein kinases modulates the activity of a variety of effector proteins including ion channels. Anti-peptide antibodies specific for the alpha 1 subunits of the class B, C or E calcium channels from rat brain specifically recognize a pair of polypeptides of 220 and 240 kDa, 200 and 220 kDa, and 240 and 250 kDa, respectively, in hippocampal slices in vitro. These calcium channels are localized predominantly on presynaptic and dendritic, somatic and dendritic, and somatic sites, respectively, in hippocampal neurons. Both size forms of alpha 1B and alpha 1E and the full-length form of alpha 1C are phosphorylated by PKA after solubilization and immunoprecipitation. Stimulation of PKA in intact hippocampal slices also induced phosphorylation of 25-50% of the PKA sites on class B N-type calcium channels, class C L-type calcium channels and class E calcium channels, as assessed by a back-phosphorylation method. Tetraethylammonium ion (TEA), which causes neuronal depolarization and promotes repetitive action potentials and neurotransmitter release by blocking potassium channels, also stimulated phosphorylation of class B, C and E alpha 1 subunits, suggesting that these three classes of channels are phosphorylated by PKA in response to endogenous electrical activity in the hippocampus. Regulation of calcium influx through these calcium channels by PKA may influence calcium-dependent processes within hippocampal neurons, including neurotransmitter release, calcium-activated enzymes and gene expression.

BURSTING, SPIKING, CHAOS, FRACTALS, AND UNIVERSALITY IN BIOLOGICAL RHYTHMS

Biological systems offer many interesting examples of oscillations, chaos, and bifurcations. Oscillations in biology arise because most cellular processes contain feedbacks that are appropriate for generating rhythms. These rhythms are essential for regulating cellular function. In this tutorial review, we treat two interesting nonlinear dynamic processes in biology that give rise to bursting, spiking, chaos, and fractals: endogenous electrical activity of excitable cells and Ca2+ releases from the Ca2+ stores in nonexcitable cells induced by hormones and neurotransmitters. We will first show that each of these complex processes can be described by a simple, yet elegant, mathematical model. We then show how to utilize bifurcation analyses to gain a deeper insight into the mechanisms involved in the neuronal and cellular oscillations. With the bifurcating diagrams, we explain how spiking can be transformed to bursting via a complex type of dynamic structure when the key parameter in the model varies. Understanding how this parameter would affect the bifurcation structure is important in predicting and controlling abnormal biological rhythms. Although we describe two very different dynamic processes in biological rhythms, we will show that there is universality in their bifurcation structures.

Presynaptic Excitability

Based on functional characterizations with electrophysiological techniques, the channels in nerve terminals appear to be as diverse as channels in nerve cell bodies (Table I). While most presynaptic Ca2+ channels superficially resemble either N-type or L-type channels, variations in detail have necessitated the use of subscripts and other notations to indicate a nerve terminal-specific subtype (e.g., Wang et al., 1993). Variations such as these pose a serious obstacle to the identification of presynaptic channels based solely on the effects of channel blockers on synaptic transmission. Pharmacological sensitivity alone is not likely to help in determining functional properties. Crucial details, such as voltage sensitivity and inactivation, require direct examination. It goes without saying that every nerve terminal membrane contains Ca2+ channels as an entry pathway so that Ca2+ can trigger secretion. However, there appears to be no general specification of channel type, other than the exclusion of T-type Ca2+ channels. T-type Ca2+ channels are defined functionally by strong inactivation and low threshold. Some presynaptic Ca2+ channels inactivate (posterior pituitary and Xenopus nerve terminals), and others have a somewhat reduced voltage threshold (retinal bipolar neurons and squid giant synapse). Perhaps it is just a matter of time before a nerve terminal Ca2+ channel is found with both of these properties. The high threshold and strong inactivation of T-type Ca2+ channels are thought to be adaptations for oscillations and the regulation of bursting activity in nerve cell bodies. The nerve terminals thus far examined have no endogenous electrical activity, but rather are driven by the cell body. On functional grounds, it is then reasonable to anticipate finding T-type Ca2+ channels in nerve terminals that can generate electrical activity on their own. The rarity of such behavior in nerve terminals may be associated with the rarity of presynaptic T-type Ca2+ channels. In four of the five preparations reviewed in this chapter--motor nerve, squid giant synapse, ciliary ganglion, and retina bipolar neurons--evidence was presented that supports a location for Ca2+ channels that is very close to active zones of secretion. All of these synapses secrete from clear vesicles, and the speed and specificity of transduction provided by proximity may be a common feature of these rapid synapses. In contrast, the posterior pituitary secretion apparatus may be triggered by higher-affinity Ca2+ receptors and lower concentrations of Ca2+ (Lindau et al., 1992). This would correspond with the slower performance of peptidergic secretion, but because of the large stimuli needed to evoke release from neurosecretosomes, the possibility remains that the threshold for secretion is higher than that reported. While the role of Ca2+ as a trigger of secretion dictates a requirement for voltage-activated Ca2+ channels as universal components of the presynaptic membrane, the presence of other channels is more difficult to predict. Depolarizations caused by voltage-activated Na+ channels activate the presynaptic Ca2+ channels, but whether this depolarization requires Na+ channels in the presynaptic membrane itself may depend on the electrotonic length of the nerve terminal. Variations in density between motor nerve terminals may reflect species differences in geometry. The high Na+ channel density in the posterior pituitary reflects the great electrotonic length of this terminal arbor. Whether Na+ channels are abundant or not in a presynaptic membrane, K+ channels provide the most robust mechanism for limiting depolarization-induced Ca2+ entry. K+ channel blockers enhance transmission at most synapses. In general, K+ channels are abundant in nerve terminals, although their apparent lower priority compared to Ca2+ channels in the eyes of many investigators leaves us with fewer detailed investigations in some preparations. Most nerve terminals have more than

Ion channel properties and episodic activity in isolated immortalized gonadotropin-releasing hormone (GnRH) neurons.

The mechanism of periodic gonadotropin-releasing hormone (GnRH) secretion from hypothalamic neurons is difficult to elucidate due to the diffuse distribution of GnRH neurons and the complex interaction of neuronal inputs onto them. Recent use of transgenic techniques allowed construction of an immortalized GnRH neuronal cell line (GT1), which has neuronal markers and secretes GnRH in a periodic fashion. Using the patch-clamp recording technique in the whole-cell and nystatin perforated-patch configuration, the present experiments show that this cell line expressed a tetrodotoxin-sensitive Na channel, two types of Ca channels, three types of outward K channels and a K inward rectifier. The latter current was suppressed in some cells by GnRH or somatostatin. In addition, a gamma-aminobutyric acid (GABA) response, presumably through GABAA receptors, is recorded. In long-term current-clamp recordings, spontaneous depolarizing activity was found to increase, and then decrease, between 20-35 min after removal of the cells from serum- and steroid-containing medium. In some cases, more than one cycle of activity was seen. Under voltage clamp, an inward current was recorded at similar times, with reversal at about -15 mV. Thus, two mechanisms of cell interaction, GABAA responses and feedback through GnRH responses, and one mechanism of endogenous periodic electrical activity were observed in these cells, which could synchronize periodic GnRH release.

Electrical activity in cerebellar cultures determines Purkinje cell dendritic growth patterns

In primary dissociated cultures of mouse cerebellum a number of Purkinje cell-specific marker proteins and characteristic ionic currents appear at the appropriate developmental time. During the first week after plating, Purkinje cell dendrites elongate, but as electrical activity emerges the dendrites stop growing and branch. If endogenous electrical activity is inhibited by chronic tetrodotoxin or high magnesium treatment, dendrites continue to elongate, as if they were still immature. At the time that branching begins, intracellular calcium levels become sensitive to tetrodotoxin, suggesting that this cation may be involved in dendrite growth. Even apparently mature Purkinje cells alter their dendritic growth in response to changes in activity, suggesting long-term plasticity.

Both survival and development of spontaneously active rat hypothalamic neurons in dissociated culture are dependent on membrane depolarization

Suppression of endogenous electrical activity was found to have an adverse effect on the survival and bioelectric development of dissociated, embryonic rat hypothalamic neurons in long-term culture. Cultures were treated during the first two weeks in vitro with tetrodotoxin (TTX), a selective blocker of voltage-gated sodium channels, alone and in combination with high extracellular KCl ([K +] o), a membrane depolarizer. Neuron survival was assessed through cell counting experiments, while the development of spontaneous electrical activity was examined with extracellular, patch-electrode recordings. TTX caused both a decrease in cell survival and a decrease in spontaneously active cells; concurrent treatment with K + protected cells from the adverse effects of TTX. K + treatment alone increased the fraction of spontaneously active neurons without significantly affecting cell survival. When taken together, these results suggest that the long-term survival of active cells depends on continual membrane depolarization. From these observations, we conclude that there exists two populations of neurons: the electrically active population, whose survival is sensitive to electrical activity, and the quiescent population, whose survival is not.

Cardiac Tumors and Dysrhythmias in Transgenic Mice

Transgenic mice expressing atrial natriuretic factor-SV40 T-antigen fusion genes (ANF-TAG) developed cardiac tumors asymmetrically in the right atrium. Features associated with cardiac failure, including increased plasma creatine kinase activity (MM and MB) and ventricular dysrhythmias, also were associated with atrial tumor growth. These atrial tumors were able to grow at histocompatible sites (subcutaneously in syngeneic animals) for protracted periods of time yielding a series of transplantable atrial tumor lineages. The transplantable tumors displayed several cardiac-specific characteristics, such as endogenous electrical activity and expression of cardiac-specific proteins. These transplantable atrial tumors constitute a novel experimental resource for developing cell lines which display an adult cardiac phenotype.