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PubMed2005

Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures.

Pre-clinical trials of treatment in retinal degenerations have shown progress toward preventing loss or restoring function of rod photoreceptors. In anticipation of human clinical trials, we assessed two psychophysical methods of quantifying rod photoreceptor-mediated function as potential outcome measures. Modified automated perimeters were used to deliver focal or full-field light stimuli and dark-adapted thresholds were measured. Patients with retinal degeneration were studied in two experimental protocols. Experiment 1 (n = 35 patients) studied dark-adapted focal chromatic stimuli in central retinal locations along the horizontal meridian. Experiment 2 (n = 146 patients) studied dark-adapted responses to a full-field stimulus test (FST) using white and chromatic stimuli. Patients in both experimental groups had testing on two different visits to determine inter-visit variability. In Experiment 1, two subgroups of patients were identified: a group with a majority of test loci detected by rod photoreceptors and a group with only cone-mediated detection. Inter-visit variability (95% confidence interval) was +/-3.1 dB for normals, +/-3.0 dB for patients with rod-mediated function and +/-2.8 dB for patients with only cone-mediated function. In Experiment 2, the dynamic range of the FST using white stimuli was sufficient to quantify sensitivity in all patients studied, including those with severe retinal degenerations. Chromatic stimuli in the FST were detectable by 85% of patients and rod- or cone-mediation could be determined. Regional retinal sources of FST were explored by comparing FST and dark-adapted perimetry in the same patients; there was a strong correlation between FST level and the loci with highest sensitivity by perimetry. Inter-visit variability (95% confidence interval) in the patients was +/-3.9 dB compared to +/-3.5 dB in normals. Dark-adapted focal threshold measurements with an abbreviated protocol in retinal degeneration patients with stable fixation may be useful as an outcome measure for therapies that can affect rod vision. FST measurements were feasible and reproducible in a large spectrum of retinal degenerative diseases and will be most applicable as a psychophysical outcome measure for treatment trials of very severe disorders in which fixation is lost and there is need for a large dynamic range of stimulus intensity.

Adolescent↗
PubMed2006

Electrochemical microfluidic biosensor for the detection of nucleic acid sequences.

A microfluidic biosensor with electrochemical detection for the quantification of nucleic acid sequences was developed. In contrast to most microbiosensors that are based on fluorescence for signal generation, it takes advantage of the simplicity and high sensitivity provided by an amperometric and coulorimetric detection system. An interdigitated ultramicroelectrode array (IDUA) was fabricated in a glass chip and integrated directly with microchannels made of poly(dimethylsiloxane) (PDMS). The assembly was packaged into a Plexiglas housing providing fluid and electrical connections. IDUAs were characterized amperometrically and using cyclic voltammetry with respect to static and dynamic responses for the presence of a reversible redox couple-potassium hexacyanoferrate (ii)/hexacyanoferrate (iii) (ferri/ferrocyanide). A combined concentration of 0.5 microM of ferro/ferricyanide was determined as lower limit of detection with a dynamic range of 5 orders of magnitude. Background signals were negligible and the IDUA responded in a highly reversible manner to the injection of various volumes and various concentrations of the electrochemical marker. For the detection of nucleic acid sequences, liposomes entrapping the electrochemical marker were tagged with a DNA probe, and superparamagnetic beads were coated with a second DNA probe. A single stranded DNA target sequence hybridized with both probes. The sandwich was captured in the microfluidic channel just upstream of the IDUA via a magnet located in the outside housing. Liposomes were lysed using a detergent and the amount of released ferro/ferricyanide was quantified while passing by the IDUA. Optimal location of the magnet with respect to the IDUA was investigated, the effect of dextran sulfate on the hybridization reaction was studied and the amount of magnetic beads used in the assay was optimized. A dose response curve using varying concentrations of target DNA molecules was carried out demonstrating a limit of detection at 1 fmol assay(-1) and a dynamic range between 1 and 50 fmol. The overall assay took 6 min to complete, plus 15-20 min of pre-incubation and required only a simple potentiostat for signal recording and interpretation.

Biosensing Techniques↗
PubMed2002

The use of accurate mass tags for high-throughput microbial proteomics.

We describe and review progress towards a global strategy that aims to extend the sensitivity, dynamic range, comprehensiveness, and throughput of proteomic measurements for microbial systems based upon the use of polypeptide accurate mass tags (AMTs) produced by global protein enzymatic digestions. The two-stage strategy exploits high accuracy mass measurements using Fourier transform ion cyclotron resonance mass spectrometry (FTICR) to validate polypeptide AMTs for a specific organism, from potential mass tags tentatively identified using tandem mass spectrometry (MS/MS), providing the basis for subsequent measurements without the need for routine MS/MS. A high-resolution capillary liquid chromatography separation combined with high sensitivity, and high-resolution accurate FTICR measurements is shown to be capable of characterizing polypeptide mixtures of more than 10(5) components, sufficient for broad protein identification using AMTs. Advantages of the approach include the high confidence of protein identification, its broad proteome coverage, and the capability for stable-isotope labeling methods for precise relative protein abundance measurements. The strategy has been initially evaluated using the microorganisms Saccharomyces cerevisiae and Deinococcus radiodurans. Additional developments, including the use of multiplexed-MS/MS capabilities and methods for dynamic range expansion of proteome measurements that promise to further extend the quality of proteomics measurements, are also described.

Amino Acid Sequence↗
PubMed1994

[The compression of numerical radiological images].

A digital radiological image is made by a number of pixels, each of them characterized by a definite numerical value obtained by quantization which represents the luminance in that specific image unit. Spatial resolution and dynamic range are the main factors in determining the quality of a digital radiological image. The product of the two above factors defines the global dimensions of the image and is expressed in bits. In conventional radiographic images the global dimension of the image is expressed in MBytes, because of its high spatial and contrast resolution. To reduce the visualization and storage requirements as well as the transmission time of large image data sets, compression algorithms have been recently introduced. These algorithms are based on the fact that often in a digital image parts of the binary data are "redundant", that is they are not necessary for correct image representation. Therefore, compression methods are aimed at reducing both statistical and perceptive redundancy. Statistical redundancy is reduced by means of lossless coding which does not allow to compress images with a ratio higher than 4-5:1 and that--by definition--allows to recover the original image quality. On the other hand "lossy" compression algorithms, which eliminate the perceptive redundancy, are based on the reduction of spatial resolution and dynamic range and on transform-based methods. In particular, the latter have usually been more successful in terms of efficient compression, even when applied to conventional radiographic images. The basic transform procedure can be modified at various levels. JPEG is one of these methods, originally developed for photographic images, which can be usefully applied to radiological images as well. Lossy procedures allow to reach higher compression ratios than lossless methods, but the decrease in information content must be prevented from reducing diagnostic accuracy. In order to assess the diagnostic efficiency of the images compressed with lossy methods, semi-objective analyses are usually performed and ROC curves are produced and evaluated. A model ROC analysis is presented.

Algorithms↗
PubMed2005

Automated comparative proteomics based on multiplex tandem mass spectrometry and stable isotope labeling.

Comparative proteomic approaches using isotopic labeling and MS have become increasingly popular. Conventionally quantification is based on MS or extracted ion chromatogram (XIC) signals of differentially labeled peptides. However, in these MS-based experiments, the accuracy and dynamic range of quantification are limited by the high noise levels of MS/XIC data. Here we report a quantitative strategy based on multiplex (derived from multiple precursor ions) MS/MS data. One set of proteins was metabolically labeled with [13C6]lysine and [15N4]arginine; the other set was unlabeled. For peptide analysis after tryptic digestion of the labeled proteins, a wide precursor window was used to include both the light and heavy versions of each peptide for fragmentation. The multiplex MS/MS data were used for both protein identification and quantification. The use of the wide precursor window increased sensitivity, and the y ion pairs in the multiplex MS/MS spectra from peptides containing labeled and unlabeled lysine or arginine offered more information for, and thus the potential for improving, protein identification. Protein ratios were obtained by comparing intensities of y ions derived from the light and heavy peptides. Our results indicated that this method offers several advantages over the conventional XIC-based approach, including increased sensitivity for protein identification and more accurate quantification with more than a 10-fold increase in dynamic range. In addition, the quantification calculation process was fast, fully automated, and independent of instrument and data type. This method was further validated by quantitative analysis of signaling proteins in the EphB2 pathway in NG108 cells.

Amino Acid Sequence↗
PubMed1998

Establishing minimum performance standards, calibration intervals, and optimal exposure values for a whole breast digital mammography unit.

Methods are developed to establish minimum performance standards, calibration intervals, and criteria for exposure control for a whole breast digital mammography system. A prototype phantom was designed, and an automatic method programmed, to analyze CNR, resolution, and dynamic range between CCD components in the image receptor and over time. The phantom was imaged over a 5 month period and the results are analyzed to predict future performance. White field recalibration was analyzed by subtracting white fields obtained at different intervals. Exposure effects were compared by imaging the prototype phantom at different kVp, filtration (Mo vs Rh) and mAs. Calcification detection tests showed that phantom images, obtained at 28 kVp with a Mo/Mo anode/filter and low mAs technique, often could not depict Al2O3 specks 0.24 mm in diameter, while a 28 kVp Mo/Rh, higher mAs technique usually could. Stability of the system tested suggests that monthly phantom imaging may suffice. Differences in CCD performance are greater (12%) than differences in a single CCD over time (6%). White field recalibration is needed weekly because of pixel variations in sensitivity which occur if longer intervals between recalibration occur. When mean glandular dose is matched, Rh filtration gives better phantom performance at 28 kVp than Mo filtration at 26 kVp and is recommended for clinical exposures. An aluminum step wedge shows markedly increased dynamic range when exit exposure is increased by using a higher energy spectrum beam. Phantoms for digital mammography units should cover the entire image receptor, should test intersections between components of the receptor, and should be automatically analyzed.

Female↗
PubMed2004

An automated high performance capillary liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometer for high-throughput proteomics.

We describe a fully automated high performance liquid chromatography 9.4 tesla Fourier transform ion resonance cyclotron (FTICR) mass spectrometer system designed for proteomics research. A synergistic suite of ion introduction and manipulation technologies were developed and integrated as a high-performance front-end to a commercial Bruker Daltonics FTICR instrument. The developments incorporated included a dual-ESI-emitter ion source; a dual-channel electrodynamic ion funnel; tandem quadrupoles for collisional cooling and focusing, ion selection, and ion accumulation, and served to significantly improve the sensitivity, dynamic range, and mass measurement accuracy of the mass spectrometer. In addition, a novel technique for accumulating ions in the ICR cell was developed that improved both resolution and mass measurement accuracy. A new calibration methodology is also described where calibrant ions are introduced and controlled via a separate channel of the dual-channel ion funnel, allowing calibrant species to be introduced to sample spectra on a real-time basis, if needed. We also report on overall instrument automation developments that facilitate high-throughput and unattended operation. These included an automated version of the previously reported very high resolution, high pressure reversed phase gradient capillary liquid chromatography (LC) system as the separations component. A commercial autosampler was integrated to facilitate 24 h/day operation. Unattended operation of the instrument revealed exceptional overall performance: Reproducibility (1-5% deviation in uncorrected elution times), repeatability (<20% deviation in detected abundances for more abundant peptides from the same aliquot analyzed a few weeks apart), and robustness (high-throughput operation for 5 months without significant downtime). When combined with modulated-ion-energy gated trapping, the dynamic calibration of FTICR mass spectra provided decreased mass measurement errors for peptide identifications in conjunction with high resolution capillary LC separations over a dynamic range of peptide peak intensities for each spectrum of 10(3), and >10(5) for peptide abundances in the overall separation.

Amino Acid Sequence↗
PubMed1998

Characterization of elastographic noise using the envelope of echo signals.

A theoretical formulation characterizing the noise performance of strain estimation using envelope signals is presented for the cross-correlation based strain estimator in elastography, using a modified strain filter approach. The strain filter describes the relationship among the elastographic signal-to-noise ratio (SNRe), sensitivity, contrast-to-noise ratio and dynamic range for a given resolution in the elastogram, as determined by the cross-correlation window length and window overlap. Theoretical results indicate that the envelope strain filter noise performance (SNRe level) is about half that obtained in the ratio frequency (RF) case (fo = 7.5 MHz). Simulation results corroborate the trend predicted using the strain filter. Experimental SNRe vs. strain plots presented in this article illustrate the same trend as the theoretical results. These plots allow a quantitative comparison of the elastograms obtained with RF and envelope signal processing. For small strains, the performance obtained using RF signals is superior to that obtained for envelope signals (since jitter errors are smaller due to the utilization of phase information in RF signals). However, for large tissue strains, envelope analysis provides an accurate estimate of the tissue strain (since envelope signal decorrelation is smaller than RF signal decorrelation at large strains). An algorithm that combines the low-noise characteristics of the cross-correlation analysis using RF signals at small strains and envelope signals for estimation of large tissue strains is proposed to improve the dynamic range in the elastogram.

Algorithms↗
PubMed1983

The properties of neurones recorded in the superficial dorsal horn of the rat spinal cord.

The physiological properties of neurones in the superficial laminae of the dorsal horn of the fourth and fifth lumbar segments of the rat spinal cord have been investigated in decerebrate spinal animals. Both extracellular recordings with platinum-plated tungsten microelectrodes (n = 72) and intracellular recordings with glass microelectrodes (N = 79) were made. Attempts were made to fill cells intracellularly with horseradish peroxidase or Lucifer Yellow. Thirty-seven percent of the intracellularly injected neurones were recovered after histological processing and their cell bodies found to be in lamina 1 or 2 and in the dorsal white matter overlying lamina 1. The dendritic spread of the stained neurones was maximal in the rostrocaudal plane with a restricted mediolateral spread. The physiological properties of the extracellularly recorded units, the intracellularly unidentified units, and the intracellularly stained units were the same. The neurones were characterized by low background activity and all had excitatory receptive fields on the lower limb. Some neurones responded only to low-threshold mechanical stimulation of the skin or only to noxious skin stimulation but the majority of units (58%) were wide-dynamic-range cells responding to both types of stimuli. Receptive field classification was made questionable, however, by the existence of cells (9%) that exhibited a spontaneous shift in the size of their receptive fields and in the type of stimulus that elicited a response. The neurones in the superficial dorsal horn commonly showed a marked inhibition to repeated cutaneous stimuli (27%) or a prolonged afterdischarge followed a single stimulus (20%). Afferent input from the sural nerve was found to be from A and C fibres in both extra-and intracellular recordings. A delta- and C-mediated excitations were most common although convergent inputs from A beta-fibres occurred in 40% of units. No correlation was found between cell structure or distribution of dendritic fields and physiological properties in our small sample of intracellularly stained cells. The morphology of the cells was highly diverse, as were the different receptive fields. There was, however, some correlation between the location of cell bodies and their responses. Neurones responding only to low-threshold stimuli were distributed either in the dorsal white matter or in inner lamina 2. Wide-dynamic-range cells were distributed throughout the superficial dorsal horn. These results suggest that neurones of different shapes and positions may subserve the same function and, conversely, that neurones of the same shape and position may subserve different functions.

Animals↗
PubMed2002

Beamforming with a reduced sampling rate.

The beamforming process requires a high delay resolution to avoid the deteriorating effects of the delay quantization lobes on the image dynamic range and signal to noise ratio. Wideband transducers require delay resolutions in the order of 1/16 the signal period. If oversampling is used to achieve this timing resolution, a huge data volume has to be acquired and processed in real time. This is usually avoided by sampling just above the Nyquist rate and interpolating to achieve the required delay resolution. However this increases the hardware complexity. Baseband sampling has been alternatively proposed with sampling rates as low as the transducer frequency or even lower. This approach uses two A/D converters and processing chains for every channel, thus doubling the hardware requirements. Quadrature sampling can be used instead with a single A/D converter, but the sampling rate must be a multiple of four times the transducer frequency, decreasing the application flexibility. Furthermore, it produces relatively high errors in the detected envelope if wideband transducers are used. This work presents a new approach, the selective sampling technique (SST), which keeps the lowest sampling rate required by the imaging process or the signal bandwidth (whatever is larger) and, at the same time, provides a high delay resolution to keep the highest image dynamic range. The SST is based on a second order sampling process which, differently from the mentioned approaches, does not pose any constraints in the time interval between samples and produce lower errors in the detected envelope. The hardware requirements are low (a single A/D converter and processing chain for every transducer element), working at the lowest data rate compatible with the Nyquist criterion, thus reducing the data bandwidth. Furthermore, the sampling points can be also freely chosen, so that the SST simplify the usually required scan conversion process to a simple linear interpolation easily carried out by software in real-time.

Journal Article↗
PubMed2001

Single rapid real-time monitored isothermal RNA amplification assay for quantification of human immunodeficiency virus type 1 isolates from groups M, N, and O.

Because human immunodeficiency virus type 1 (HIV-1) subtypes and circulating recombinant forms (CRFs) are spreading rapidly worldwide and are becoming less confined to a geographical area, RNA assays that can detect and quantify all HIV-1 isolates reliably are in demand. We have developed a fast, real-time monitored RNA assay based on an isothermal nucleic acid sequence-based amplification technology that amplifies a part of the long terminal repeat region of the HIV-1 genome. Real-time detection was possible due to the addition of molecular beacons to the amplification reaction that was monitored in a fluorimeter with a thermostat. The lower level of detection of the assay was 10 HIV-1 RNA molecules per reaction, and the lower level of quantification was 100 copies of HIV-1 RNA with a dynamic range of linear quantification between 10(2) and 10(7) RNA molecules. All HIV-1 groups, subtypes, and CRFs could be detected and quantified with equal efficiency, including the group N isolate YBF30 and the group O isolate ANT70. To test the clinical utility of the assay, a series of 62 serum samples containing viruses that encompassed subtypes A through G and CRFs AE and AG of HIV-1 group M were analyzed, and these results were compared to the results of a commercially available assay. This comparison showed that the quantification results correlated highly (R(2) = 0.735) for those subtypes that could be well quantified by both assays (subtypes B, C, D, and F), whereas improved quantification was obtained for subtypes A and G and CRFs AE and AG. A retrospective study with six individuals infected with either a subtype A, B, C, or D or an AG isolate of HIV-1 group M, who were treated with highly active antiretroviral therapy, revealed that the assay was well suited to the monitoring of therapy effects. In conclusion, the newly developed real-time monitored HIV-1 assay is a fast and sensitive assay with a large dynamic range of quantification and is suitable for quantification of most if not all subtypes and groups of HIV-1.

Anti-HIV Agents↗
PubMed1996

The effect of 5-HT1A receptor stimulation on nociceptive dorsal horn neurones in rats.

Spinal 5-HT1A receptor subtypes are involved in regulation of nociception. This study was performed to investigate the effect of stimulation of these receptors on wide dynamic range neurones in the spinal cord. Extracellular single unit recordings of dorsal horn neurones were performed in intact urethane-anaesthetized female Sprague-Dawley rats. The receptive field distally on one hind paw was electrically stimulated with needle electrodes applied to the skin. The 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) , and the 5-HT1A receptor antagonist, WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl ]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride), were applied directly onto the spinal cord, and single unit responses were counted separately for Abeta-, Adelta-, C-fibre responses and post-discharge according to the latencies. Only 500 nmol 8-OH-DPAT caused a significant inhibition of all the neuronal responses. Cells with a pronounced wind-up, limited C-fibre response before drug application and relatively large receptive field for pinch in laminae III-IV were most powerfully inhibited by 500 nmol 8-OH-DPAT. 50 nmol WAY100635 alone did not affect the neuronal responses but blocked the effect of 500 nmol 8-OH-DPAT. These results suggest that stimulation of 5-HT1A receptors inhibits the activity in spinal wide dynamic range neurones after repeated electrical stimulation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1980

Physiology and morphology of substantia gelatinosa neurons intracellularly stained with horseradish peroxidase.

Neurons in Rexed's layer II were physiologically characterized with natural and electrical stimuli applied to their cutaneous receptive fields. The neurons were then intracellularly stained with horseradish peroxidase. Three general patterns of physiological responses were found. Nociceptive specific neurons did not respond to gentle mechanical stimulation. Most responded exclusively to tissue-damaging stimuli. Some also responded to moderately heavy pressure, but these responded to noxious stimuli with an increased discharge frequency. Wide dynamic range neurons responded to both gentle mechanical stimulation and to tissue-damaging stimulation. Low-threshold mechanoreceptive neurons responded only to gentle mechanical stimulation. Some of the low-threshold mechanoreceptive neurons were innervated by primary afferents with unmyelinated axons. Excepting those low-threshold mechanoreceptive neurons with input from unmyelinated afferents, the patterns of primary afferents innervation of layer II neurons were similar to the patterns of innervation that have been found for neurons in layers I and IV-V. All but 2 of the 22 neurons that we found were recognized as being of two general morphological types. Stalked cells had their perikarya situated along the superficial border of layer II. Most of their dendrites traveled ventrally while spreading out rostrocaudally. This gave their dendritic arbors a fan-like shape. Stalked cell axons arborized largely in layer I. Islet cell perikarya were found throughout layer II. Most of their dendrites traveled rostrocaudally. Their dendritic arbors were shaped like cylinders with their long axes parallel to the long axis of the spinal cord. Islet cell axons arborized in the immediate vicinity of their dendritic territories, within layer II. Stalked cells and those islet cells whose dendritic arbors were largely contained within the superficial one-third of layer II (layer IIa) were either nociceptive specific or wide dynamic range neurons. The islet cells whose dendritic arbors were largely within the deeper two-thirds of layer II (layer IIb) were all low-threshold mechanoreceptive neurons. These observations suggest that layers IIa and IIb have different functional roles and that stalked cells and islet cells are separate and distinct components of the neural circuitry of the superficial dorsal horn.

Animals↗
PubMed1996

A fluorescence digital image microscopy system for quantifying relative cell numbers in tissue culture plates.

Microwell tissue culture plates provide a convenient format for conducting cell growth and cellular cytotoxicity assays, but such assays often have a limited dynamic range. We have developed the digital imaging microscopy scanning system (DIM-SCAN), which is a semiautomated fluorescence digital imaging system for quantifying relative cell numbers in situ in a variety of tissue culture plate formats, especially 96-well plates. The system consists of an epifluorescence inverted microscope with a motorized stage, video camera, image intensifier, and an 80386 microcomputer with a PC-Vision digitizer. Turbo Pascal software controls the stage and scans the plate taking multiple images per well, calculates total fluorescence per well, provides for daily calibration, and configures easily for a variety of tissue culture plate formats. Thresholding of digital images is used to remove background fluorescence without rinsing. Using cells pretreated with fluorescein diacetate (FDA) and loaded into 96-well plates, linearity was seen over 3.0 logs of cell density (r = 0.996), with similar results in 6-well (r = 0.972), 24-well (r = 0.970), and 48-well plates (r = 0.981). For cells stained directly in plates with Hoechst 33342, linearity was observed over 2.7 logs of cell density (r = 0.975). In low-viability cultures stained with FDA in 96-well plates, excessive background fluorescence completely masked viable cells, but digital thresholding dramatically reduced background fluorescence, producing a linear response (r = 9.333) over 2.7 logs of cell density (from 264 cells/well to 1.35 x 10(5) cells/well). DIM-SCAN is a versatile system for quantifying total or viable cell numbers in tissue culture plates over a wide dynamic range.

Algorithms↗
PubMed2003

Developmental decrease in synaptic facilitation at the mouse hippocampal mossy fibre synapse.

Transmission at the hippocampal mossy fibre (MF)-CA3 pyramidal cell synapse is characterized by prominent activity-dependent facilitation, which is thought to provide a wide dynamic range in hippocampal informational flow. At this synapse in mice the magnitude of paired-pulse facilitation and frequency-dependent facilitation markedly decreased with postnatal development from 3 weeks (3W) to 9 weeks (9W). Throughout this period the mean amplitude and variance of unitary EPSCs stayed constant. By altering extracellular Ca2+/Mg2+ concentrations the paired-pulse ratio could be changed to a similar extent as observed during development. However, this was accompanied by an over 30-fold change in EPSC amplitude, suggesting that the developmental change in facilitation ratio cannot simply be explained by a change in release probability. With paired-pulse stimulation the Ca2+ transients at MF terminals, monitored using mag-fura-5, showed a small facilitation, but its magnitude remained similar between 3W and 9W mice. Pharmacological tests using CNQX, adenosine, LY341495, H-7 or KN-62 suggested that neither presynaptic receptors (kainate, adenosine and metabotropic glutamate) nor protein kinases are responsible for the developmental change in facilitation. Nevertheless, loading the membrane-permeable form of BAPTA attenuated the paired-pulse facilitation in 3W mice to a much greater extent than in 9W mice, resulting in a marked reduction in age difference. These results suggest that the developmental decrease in the MF synaptic facilitation arises from a change associated with residual Ca2+, a decrease in residual Ca2+ itself or a change in Ca2+-binding sites involved in the facilitation. A developmental decline in facilitation ratio reduces the dynamic range of MF transmission, possibly contributing to the stabilization of hippocampal circuitry.

Aging↗
PubMed2000

Inhibition of spinal nociceptive responses after intramuscular injection of capsaicin involves activation of noradrenergic and opioid systems.

Extracellular recordings of wide dynamic range neurones in the dorsal horn driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. The electrically evoked neuronal responses were defined as A- and C-fibres responses according to latencies, and the effect of a deep nociceptive conditioning stimulus induced by 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was studied for at least 30 min. Independent of the size and location of the receptive field of the neurone under study, a clear inhibition of the neuronal responses was observed. The electrically evoked C-fibre responses were inhibited to 53% of baseline 15-30 min after injection of capsaicin. This inhibition was only slightly attenuated by 125 nmol of the alpha-adrenoceptor antagonist phentolamine or 250 nmol of the opioid receptor antagonist naloxone applied directly onto the spinal cord when the two compounds were administered separately 5 min before capsaicin. In contrast, when a mixture of the two compounds was given 5 min before capsaicin, the effect of capsaicin was completely abolished. These results indicate that activation of the capsaicin-sensitive afferents in the gastrocnemius-soleus muscle inhibits the electrically evoked C-fibre responses in the dorsal horn by activating noradrenergic and opioidergic inhibitory systems. Moreover, our data indicate that the activation of these two systems following injection of capsaicin has a sub-additive inhibitory effect on the wide dynamic range neurones in the spinal cord. We conclude that only one of these systems is sufficient for the inhibition to occur.

Adrenergic alpha-Antagonists↗
PubMed1997

Auditory cortical onset responses revisited. II. Response strength.

Most neurons of the auditory pathway discharge spikes locked to the onset of an acoustic stimulus, but it is largely unknown in which way the acoustic parameters of sound onsets shape the neuronal responses. In this paper is analyzed the number of spikes discharged by single neurons in primary auditory cortex of barbiturate-anesthetized cats to the onsets of tones of characteristic frequency. The time course of the peak pressure (i.e., the envelope) was altered by parametrically varying sound pressure level (SPL), rise time, and rise function (linear or cosine-squared). For both rise functions, rise time had manifold, and in some cases dramatic, effects on conventional spike count-level functions. In general, threshold SPL, dynamic range, and the lowest SPL at which monotonic spike count functions saturated increased with prolongation of the rise time. In neurons with mostly nonmonotonic spike count-level functions, "best SPL" increased and the descending high-SPL arms flattened, so that functions obtained with long rise times were often monotonic whereas those obtained with shorter rise times were highly nonmonotonic. Consequently, the "tuning" to SPL was less sharp for longer rise time tones, and spike count versus rise time functions changed from "short-pass" to "long-pass" with an increase in SPL. Systematic effects of rise time persisted when spike counts were plotted against the rate of change of peak pressure or against the maximum acceleration of peak pressure. However, when spike counts were plotted as a function of the instantaneous peak pressure at the time of response initiation, the functions obtained with different rise times, and even with different rise functions, were in close register. This suggests that the stimulus-dependent component of first-spike latency can be viewed as an integration window, during which rate of change of peak pressure is integrated. The window commences with tone onset and its duration is inversely related to the maximum acceleration (or, for linear rise functions, the rate of change) of peak pressure and the neuron's transient sensitivity. The present findings seriously question, for onset responses, the usefulness of the spike count-level function and measures derived from it, such as threshold SPL, dynamic range, best SPL, or degree of nonmonotonicity. They further cast doubt onto the validity of current concepts of intensity coding at cortical levels, because most neurons' onset responses are not indicative of a signal's steady-state SPL. However, they suggest a mechanism by which a neuronal population will sample a given transient in an orderly, sensitivity-dependent, temporal sequence. The sampling rate is automatically adjusted to, and adjusted by, the rapidity of the signal's change. And the instantaneous properties of the transient could be represented by the ratios and spatial distribution of responses across the simultaneously active subpopulation. Such a mechanism could provide the basis for the demonstrated capability of discrimination of rapid transients.

Animals↗
PubMed2004

Synaptic circuitry mediating light-evoked signals in dark-adapted mouse retina.

Light-evoked excitatory cation current (DeltaIC) and inhibitory chloride current (DeltaICl) of rod and cone bipolar cells and AII amacrine cells (AIIACs) were recorded from slices of dark-adapted mouse retinas, and alpha ganglion cells were recorded from flatmounts of dark-adapted mouse retinas. The cell morphology was revealed by Lucifer yellow fluorescence with a confocal microscope. DeltaIC of all rod depolarizing bipolar cells (DBCRs) exhibited similar high sensitivity to 500 nm light, but two patterns of DeltaICl were observed with slightly different axon morphologies. At least two types of cone depolarizing bipolar cells (DBCCs) were identified: one with axon terminals ramified in 70-85% of IPL depth and DBCR-like DeltaIC sensitivity, and the other with axon terminals ramified in 55-75% of IPL depth and much lower DeltaIC sensitivity. The relative rod/cone inputs to DBCs and AIIACs were analyzed by comparing the DeltaIC and DeltaICl thresholds and dynamic ranges with the corresponding values of rods and cones. On average, the sensitivity of a DBCR to the 500 nm light is about 20 times higher than that of a rod. The sensitivity of an AIIAC is more than 1000 times higher than that of a rod, suggesting that AIIAC responses are pooled through a coupled network of about 40 AIIACs. Interactions of rod and cone signals in dark-adapted mouse retinas appear asymmetrical: rod signals spread into the cone system more efficiently than cone signals into the rod system. The mouse synaptic circuitry allows small rod signals to be highly amplified and effectively transmitted to the cone system via rod/cone and AIIAC/DBCC coupling. Three types of alpha ganglion cells (alphaGCs) were identified. (1) ONGCs exhibits no spike activity in darkness, increased spikes in light, sustained inward DeltaIC, sustained outward DeltaICl of varying amplitude, and large soma (20-25 microm in diameter) with an alpha-cell-like dendritic field about 180-350 microm stratifying near 70% of the IPL depth. (2) Transient OFFalphaGCs (tOFFalphaGCs) exhibit no spike activity in darkness, transient increased spikes at light offset, small sustained outward DeltaIC in light, a large transient inward DeltaIC at light offset, a sustained outward DeltaICl, and a morphology similar to the ONalphaGCs except for that their dendrites stratified near 30% of the IPL depth. (3) Sustained OFFalpha GCs (sOFFalphaGCs) exhibit maintained spike activity of 5-10 Hz in darkness, sustained decrease of spikes in light, sustained outward DeltaIC, sustained outward DeltaICl, and a morphology similar to the tOFFalphaGCs. By comparing the response thresholds and dynamic ranges of alphaGCs with those of the pre-ganglion cells, our data suggest that the light responses of each type of alphaGCs are mediated by different sets of bipolar cells and amacrine cells.

Amacrine Cells↗