Amplitude Of Field Potentials Research Articles

Pathological Human Tau Induces Alterations in the Brain Insulin Signaling Cascade.

The process of neurodegeneration in Alzheimer’s disease has been associated with a disruption of insulin signaling cascade in neurons, and to insulin resistance. T2DM correlates with Alzheimer’s disease, but mechanisms of interaction are unknown. We have developed a mouse model of tau induced neurodegeneration expressing pseudo-phosphorylated tau [Pathological Human Tau (PH-Tau)] in neurons. This model (PH-Tau-Tg) recapitulated cognitive decline and neurodegeneration observed in AD. In this study we examined if expression of PH-Tau could affect neuronal excitability and insulin receptor signaling. Neuronal excitability was investigated using intracerebral recordings of extracellular field potentials from prefrontal cortex after insulin and kainic acid (KA) injection. Analysis of baseline recordings indicated an increased excitability of PH-Tau-Tg as evidenced by higher spectrum densities (PSDs) of high frequencies brain waves. Injection of insulin (1IU, s.c) led to a decrease of fast ripples PSDs, more pronounced in PH-Tau-Tg mice than controls. Subsequent injection of kainic acid (KA, 5 mg/kg, s.c) led to significant increase in firing rate, amplitude of extracellular field potentials and PSDs of high frequency brain waves in control mice only. To further investigate the role of insulin in PH-Tau-Tg mice, we subjected mice to a glucose tolerance test. We found that PH-Tau-Tg mice were significantly hyperglycemic prior to glucose injection. Interestingly, the PH-Tau-Tg mice showed a moderate increase at 30 min due to the higher baseline, indicating a low sensitivity of insulin receptor in these mice. This is consistent with increased levels of activated insulin receptors in the brain and the inhibitory effect of insulin on ictal activity post KA injection in PH-Tau-Tg mice. We suggest that these mice have reduced insulin sensitivity (hyperglycemia) and as a compensatory mechanism there is overactivation/expression of insulin receptor in the brain rendering neuronal circuits resistant to seizure induction after injection of insulin. These data indicate that insulin signal transduction pathway is altered in PH-Tau-Tg mice, and that injection of exogenous insulin reduces hypersynchronous bursting activity of field potentials recorded from cortical neuronal circuits. We propose that the appearance of abnormal tau might potentiate the toxic environment by interfering with the insulin signaling cascade in the brain of patients with Alzheimer’s disease.

Uncovering spatial representations from spatiotemporal patterns of rodent hippocampal field potentials

SummarySpatiotemporal patterns of large-scale spiking and field potentials of the rodent hippocampus encode spatial representations during maze runs, immobility, and sleep. Here, we show that multisite hippocampal field potential amplitude at ultra-high-frequency band (FPAuhf), a generalized form of multiunit activity, provides not only a fast and reliable reconstruction of the rodent's position when awake, but also a readout of replay content during sharp-wave ripples. This FPAuhf feature may serve as a robust real-time decoding strategy from large-scale recordings in closed-loop experiments. Furthermore, we develop unsupervised learning approaches to extract low-dimensional spatiotemporal FPAuhf features during run and ripple periods and to infer latent dynamical structures from lower-rank FPAuhf features. We also develop an optical flow-based method to identify propagating spatiotemporal LFP patterns from multisite array recordings, which can be used as a decoding application. Finally, we develop a prospective decoding strategy to predict an animal's future decision in goal-directed navigation.

Visual Information Routes in the Posterior Dorsal and Ventral Face Network Studied with Intracranial Neurophysiology and White Matter Tract Endpoints.

Occipitotemporal regions within the face network process perceptual and socioemotional information, but the dynamics and information flow between different nodes of this network are still debated. Here, we analyzed intracerebral EEG from 11 epileptic patients viewing a stimulus sequence beginning with a neutral face with direct gaze. The gaze could avert or remain direct, while the emotion changed to fearful or happy. N200 field potential peak latencies indicated that face processing begins in inferior occipital cortex and proceeds anteroventrally to fusiform and inferior temporal cortices, in parallel. The superior temporal sulcus responded preferentially to gaze changes with augmented field potential amplitudes for averted versus direct gaze, and large effect sizes relative to other network regions. An overlap analysis of posterior white matter tractography endpoints (from 1066 healthy brains) relative to active intracerebral electrodes in the 11 patients showed likely involvement of both dorsal and ventral posterior white matter pathways. Overall, our data provide new insight into the timing of face and social cue processing in the occipitotemporal brain and anchor the superior temporal cortex in dynamic gaze processing.

EFFECTS OF CHAGASIC PATIENT'S SERA ON HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES

<h3>Background</h3> Chagas disease is an infectious disease caused by the protozoan Trypanosoma cruzi and can lead to cardiac dysfunction characterized by arrhythmias and heart failure. The presence of circulating autoantibodies capable of recognizing G-protein coupled receptors (GPCR) and activating β-adrenergic and muscarinic receptors has been proposed as an interactive and relevant pathophysiological factor in the development of the disease. However, the interaction of the sera from chronic chagasic patients with human cardiomyocytes has never been tested. This study investigated if chronic chagasic sera previously shown to activate β-adrenergic and muscarinic receptors in rodent and rabbit hearts could also activate these receptors in human cardiomyocytes. <h3>Methods</h3> An induced pluripotent stem cell (iPS) line derived from a healthy donor, previously generated, and characterized in our laboratory, was differentiated into cardiomyocytes (CM-iPS) and their electrophysiology was characterized by Multielectrode Array (MEA) system. We evaluated the effects of an anti-β-adrenergic (Aβ82) and an anti-muscarinic serum (M32) on spontaneous beat rate (BR), field potential amplitude (FPA), and field potential duration (FPD). To minimize the effect of BR on FPD, FPD was corrected (FPDc) using an adaptation of the Bazett equation (FPDc = FPD/√BP), where BP is the interval between spontaneous beats. During recordings, CM-iPS were continuously perfused with Tyrode solution containing or not chagasic sera from patients diluted at 1:100 (v:v). <h3>Results</h3> Sera Aβ-82 induced an increase in BR (16,90±4,22 bpm to 26,60±5,62 bpm, n=5, <i>p</i>=0.0177), FPD (164,03±6,18 ms to 208,73±9,44 ms, n=5, p<0.001), FPDc (80,18±3,16 ms to 139,29±5,90 ms, n=5, <i>p</i><0.001) and did not significantly alter the FPA in CM-iPS. When perfused in presence of atenolol 10µM, no changes in BR, FPD and FPA were observed. In contrast, perfusion of sera M32 decreased BR (46,33±2,46 bpm to 38,16±3,17bpm, n=4, p=0.0011), FPD (225,48±19,48 ms to 186,78±12,05 ms, n=4, <i>p</i>=0.0137), FPDc (179,61±9,66 ms to 131,72±6,14 ms n=4, <i>p</i><0.001) and FPA (675,64±58,61 µV to 458,25±54,09 µV, n=4, p=0,0009). When in presence of atropine 10µM, no changes in BR, FPD and FPA were observed. <h3>Conclusion</h3> We conclude that antibodies present in chronic chagasic patients‘ sera are capable of modulating GCPR activity in the human heart interacting with β-adrenergic and muscarinic receptors present in human cardiomyocytes.

Inflammatory Foreign Body Response Induced by Neuro-Implants in Rat Cortices Depleted of Resident Microglia by a CSF1R Inhibitor and Its Implications.

Inflammatory encapsulation of implanted cortical-neuro-probes [the foreign body response (FBR)] severely limits their use in basic brain research and in clinical applications. A better understanding of the inflammatory FBR is needed to effectively mitigate these critical limitations. Combining the use of the brain permeant colony stimulating factor 1 receptor inhibitor PLX5622 and a perforated polyimide-based multielectrode array platform (PPMP) that can be sectioned along with the surrounding tissue, we examined the contribution of microglia to the formation of inflammatory FBR. To that end, we imaged the inflammatory processes induced by PPMP implantations after eliminating 89–94% of the cortical microglia by PLX5622 treatment. The observations showed that: (I) inflammatory encapsulation of implanted PPMPs proceeds by astrocytes in microglia-free cortices. The activated astrocytes adhered to the PPMP’s surfaces. This suggests that the roles of microglia in the FBR might be redundant. (II) PPMP implantation into control or continuously PLX5622-treated rats triggered a localized surge of microglia mitosis. The daughter cells that formed a “cloud” of short-lived (T1/2 ≤ 14 days) microglia around and in contact with the implant surfaces were PLX5622 insensitive. (III) Neuron degeneration by PPMP implantation and the ensuing recovery in time, space, and density progressed in a similar manner in the cortices following 89–94% depletion of microglia. This implies that microglia do not serve a protective role with respect to the neurons. (IV) Although the overall cell composition and dimensions of the encapsulating scar in PLX5622-treated rats differed from the controls, the recorded field potential (FP) qualities and yield were undistinguishable. This is accounted for by assuming that the FP amplitudes in the control and PLX5622-treated rats were related to the seal resistance formed at the interface between the adhering microglia and/or astrocytes and the PPMP platform rather than across the scar tissue. These observations suggest that the prevention of both astrocytes and microglia adhesion to the electrodes is required to improve FP recording quality and yield.

Psychosocial Crowding Stress-Induced Changes in Synaptic Transmission and Glutamate Receptor Expression in the Rat Frontal Cortex.

This study demonstrates how exposure to psychosocial crowding stress (CS) for 3, 7, and 14 days affects glutamate synapse functioning and signal transduction in the frontal cortex (FC) of rats. CS effects on synaptic activity were evaluated in FC slices of the primary motor cortex (M1) by measuring field potential (FP) amplitude, paired-pulse ratio (PPR), and long-term potentiation (LTP). Protein expression of GluA1, GluN2B mGluR1a/5, VGLUT1, and VGLUT2 was assessed in FC by western blot. The body’s response to CS was evaluated by measuring body weight and the plasma level of plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH), and interleukin 1 beta (IL1B). CS 3 14d increased FP and attenuated LTP in M1, while PPR was augmented in CS 14d. The expression of GluA1, GluN2B, and mGluR1a/5 was up-regulated in CS 3d and downregulated in CS 14d. VGLUTs expression tended to increase in CS 7d. The failure to blunt the effects of chronic CS on FP and LTP in M1 suggests the impairment of habituation mechanisms by psychosocial stressors. PPR augmented by chronic CS with increased VGLUTs level in the CS 7d indicates that prolonged CS exposure changed presynaptic signaling within the FC. The CS bidirectional profile of changes in glutamate receptors’ expression seems to be a common mechanism evoked by stress in the FC.

Neuroplastic changes in auditory cortex induced by long-duration “non-traumatic” noise exposures are triggered by deficits in the neural output of the cochlea

Long-term exposure to moderate intensity noise that does not cause measureable hearing loss can cause striking changes in sound-evoked neural activity in auditory cortex. It is unclear if these changes originate in the cortex or result from functional deficits in the neural output of the cochlea. To explore this issue, rats were exposed for 6-weeks to 18–24 kHz noise at 45, 65 or 85 dB SPL and then compared the noise-induced changes in the cochlear compound action potential (CAP) with the neurophysiological alterations in the anterior auditory field (AAF) of auditory cortex. The 45-dB exposure, which had no effect on the cochlear CAP also had no effect on the AAF. In contrast, the 85-dB exposure greatly reduced CAP amplitudes at high frequencies, but had little or no effect on low frequencies. Despite the large reduction in high-frequency CAP neural responses, high frequency AAF neural responses (spike rate and local field potential amplitude) remained largely within normal limits, evidence of central gain compensation. AAF responses were also enhanced at the low frequencies even though CAP responses were normal; this AAF hyperactivity only occurred at low-moderate intensities (level-dependent enhanced central gain). The 65-dB exposure also caused a moderate reduction in high-frequency CAP amplitudes. Notwithstanding this cochlear loss, AAF responses were boosted into the normal range, evidence of homeostatic gain compensation. Our results suggest that the noise-induced neuroplastic changes in the auditory cortex from so-called “non-traumatic” exposures are triggered from functional deficits in the neural output of the cochlea.

Vision Outcomes for Pediatric Patients With Optic Pathway Gliomas Associated With Neurofibromatosis Type I: A Systematic Review of the Clinical Evidence.

Children with neurofibromatosis type I (NF1) have a higher predisposition for low-grade astrocytomas of the optic pathway, commonly referred to as optic pathway gliomas (OPGs). OPGs can result in visual deterioration. Treatment outcomes in OPG-NF1 management are often reported around tumor stabilization. We sought to compare vision outcomes associated with different OPG treatment strategies to inform about this important functional metric. A meta-analysis exploring the different modalities to treat children with OPG-NF1 was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using multiple databases. Of the 113 articles identified in the search, 23 full text articles, representing 564 patients, were included for review. These articles included retrospective, prospective, and randomized controlled studies on observation (n=9), chemotherapy (n=19), radiation therapy (n=6), and surgery (n=7). Of the patients undergoing observation, 87% (60/69) demonstrated stable acuity. In the chemotherapy studies, 27.3% (72/264) demonstrated improved acuity/visual field and/or visual-evoked potential amplitudes, 39.4% (104/264) stable acuity, and 33.3% (88/264) deterioration. Both the radiation and surgical treatments reported worsening acuity at 90.9% (10/11) and 73.3% (11/15), respectively. Causal associations are not known. Indications for and timing of treatment choice warrant larger scale study to provide further understanding.

Three rules govern thalamocortical connectivity of fast-spike inhibitory interneurons in the visual cortex.

Some cortical neurons receive highly selective thalamocortical (TC) input, but others do not. Here, we examine connectivity of single thalamic neurons (lateral geniculate nucleus, LGN) onto putative fast-spike inhibitory interneurons in layer 4 of rabbit visual cortex. We show that three 'rules' regulate this connectivity. These rules concern: (1) the precision of retinotopic alignment, (2) the amplitude of the postsynaptic local field potential elicited near the interneuron by spikes of the LGN neuron, and (3) the interneuron's response latency to strong, synchronous LGN input. We found that virtually all first-order fast-spike interneurons receive input from nearly all LGN axons that synapse nearby, regardless of their visual response properties. This was not the case for neighboring regular-spiking neurons. We conclude that profuse and highly promiscuous TC inputs to layer-4 fast-spike inhibitory interneurons generate response properties that are well-suited to mediate a fast, sensitive, and broadly tuned feed-forward inhibition of visual cortical excitatory neurons.

Immunohistological and Ultrastructural Study of the Inflammatory Response to Perforated Polyimide Cortical Implants: Mechanisms Underlying Deterioration of Electrophysiological Recording Quality.

The deterioration of field potential (FP) recording quality and yield by in vivo multielectrode arrays (MEA) within days to weeks of implantation severely limits progress in basic and applied brain research. The prevailing hypothesis is that implantation of MEA platforms initiate and perpetuate inflammatory processes which culminate in the formation of scar tissue (the foreign body response, FBR) around the implant. The FBR leads to progressive degradation of the recording qualities by displacing neurons away from the electrode surfaces, increasing the resistance between neurons (current source) and the sensing pads and by reducing the neurons’ excitable membrane properties and functional synaptic connectivity through the release of pro-inflammatory cytokines. Meticulous attempts to causally relate the cellular composition, cell density, and electrical properties of the FBR have failed to unequivocally correlate the deterioration of recording quality with the histological severity of the FBR. Based on confocal and electron microscope analysis of thin sections of polyimide based MEA implants along with the surrounding brain tissue at different points in time after implantation, we propose that abrupt FP amplitude attenuation occurs at the implant/brain-parenchyma junction as a result of high seal resistance insulation formed by adhering microglia to the implant surfaces. In contrast to the prevailing hypothesis, that FP decrease occurs across the encapsulating scar of the implanted MEA, this mechanism potentially explains why no correlations have been found between the dimensions and density of the FBR and the recording quality. Recognizing that the seal resistance formed by adhering-microglia to the implant constitutes a downstream element undermining extracellular FP recordings, suggests that approaches to mitigate the formation of the insulating glial could lead to improved recording quality and yield.

The conductive function of biopolymer corrects myocardial scar conduction blockage and resynchronizes contraction to prevent heart failure

Myocardial fibrosis, resulting from ischemic injury, increases tissue resistivity in the infarct area, which impedes heart synchronous electrical propagation. The uneven conduction between myocardium and fibrotic tissue leads to dys-synchronous contraction, which progresses towards ventricular dysfunction. We synthesized a conductive poly-pyrrole-chitosan hydrogel (PPY–CHI), and investigated its capabilities in improving electrical propagation in fibrotic tissue, as well as resynchronizing cardiac contraction to preserve cardiac function. In an in vitro fibrotic scar model, conductivity increased in proportion to the amount of PPY-CHI hydrogel added. To elucidate the mechanism of interaction between myocardial ionic changes and electrical current, an equivalent circuit model was used, which showed that PPY-CHI resistance was 10 times lower, and latency time 5 times shorter, compared to controls. Using a rat myocardial infarction (MI) model, PPY-CHI was injected into fibrotic tissue 7 days post MI. There, PPY-CHI reduced tissue resistance by 30%, improved electrical conduction across the fibrotic scar by 33%, enhanced field potential amplitudes by 2 times, and resynchronized cardiac contraction. PPY-CHI hydrogel also preserved cardiac function at 3 months, and reduced susceptibility to arrhythmia by 30% post-MI. These data demonstrated that the conductive PPY-CHI hydrogel reduced fibrotic scar resistivity, and enhanced electrical conduction, to synchronize cardiac contraction.

A self-doping conductive polymer hydrogel that can restore electrical impulse propagation at myocardial infarct to prevent cardiac arrhythmia and preserve ventricular function

Following myocardial infarction (MI), necrotic cardiomyocytes (CMs) are replaced by fibroblasts and collagen tissue, causing abnormal electrical signal propagation, desynchronizing cardiac contraction, resulting in cardiac arrhythmia. In this work, a conductive polymer, poly-3-amino-4-methoxybenzoic acid (PAMB), is synthesized and grafted onto non-conductive gelatin. The as-synthesized PAMB-G copolymer is self-doped in physiological pH environments, making it an electrically active material in biological tissues. This copolymer is cross-linked by carbodiimide to form an injectable conductive hydrogel (PAMB-G hydrogel). The un-grafted gelatin hydrogel is prepared in a similar manner as a control. Both test hydrogels not only provide an optimal matrix for CM adhesion and growth but also maintain CM morphology and functional proteins. The conductivity of PAMB-G hydrogel is ca. 12 times higher than that of gelatin hydrogel. Microelectrode array analyses reveal that a heart placed on the PAMB-G hydrogel has a higher field potential amplitude than that placed on the gelatin hydrogel and can pass current from one heart to excite another heart at a distance. The injection of PAMB-G hydrogel into the scar zone following an MI in a rat heart improves electrical impulse propagation over that in a heart that has been treated with gelatin hydrogel, and synchronizes heart contraction, leading to preservation of the ventricular function and reduction of cardiac arrhythmia, demonstrating its potential for use in treating MI.

Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems.

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48-120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

Complex temporal patterns processing by a neural mass model of a cortical column.

It is well known that neuronal networks are capable of transmitting complex spatiotemporal information in the form of precise sequences of neuronal discharges characterized by recurrent patterns. At the same time, the synchronized activity of large ensembles produces local field potentials that propagate through highly dynamic oscillatory waves, such that, at the whole brain scale, complex spatiotemporal dynamics of electroencephalographic (EEG) signals may be associated to sensorimotor decision making processes. Despite these experimental evidences, the link between highly temporally organized input patterns and EEG waves has not been studied in detail. Here, we use a neural mass model to investigate to what extent precise temporal information, carried by deterministic nonlinear attractor mappings, is filtered and transformed into fluctuations in phase, frequency and amplitude of oscillatory brain activity. The phase shift that we observe, when we drive the neural mass model with specific chaotic inputs, shows that the local field potential amplitude peak appears in less than one full cycle, thus allowing traveling waves to encode temporal information. After converting phase and amplitude changes obtained into point processes, we quantify input-output similarity following a threshold-filtering algorithm onto the amplitude wave peaks. Our analysis shows that the neural mass model has the capacity for gating the input signal and propagate selected temporal features of that signal. Finally, we discuss the effect of local excitatory/inhibitory balance on these results and how excitability in cortical columns, controlled by neuromodulatory innervation of the cerebral cortex, may contribute to set a fine tuning and gating of the information fed to the cortex.

Efficacy and cardiotoxicity integrated assessment of anticancer drugs by a dual functional cell-based biosensor

Cancer significantly threatens human life, and the chemotherapy drugs are developed and widely used in the cancer treatment. However, the side effects of drugs on heart cause other serious problems. In this study, a dual functional cell-based biosensor integrating interdigitated electrodes (IDEs, monitoring cell viability) and microelectrodes (monitoring electrophysiology) is developed to comprehensively evaluate the efficacy and cardiotoxicity of anticancer drugs. Hela cells and cardiomyocytes of neonatal rats were cultured on this cell-based biosensor. Taxol (TAX) and vinblastine (VBL) were utilized to verify the performance of this platform. The efficacy of TAX and VBL were verified by comparing the results of traditional method and this method. As for cardiotoxicity, TAX showed little effect on cell viability, and slightly influenced the electrophysiological activity of cardiomyocytes at the range of 50–800 nM (with the sensitivity of -13.48%/lg TAX (nM) in field potential amplitude (FPA)) and 7.12%/lg TAX (nM) in firing rate (FR)). By contrast, VBL presented a relatively strong effect on both cell viability and electrophysiological activity of cardiomyocytes, which show a dose-dependent manner within a certain concentration range (with the sensitivity of -41.86%/lg VBL (nM) in FPA and -30.45%/lg VBL (nM) in FR). Owing to its simultaneously monitoring cell viability and electrophysiological activity of cells in a real-time and dynamic way, the dual functional cell-based biosensors will be a utility platform to evaluate the efficacy and cardiotoxicity of candidate compounds in new drug development.

Developmental maturation of activity-induced K+ and pH transients and the associated extracellular space dynamics in the rat hippocampus.

Neuronal activity induces fluctuation in extracellular space volume, [K+ ]o and pHo , the management of which influences neuronal function The neighbour astrocytes buffer the K+ and pH and swell during the process, causing shrinkage of the extracellular space In the present study, we report the developmental rise of the homeostatic control of the extracellular space dynamics, for which regulation becomes tighter with maturation and thus is proposed to ensure efficient synaptic transmission in the mature animals The extracellular space dynamics of volume, [K+ ]o and pHo evolve independently with developmental maturation and, although all of them are inextricably tied to neuronal activity, they do not couple directly. Neuronal activity in the mammalian central nervous system associates with transient extracellular space (ECS) dynamics involving elevated K+ and pH and shrinkage of the ECS. These ECS properties affect membrane potentials, neurotransmitter concentrations and protein function and are thus anticipated to be under tight regulatory control. It remains unresolved to what extent these ECS dynamics are developmentally regulated as synaptic precision arises and whether they are directly or indirectly coupled. To resolve the development of homeostatic control of [K+ ]o , pH, and ECS and their interaction, we utilized ion-sensitive microelectrodes in electrically stimulated rat hippocampal slices from rats of different developmental stages (postnatal days 3-28). With the employed stimulation paradigm, the stimulus-evoked peak [K+ ]o and pHo transients were stable across age groups, until normalized to neuronal activity (field potential amplitude), in which case the K+ and pH shifted significantly more in the younger animals. By contrast, ECS dynamics increased with age until normalized to the field potential, and thus correlated with neuronal activity. With age, the animals not only managed the peak [K+ ]o better, but also displayed swifter post-stimulus removal of [K+ ]o , in correlation with the increased expression of the α1-3 isoforms of the Na+ /K+ -ATPase, and a swifter return of ECS volume. The different ECS dynamics approached a near-identical temporal pattern in the more mature animals. In conclusion, although these phenomena are inextricably tied to neuronal activity, our data suggest that they do not couple directly.

A Dual Functional Cardiomyocyte-based Hybrid-biosensor for the Detection of Diarrhetic Shellfish Poisoning and Paralytic Shellfish Poisoning Toxins.

Okadaic acid (OA) and saxitoxin (STX) are typical toxins of diarrhetic shellfish poisoning (DSP) and paralytic shellfish poisoning (PSP), respectively, which are highly toxic marine toxins threatening human health and environmental safety. OA is a potent inhibitor of serine/threonine protein phosphatases that can cause cellular death, while STX is an inhibitor of sodium channel that can lead to neurological damage. In this work, a dual functional cardiomyocyte-based biosensor was proposed to detect DSP and PSP toxins by monitoring the viability and electrophysiology of cardiomyocytes. The results showed that the viability of cardiomyocytes was sensitive to the OA and STX, resulting in significant changes of the electrophysiological properties, including amplitude, firing rate and duration of the extracellular field potential (EFP). The detection limits of the hybrid-biosensor are as low as 7.16 ng/mL for OA and 5.19 ng/mL for STX. In summary, all of the results indicate that the dual functional cardiomyocyte-based hybrid-biosensor will be a promising and utility tool for shellfish toxin detection.

Status epilepticus induced by pentylenetetrazole increases short-term synaptic facilitation in the hippocampus of juvenile rats.

We studied the effect of status epilepticus (SE) on short-term synaptic plasticity. The amplitudes of field potentials in response to extracellular stimulation of the Schaffer collaterals were recorded in hippocampal slices. Subtle modifications were revealed on day 1 after SE, whereas on days 3 and 7 we did not find any differences from the control. These data show that, one day after SE, the probability of a transmitter release in hippocampal synapses decreases that serves as a compensatory mechanism, which prevents seizure activity.

Stimulation of Cortico-Subthalamic Projections Amplifies Resting Motor Circuit Activity and Leads to Increased Locomotion in Dopamine-Depleted Mice.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor function in patients with Parkinson’s disease (PD). STN-DBS enables similar improved motor function, including increased movement speed (reduced bradykinesia), in the 6-OHDA dopamine-depletion mouse model of PD. Previous analyses of electrophysiological recordings from STN and motor cortex (M1) have explored signaling changes that correspond to PD and amelioration of PD symptoms. The most common results show an increase in beta frequency power during ‘off’ states and a reduction in beta during ‘on’ states. Surprisingly, however, few studies have analyzed whole signal measures of amplitude and coherence during stimulation in freely moving subjects. In previous work by the author, specific transfection of layer five motor cortex projections to the STN revealed an axonal network with collaterals reaching to multiple non-dopaminergic subcortical areas of the brain. The large excitatory shift that stimulation of this axonal network could potentially induce inspired the current study’s hypothesis that amplification of excitatory signaling occurs during stimulation of cortico-subthalamic projections. The results show that, in awake mice, (1) the root-mean-square amplitudes of STN and M1 local field potentials (LFPs) are significantly decreased ipsilateral to chronic unilateral 6-OHDA lesions, (2) stimulation of cortico-subthalamic projections increases the amplitude of M1- and STN-LFPs, and 3) M1-LFP amplitude correlates strongly with locomotion speed in lesioned mice. Together, these findings demonstrate that bradykinesia-reducing stimulation of cortico-subthalamic projections amplifies both cortical and subcortical motor circuit activity in unilaterally dopamine-depleted mice. Most PD treatments are focused on increasing dopamine in the dorsal striatum. However, in this study, stimulation of layer five cortico-subthalamic glutamatergic axons that do not directly project to dopaminergic neurons increased movement and amplified cortico-subthalamic excitatory signaling in dopamine-depleted mice. The correlation between M1-LFP amplitude and locomotion speed observed in these mice points to a role for upregulated hyperdirect pathway excitatory signaling in bradykinesia amelioration. In addition to providing insight into the elusive mechanisms of DBS, these motor circuit amplification relationships suggest that specific manipulation of NMDA, AMPA, and/or metabotropic glutamate receptors in the hyperdirect pathway may be beneficial for upregulating signaling and movement in PD.

Primary Generators of Visually Evoked Field Potentials Recorded in the Macaque Auditory Cortex.

Prior studies have reported "local" field potential (LFP) responses to faces in the macaque auditory cortex and have suggested that such face-LFPs may be substrates of audiovisual integration. However, although field potentials (FPs) may reflect the synaptic currents of neurons near the recording electrode, due to the use of a distant reference electrode, they often reflect those of synaptic activity occurring in distant sites as well. Thus, FP recordings within a given brain region (e.g., auditory cortex) may be "contaminated" by activity generated elsewhere in the brain. To determine whether face responses are indeed generated within macaque auditory cortex, we recorded FPs and concomitant multiunit activity with linear array multielectrodes across auditory cortex in three macaques (one female), and applied current source density (CSD) analysis to the laminar FP profile. CSD analysis revealed no appreciable local generator contribution to the visual FP in auditory cortex, although we did note an increase in the amplitude of visual FP with cortical depth, suggesting that their generators are located below auditory cortex. In the underlying inferotemporal cortex, we found polarity inversions of the main visual FP components accompanied by robust CSD responses and large-amplitude multiunit activity. These results indicate that face-evoked FP responses in auditory cortex are not generated locally but are volume-conducted from other face-responsive regions. In broader terms, our results underscore the caution that, unless far-field contamination is removed, LFPs in general may reflect such "far-field" activity, in addition to, or in absence of, local synaptic responses.SIGNIFICANCE STATEMENT Field potentials (FPs) can index neuronal population activity that is not evident in action potentials. However, due to volume conduction, FPs may reflect activity in distant neurons superimposed upon that of neurons close to the recording electrode. This is problematic as the default assumption is that FPs originate from local activity, and thus are termed "local" (LFP). We examine this general problem in the context of previously reported face-evoked FPs in macaque auditory cortex. Our findings suggest that face-FPs are indeed generated in the underlying inferotemporal cortex and volume-conducted to the auditory cortex. The note of caution raised by these findings is of particular importance for studies that seek to assign FP/LFP recordings to specific cortical layers.