Short-duration Spikes Research Articles

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition.

Interictal spikes are electroencephalographic discharges that occur at or near brain regions that produce epileptic seizures. While their role in generating seizures is not well understood, spikes have profound effects on cognition and behaviour, depending on where and when they occur. We previously demonstrated that spiking areas of human neocortex show sustained MAPK activation in superficial cortical Layers I-III and are associated with microlesions in deeper cortical areas characterized by reduced neuronal nuclear protein staining and increased microglial infiltration. Based on these findings, we chose to investigate additional neuronal populations within microlesions, specifically inhibitory interneurons. Additionally, we hypothesized that spiking would be sufficient to induce similar cytoarchitectonic changes within the rat cortex and that inhibition of MAPK signalling, using a MAP2K inhibitor, would not only inhibit spike formation but also reduce these cytoarchitectonic changes and improve behavioural outcomes. To test these hypotheses, we analysed tissue samples from 16 patients with intractable epilepsy who required cortical resections. We also utilized a tetanus toxin-induced animal model of interictal spiking, designed to produce spikes without seizures in male Sprague-Dawley rats. Rats were fitted with epidural electrodes, to permit EEG recording for the duration of the study, and automated algorithms were implemented to quantify spikes. After 6 months, animals were sacrificed to assess the effects of chronic spiking on cortical cytoarchitecture. Here, we show that microlesions may promote excitability due to a significant reduction of inhibitory neurons that could be responsible for promoting interictal spikes in superficial layers. Similarly, we found that the induction of epileptic spikes in the rat model produced analogous changes, including reduced neuronal nuclear protein, calbindin and parvalbumin-positive neurons and increased microglia, suggesting that spikes are sufficient for inducing these cytoarchitectonic changes in humans. Finally, we implicated MAPK signalling as a driving force producing these pathological changes. Using CI-1040 to inhibit MAP2K, both acutely and after spikes developed, resulting in fewer interictal spikes, reduced microglial activation and less inhibitory neuron loss. Treated animals had significantly fewer high-amplitude, short-duration spikes, which correlated with improved spatial memory performance on the Barnes maze. Together, our results provide evidence for a cytoarchitectonic pathogenesis underlying epileptic cortex, which can be ameliorated through both early and delayed MAP2K inhibition. These findings highlight the potential role for CI-1040 as a pharmacological treatment that could prevent the development of epileptic activity and reduce cognitive impairment in both patients with epilepsy and those with non-epileptic spike-associated neurobehavioural disorders.

Signal processing and computational modeling for interpretation of SEEG-recorded interictal epileptiform discharges in epileptogenic and non-epileptogenic zones

Objective. In partial epilepsies, interictal epileptiform discharges (IEDs) are paroxysmal events observed in epileptogenic zone (EZ) and non-epileptogenic zone (NEZ). IEDs’ generation and recurrence are subject to different hypotheses: they appear through glutamatergic and gamma-aminobutyric acidergic (GABAergic) processes; they may trigger seizures or prevent seizure propagation. This paper focuses on a specific class of IEDs, spike-waves (SWs), characterized by a short-duration spike followed by a longer duration wave, both of the same polarity. Signal analysis and neurophysiological mathematical models are used to interpret puzzling IED generation. Approach. Interictal activity was recorded by intracranial stereo-electroencephalography (SEEG) electrodes in five different patients. SEEG experts identified the epileptic and non-epileptic zones in which IEDs were detected. After quantifying spatial and temporal features of the detected IEDs, the most significant features for classifying epileptic and non-epileptic zones were determined. A neurophysiologically-plausible mathematical model was then introduced to simulate the IEDs and understand the underlying differences observed in epileptic and non-epileptic zone IEDs. Main results. Two classes of SWs were identified according to subtle differences in morphology and timing of the spike and wave component. Results showed that type-1 SWs were generated in epileptogenic regions also involved at seizure onset, while type-2 SWs were produced in the propagation or non-involved areas. The modeling study indicated that synaptic kinetics, cortical organization, and network interactions determined the morphology of the simulated SEEG signals. Modeling results suggested that the IED morphologies were linked to the degree of preserved inhibition. Significance. This work contributes to the understanding of different mechanisms generating IEDs in epileptic networks. The combination of signal analysis and computational models provides an efficient framework for exploring IEDs in partial epilepsies and classifying EZ and NEZ.

Representation of the body in the lateral striatum of the freely moving rat: Fast Spiking Interneurons respond to stimulation of individual body parts

Numerous studies have shown that certain types of striatal interneurons play a crucial role in selection and regulation of striatal output. Striatal Fast-Spiking Interneurons (FSIs) are parvalbumin positive, GABAergic interneurons that constitute less than 1% of the total striatal population. It is becoming increasingly evident that these sparsely distributed neurons exert a strong inhibitory effect on Medium Spiny projection Neurons (MSNs). MSNs in lateral striatum receive direct synaptic input from regions of cortex representing discrete body parts, and show phasic increases in activity during touch or movement of specific body parts. In the present study, we sought to determine whether lateral striatal FSIs identified by their electrophysiological properties, i.e., short-duration spike and fast firing rate (FR), display body part sensitivity similar to that exhibited by MSNs. During video recorded somatosensorimotor exams, each individual body part was stimulated and responses of single neurons were observed and quantified. Individual FSIs displayed patterns of activity related selectively to stimulation of a discrete body part. Most patterns of activity were similar to those exhibited by typical MSNs, but some phasic decreases were observed. These results serve as evidence that some striatal FSIs process information related to discrete body parts and participate in sensorimotor processing by striatal networks that contribute to motor output. Statement of SignificanceParvalbumin positive, striatal FSIs are hypothesized to play an important role in behavior by inhibiting MSNs. We asked a fundamental question regarding information processed during behavior by FSIs: whether FSIs, which preferentially occupy the sensorimotor portion of the striatum, process activity of discrete body parts. Our finding that they do, in a selective manner similar to MSNs, begins to reveal the types of phasic signals that FSI feed forward to projection neurons during striatal processing of cortical input regarding a specific sensorimotor event. These findings suggest new avenues for testing feed-forward inhibition theory as applied to striatum in naturalistic conditions, such as whether FSI decreases facilitate excitation of MSNs related to the current movement while FSI increases silence MSNs unrelated to the current movement.

Water-quality response to a high-elevation wildfire in the Colorado Front Range

: Water quality of the Big Thompson River in the Front Range of Colorado was studied for 2 years following a high-elevation wildfire that started in October 2012 and burned 15% of the watershed. A combination of fixed-interval sampling and continuous water-quality monitors was used to examine the timing and magnitude of water-quality changes caused by the wildfire. Prefire water quality was well characterized because the site has been monitored at least monthly since the early 2000s. Major ions and nitrate showed the largest changes in concentrations; major ion increases were greatest in the first postfire snowmelt period, but nitrate increases were greatest in the second snowmelt period. The delay in nitrate release until the second snowmelt season likely reflected a combination of factors including fire timing, hydrologic regime, and rates of nitrogen transformations. Despite the small size of the fire, annual yields of dissolved constituents from the watershed increased 20–52% in the first 2 years following the fire. Turbidity data from the continuous sensor indicated high-intensity summer rain storms had a much greater effect on sediment transport compared to snowmelt. High-frequency sensor data also revealed that weekly sampling missed the concentration peak during snowmelt and short-duration spikes during rain events, underscoring the challenge of characterizing postfire water-quality response with fixed-interval sampling. Copyright © 2015 John Wiley & Sons, Ltd.

Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.

Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown. To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload. Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.

Reprint of: Number concentrations and elemental compositions of aerosol particles observed at Mt. Kiso-Komagatake in central Japan, 2010–2013

Aerosols in the lower troposphere over Japan are considered being influenced by those transported from Asian continent by westerly winds. In this study, we investigated the seasonal variation of aerosol number concentrations measured by means of optical particle counters at Mt. Kiso-Komagatake (2610 m altitude) in central Japan during the period from January 2010 to May 2013. We also collected aerosol samples in different seasons during part of the observation period and investigated their elemental compositions using transmission electron microscopy (TEM) combined with energy dispersive X-ray spectroscopy (EDX). The seasonal variation of the number concentrations suggested that accumulation-mode particles (particle diameter > 0.3 μm) increased during late spring perhaps owing to gas-to-particle conversion by means of photochemical reactions. The number concentrations of supermicron particles (>1 μm) were highest in spring, during which Asian dust events were frequent. Short-duration spikes in aerosol number concentrations, which were attributed to long-range transport from the Asian continent, were frequently observed in all seasons except summer. TEM analysis indicated that sulfate was the predominant component of accumulation-mode particles throughout the year. The number fraction of carbonaceous particles was also considerable, especially in samples in fall. The predominant components of supermicron particles collected during winter, spring and fall, and summer were sulfate, minerals, and sea salt, respectively. Our results suggest that the lower tropospheric air over central Japan is strongly influenced by long-range transport of aerosols in all seasons except summer.

Number concentrations and elemental compositions of aerosol particles observed at Mt. Kiso-Komagatake in central Japan, 2010–2013

Aerosols in the lower troposphere over Japan are considered being influenced by those transported from Asian continent by westerly winds. In this study, we investigated the seasonal variation of aerosol number concentrations measured by means of optical particle counters at Mt. Kiso-Komagatake (2610 m altitude) in central Japan during the period from January 2010 to May 2013. We also collected aerosol samples in different seasons during part of the observation period and investigated their elemental compositions using transmission electron microscopy (TEM) combined with energy dispersive X-ray spectroscopy (EDX). The seasonal variation of the number concentrations suggested that accumulation-mode particles (particle diameter > 0.3 μm) increased during late spring perhaps owing to gas-to-particle conversion by means of photochemical reactions. The number concentrations of supermicron particles (>1 μm) were highest in spring, during which Asian dust events were frequent. Short-duration spikes in aerosol number concentrations, which were attributed to long-range transport from the Asian continent, were frequently observed in all seasons except summer. TEM analysis indicated that sulfate was the predominant component of accumulation-mode particles throughout the year. The number fraction of carbonaceous particles was also considerable, especially in samples in fall. The predominant components of supermicron particles collected during winter, spring and fall, and summer were sulfate, minerals, and sea salt, respectively. Our results suggest that the lower tropospheric air over central Japan is strongly influenced by long-range transport of aerosols in all seasons except summer.

Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra.

GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (Na(V)) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, Na(V) channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming Na(V)1.1 and Na(V)1.6 subunits and regulatory Na(V)β1 and Na(v)β4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming Na(V) channels conducting the transient Na(V) current (I(NaT)), persistent Na current (I(NaP)), and resurgent Na current (I(NaR)). Nucleated patch-clamp recordings showed that I(NaT) had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. I(NaT) also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger I(NaR) and I(NaP). Blockade of I(NaP) induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that Na(V) channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities.

Measurement of the effects of the exhaust gas recirculation delay on the nitrogen oxide emissions within a turbocharged passenger car diesel engine

Fast-response nitrogen oxide (NO x) and carbon dioxide (CO2) analysers have been used to study the effects of exhaust gas recirculation (EGR) delay within a modern diesel passenger car. These analysers have response times of the order of a few milliseconds, allowing the CO2 analyser to be used to study the effects of the EGR transit delay during engine transients and the effect of sudden EGR valve actuation during a drive cycle. The effect of the EGR system delays on the NO x emissions was measured with the fast-response NO x analyser. The results indicate that the EGR delay contributes to the sharp short-duration spikes of NO x. Tests have also been carried out to identify the transient cylinder-to-cylinder EGR distribution by comparing the CO2 concentrations in the inlet ports, again using the fast-response CO2 analyser. The results of these tests show a variation between the CO2 concentrations in the intake ports, suggesting a poor EGR distribution under certain conditions. Measurements have been recorded of the EGR in the intake port runner of just one of the engine’s cylinders and have been compared with the exhaust port NO x emissions. This provided some data on a cycle-by-cycle basis including the number of engine cycles required for the burned gas to complete the EGR circuit.

Kv3-Like Potassium Channels Are Required for Sustained High-Frequency Firing in Basal Ganglia Output Neurons

The GABA projection neurons in the substantial nigra pars reticulata (SNr) are key output neurons of the basal ganglia motor control circuit. These neurons fire sustained high-frequency, short-duration spikes that provide a tonic inhibition to their targets and are critical to movement control. We hypothesized that a robust voltage-activated K(+) conductance that activates quickly and resists inactivation is essential to the remarkable fast-spiking capability in these neurons. Semi-quantitative RT-PCR (qRT-PCR) analysis on laser capture-microdissected nigral neurons indicated that mRNAs for Kv3.1 and Kv3.4, two key subunits for forming high activation threshold, fast-activating, slow-inactivating, 1 mM tetraethylammonium (TEA)-sensitive, fast delayed rectifier (I(DR-fast)) type Kv channels, are more abundant in fast-spiking SNr GABA neurons than in slow-spiking nigral dopamine neurons. Nucleated patch clamp recordings showed that SNr GABA neurons have a strong Kv3-like I(DR-fast) current sensitive to 1 mM TEA that activates quickly at depolarized membrane potentials and is resistant to inactivation. I(DR-fast) is smaller in nigral dopamine neurons. Pharmacological blockade of I(DR-fast) by 1 mM TEA impaired the high-frequency firing capability in SNr GABA neurons. Taken together, these results indicate that Kv3-like channels mediating fast-activating, inactivation-resistant I(DR-fast) current are critical to the sustained high-frequency firing in SNr GABA projection neurons and hence movement control.

Cell-Type–Specific Modulation of Intrinsic Firing Properties and Subthreshold Membrane Oscillations by the M(Kv7)-Current in Neurons of the Entorhinal Cortex

The M-current (current through Kv7 channels) is a low-threshold noninactivating potassium current that is suppressed by muscarinic agonists. Recent studies have shown its role in spike burst generation and intrinsic subthreshold theta resonance, both of which are important for memory function. However, little is known about its role in principal cells of the entorhinal cortex (EC). In this study, using whole cell patch recording techniques in a rat EC slice preparation, we have examined the effects of the M-current blockers linopirdine and XE991 on the membrane dynamics of principal cells in the EC. When the M-current was blocked, layer II nonstellate cells (non-SCs) and layer III cells switched from tonic discharge to intermittent firing mode, during which layer II non-SCs showed high-frequency short-duration spike bursts due to increased fast spike afterdepolarization (ADP). When three spikes were elicited at 50 Hz, these two types of cells reacted with a slow ADP that drove delayed firing. In contrast, layer II stellate cells (SCs) and layer V cells never displayed intermittent firing, bursting behavior, or delayed firing. Under the M-current block, intrinsic excitability increased significantly in layer III and layer V cells but not in layer II SCs and non-SCs. The M-current block also had contrasting effects on the subthreshold excitability, greatly suppressing the subthreshold membrane potential oscillations in layer V cells but not in layer II SCs. Modulation of the M-current thus shifts the firing behavior, intrinsic excitability, and subthreshold membrane potential oscillations of EC principal cells in a cell-type-dependent manner.

Prevalence of Radioactive Signals from Surveillance of an Emergency Department

Since the 11 September 2001 terrorist attacks in the United States, concerns have been raised regarding the threat of a radiological terrorist weapon. Although the probability of the employment of a nuclear device is remote, the potential of a radiological dispersal device (RDD) or "dirty bomb" is of concern. While it is unlikely that such a device would produce massive numbers of casualties, it is far more likely that it would result in public panic and perhaps even disable the local healthcare system. The utility of surveillance with radiation detectors in the healthcare setting has not been fully evaluated. The objective of this study was to characterize the prevalence of radioactive sources entering an urban emergency department (ED). A retrospective review of data obtained from a radiation detector positioned to detect radioactive people entering an ED of an urban academic hospital that serves 45,000 patients/year was performed. Graphical outputs of radioactivity were recorded in Microsoft Excel (Microsoft, Redmond, WA, US) spreadsheets in microREM/hour. Data were collected continuously from 22 December 2003 to 22 January 2004. An event was defined as any elevation in radiation levels >95% confidence interval from the mean level of background radiation over 72 hours (h). A total of 215 events were observed over a 28-day period, with a mean value of 7.7 events/day, and a maximum of 15 events/day. During the 28-day period, the baseline mean level of background radiation was 2-4 microREM/h. Readings ranged from 2,148.28-17,292.25 microREM/h with a maximum sustained detector exposure of 684.37 microREM. Distinct signal patterns were seen at both detectors including tonic, phasic, dual, and short duration spikes. The number of radioactive signals detected from persons entering the ED was much higher than expected. While the vast majority of these signals pose no health threat, they may make routine screening for a radiological terrorist event difficult. Further study is needed to determine this correlation.

Effect of driving method on the degradation of organic light emitting diodes

Lifetime testing results are reported for organic light emitting diodes (OLEDs) having the structure ITO (anode)/ N, N′-diphenyl- N, N′-bis(3-methylphenyl)-1,1′-diphenyl-4,4′-diamine (TPD)/tris-(8-hydroxyquinoline)aluminum (AlQ)/Al (cathode) and operated using dc and pulsed waveforms for comparison. In ambient atmosphere non-encapsulated devices show a lifetime of about 70 h in pulsed operation at an initial luminance of 500 cd/m 2, almost four times longer than in dc operation. A fast initial decay of luminance is observed for dc operation. It is most probably due to a combination of Joule heating and mobile ionic impurities migration within the OLED structure under the continuous forward electric field. We study also the transient electroluminescence (EL) and report the observation of a short duration spike in the leading edge of the EL response. Its origin is attributed to the temporal shift of the recombination zone in the AlQ layer from the bulk to the interface with TPD subsequent the application of a voltage step.

Comparison of radar and video observations of shallow water breaking waves

Simultaneous microwave and video measurements of shallow water breaking waves are presented. A comparison of the data from the two sensors shows that short-duration spikes in the measured X-band radar cross section are highly correlated with the presence of breaking waves in the video imagery. In addition, the radar backscatter from shallow water breaking events is responsible for 40% to 50% of the total cross section, which is a much larger contribution than typically observed for deepwater breaking events. Based on estimates of the area of individual breaking regions determined from digitized video images, the radar cross section per unit area of the turbulent breaking region is shown to be well approximated by a value of -1.9 dB at 31/spl deg/ grazing. Finally, there are some differences between the radar and video signals that suggest that microwave radar may be less sensitive than video techniques to relict foam not associated with active wave breaking. In general, the results indicate that radar is a very good detector of shallow water breaking waves and suggest that radar can be used for the measurement of the spatial and temporal variations of wave breaking.

Special safeguards for developing country agriculture: a proposal for WTO negotiations

Trade liberalization, particularly QR elimination, enhances border-to-domestic price transmission. A political obstacle to further liberalization (and to exposure to greater price transmission) in developing countries is fear of extended ‘low price’ periods in import-competing sectors. World commodity prices show shock persistence and asymmetry, with short-duration spikes and longer-duration troughs. Developing countries are unlikely to adopt fiscally burdensome domestic programs to compensate for persistent low-price episodes, making border measures attractive. WTO Special Safeguards could address low price problems, but present rules exclude their use by most developing countries. A possible modification of the Special Safeguard Clause could encourage reduction of overall protection. World price characteristics and the implications of low price periods for import-competing farmers are reviewed. To manage low-price risk under WTO commitments a restricted price floor policy could be implemented through a Special Safeguard Mechanism. An example illustrates the levels, frequency and duration of such a price-floor-based surcharge.

Impulse activity of ventral tegmental area neurons during heroin self-administration in rats

To assess the pattern of mesocorticolimbic dopamine activity associated with drug-seeking and drug-taking behavior, we recorded impulse activity of ventral tegmental area neurons during intravenous heroin self-administration in trained rats. Although these neurons had considerable variability, two major groups—units with triphasic long-duration spikes and biphasic short-duration spikes—were identified. Relative to a slow and irregular basal activity of long-spike units, the first self-administration of each session was preceded by a phasic neuronal activation and followed by a more sustained drug-induced activation that reached a maximum at the time of the second self-injection. After each subsequent heroin self-injection, the discharge rate transiently decreased, correlating with the blockade of preceding motor activation and the appearance of freezing, but slowly and gradually increased again in parallel with searching behavior, reaching a maximum at the time of the next self-injection. Passive drug injections in either drug-naive, freely moving or drug-experienced, anesthetized rats caused much smaller, tonic increases in activity of long-spike units; these monophasic increases changed into biphasic responses with repeated injections. Although short-spike units had highly varying discharge rate and showed phasic activation during movement, during heroin self-injections they generally mimicked the activity pattern seen in long-spike units. Our results indicate that in behaving animals indirect “identification” of dopamine cells based on their distinctive electrophysiological features is more complex than in vitro and in anesthetized preparations. With respect to long-spike units, a candidate group of presumed dopamine neurons, our data agree with the view that mesocorticolimbic dopamine activation is important for the activational and/or motivational aspects of heroin-taking behavior and suggest the role of an abrupt termination of dopamine activation for drug reinforcement (reward). Although the neurochemical nature of long- and short-spike units is obviously different, similar changes in their activity may indicate that they are regulated by similar afferent inputs and that these inputs change similarly during drug-taking behavior.

Heterogeneity of ventral tegmental area neurons: Single-unit recording and iontophoresis in awake, unrestrained rats

Single-unit recording combined with iontophoresis of dopamine, GABA, and glutamate was used in awake, unrestrained rats to characterize the electrophysiological and receptor properties of neurons in the ventral tegmental area under naturally occurring behavioural conditions. All isolated ventral tegmental area units ( n=90) were analysed and compared with cells ( n=58) recorded from dorsally adjacent areas of the pre-rubral area and red nucleus. Two distinct neuronal groups were identified in the ventral tegmental area: units with triphasic, long-duration spikes (78/90) and units with biphasic, short-duration spikes (12/90). Although all long-spike units discharged in an irregular, bursting pattern with varying degrees of within-burst decrements in spike amplitude, they could be further subdivided into at least three distinct subgroups. Type I long-spike units (36/78) discharged at a relatively slow and stable rate (mean: 6.03 imp/s; range: 0.42–15.78) with no evident fluctuations during movement. These cells were inhibited by dopamine and GABA and responded to glutamate with a low-magnitude excitation accompanied by a pronounced decrement in spike amplitude and a powerful rebound inhibition. Type II long-spike units (23/78) had relatively high and unstable discharge rates (mean: 22.82 imp/s; range: 4.42–59.67) and showed movement-related phasic activations frequently followed by partial or complete cessation of firing. Some Type II cells (4/9) were inhibited by dopamine, but all were excited by glutamate at very low currents (0–10 nA). With an increase in current, the glutamate-induced excitation often (18/22) progressed into a cessation of firing. All these cells were inhibited by GABA followed by a strong rebound excitation (8/9), which also frequently (6/8) resulted in cessation of firing. Type III long-spike units (19/78) had properties that differed from either Type I or Type II cells, including a lack of spontaneous firing (5/19). Short-spike ventral tegmental area units were either silent (4/12) and unresponsive to dopamine and GABA or spontaneously active (range: 0.89–34.13 imp/s) and inhibited by GABA and, in some cases (2/8), by dopamine; all were phasically activated during movement and glutamate iontophoresis. It appears that ventral tegmental area neurons, including those with long-duration spikes, do not comprise a uniform population in awake, unrestrained rats. Type I, long-spike units match the characteristics of histochemically-identified dopamine neurons, and they appear to express dopamine autoreceptors, which may explain the relatively slow, stable rate of activity and the limited responsiveness to excitatory inputs. Although the nature of the other long-spike units in our sample is unclear, they may include dopamine neurons without autoreceptors as well as non-dopamine cells. The heterogeneity of ventral tegmental area neurons is an important consideration for further attempts to assess the role of the mesocorticolimbic dopamine system in motivated behaviour.

Properties of calcium spikes revealed during GABAA receptor antagonism in hippocampal CA1 neurons from guinea pigs.

Properties of calcium spikes revealed during GABAA receptor antagonism in hippocampal CA1 neurons from guinea pigs. J. Neurophysiol. 78: 2269-2279, 1997. Intracellular electrical responses and changes in intracellular calcium concentration ([Ca2+]i) in response to activation of synaptic inputs and to DC injections were recorded simultaneously from CA1 pyramidal neurons (n = 42) in guinea pig hippocampal slices. In the presence of the gamma-aminobutyric acid-A (GABAA) receptor antagonists, bicuculline (mu M) and picrotoxin (10 mu M, broad (>20 ms) all-or-none spikes were induced by activation of synaptic inputs (20 pulses, 30 Hz) and were accompanied by a simultaneous rapid and large rise in [Ca2+]i (34 of 34 cells). By contrast, direct depolarizing current (0.7 nA, 1 s) induced spikes having short duration, during which time the spike firing pattern was observed not to be significantly affected. When Na+ channels were blocked by QX-314 applied intracellularly through the recording microelectrode in the presence of GABAA receptor antagonists, broad spikes were frequently generated by activation of synaptic inputs (32 of 33 cells). These broad spikes were blocked by Cd2+ (200 mu M) or in Ca2+-free medium (6 of 6 cells) but were resistant to either tetrodotoxin (TTX; 1 micro M; 6 of 6 cells) or QX-314, whereas short-duration spikes were blocked by both TTX and QX-314. Based on these findings we conclude that broad and short-duration spikes are Ca2+ and Na+ spikes, respectively. To investigate the properties of the Ca2+ spikes, antagonists of a voltage-operated Ca2+ channel were applied to the evoked responses. Nifedipine (30 mu M), a L-type Ca2+ channel blocker, suppressed the generation of Ca2+ spikes, whereas Ni2+ (100 mu M), the T- and R-type Ca2+ channel blocker, and omega-agatoxin-IVA (omega-Aga-IVA, 60 nM), a P-type Ca2+ channel blocker, had little effect on the generation of Ca2+ spikes. Nifedipine suppressed the rise in [Ca2+]i induced by synaptic inputs up to 26% of the control in the soma and 18-32% in the dendrites (n = 5), respectively, whereas Ni2+ suppressed the rise by 12-27% (n = 5) in both soma and dendrites. omega-Aga-IVA showed little effect (less than a 10% change; n = 7). These results suggest that the GABAA inhibitory system tonically suppresses dendritic Ca2+ spikes, and the L-type Ca2+ channel plays a major role in the generation of Ca2+ spikes and in Ca2+ influx.

Somatic evoked high-frequency magnetic oscillations reflect activity of inhibitory interneurons in the human somatosensory cortex

High-frequency potential oscillations in the range of 300–900 Hz have recently been shown to concur with the primary response (N20) of the somatosensory cortex in awake humans. However, the physiological mechanisms of the high-frequency oscillations remained undetermined. We addressed the issue by analyzing magnetic fields during wakefulness and sleep over the left hemisphere to right median nerve stimulation with a wide bandpass (0.1–2000 Hz) recording with subsequent high-pass (> 300 Hz) and low-pass (< 300 Hz) filtering. With wide bandpass recordings, high-frequency magnetic oscillations with the main signal energy at 580–780 Hz were superimposed on the N20m during wakefulness. Isofield mapping at each peak of the high-pass filtered and isolated high-frequency oscillations showed a dipolar pattern and the estimated source for these peaks was the primary somatosensory cortex (area 3b) very close to that for the N20m peak. During sleep, the high-frequency oscillations showed dramatic diminution in amplitude while the N20m amplitude exhibited a moderate increment. This reciprocal relation between the high-frequency oscillations and the N20m during a wake-sleep cycle suggests that they represent different generator substrates. We speculate that the high-frequency oscillations represent a localized activity of the GABAergic inhibitory interneurons of layer 4, which have been shown in animal experiments to respond monosynaptically to thalamo-cortical input with a high-frequency (600–900 Hz) burst of short duration spikes. On the other hand, the underlying N20m represents activity of pyramidal neurons which receive monosynaptic excitatory input from the thalamus as well as a feed-forward inhibition from the interneurons.

The contribution of NMDA and non-NMDA receptors to fast and slow transmission of sensory information in the rat SI barrel cortex

The main objective of this study was to establish the contribution of NMDA receptors to natural processing of somatosensory information within rat SI barrel cortex. Responses of 52 cells in layers I-IV of the rat barrel cortex were analyzed by PSTH (peristimulus histogram) analysis of evoked spikes in reply to brief deflections of the principal whisker in animals anesthetized with urethane. Short and longer peak latency responses within PSTHs were compared in the presence and absence of the specific NMDA and non-NMDA antagonists D(-)-2-amino-5-phosphonovaleric acid and 6,7-dinitroquinoxaline-2,3-dione, which were administered locally to neurons by iontophoresis and additionally tested against their putative specific agonists, NMDA and quisqualate, respectively. The results suggest the following. (1) The generation of most spikes from cells in layers I-IV is dependent upon activation of NMDA receptors. However, NMDA receptors do not contribute to responses at very short latencies commensurate with monosynaptic thalamocortical relay for layer IV cells. These appear to be entirely mediated through non-NMDA receptors. (2) In the absence of transmission through NMDA receptors, non-NMDA receptors do not generate significant spike activity in later (10-100 msec latency) discharges. (3) NMDA receptor participation in first spike generation is directly dependent upon the latency of response of the cell to principal whisker deflection. (4) Latency of response, non-NMDA receptor-mediated spike generation and laminar location were powerfully covariant. (5) In addition, it was found that cells exhibiting short-duration spikes ( < 0.7 msec; "fast-spike units") in layer IV responded powerfully at short latencies, first spikes being entirely dependent upon non-NMDA but not NMDA receptor action, later spikes (10-100 msec poststimulus) being > 80% dependent upon NMDA receptor action. It is concluded that most sensorially driven spike activity in layers I-IV is dependent upon NMDA receptor action. This appears to be enabled by contingent subthreshold depolarization largely through non-NMDA receptor action, whereas the earliest thalamocortical discharges are evoked solely through non-NMDA receptors.