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Ideal observer analysis of the development of spatial contrast sensitivity in macaque monkeys.

To explore the factors limiting the development of visual sensitivity, we constructed an ideal observer model for the infant macaque visual system. We made measurements of retinal morphology in infant and adult macaque monkeys, and used the data in combination with published optical data to formulate the model. We compared the ideal observer's ability to detect low-contrast gratings presented either in isolation or in spatiotemporal noise with behavioral data obtained under matched conditions. The ideal observer showed some improvement in visual performance up to the age of 4 weeks, but little change thereafter. Behavioral data show extensive changes over the ages 5-50 wk, after the ideal observer's performance has become asymptotic. We conclude that the development of visual sensitivity in infant monkeys is not limited by changes in the front-end factors captured by the ideal observer model, at least after the age of 5 weeks. Using noise masking, we also estimated the variability of neural processing in comparison with the photon noise-limited ideal. We found that both additive and multiplicative components of this variability are elevated in infant monkeys, and improve (though not to ideal levels) during development. We believe that these changes all reflect maturation of visual processing in cortical circuits, and that no aspect of visual performance in the regime we studied is limited by the properties of the retina and photoreceptors, either in infant or in adult animals.

Animals↗

Spatiotemporal pattern of the mouse chondromodulin-I gene expression and its regulatory role in vascular invasion into cartilage during endochondral bone formation.

During endochondral bone formation, vascular invasion into cartilage initiates the replacement of cartilage by bone. Chondromodulin-I, a 25 kDa glycoprotein purified from bovine epiphyseal cartilage, was recently identified as a novel endothelial cell growth inhibitor. Here we cloned the mouse chondromodulin-I cDNA from a mouse whole embryo cDNA library. Northern blot analysis revealed that the chondromodulin-I transcripts were expressed in association with the formation of cartilage expressing type II collagen from days 11 to 17 of gestation in mouse embryos, at which time cartilaginous bone rudiments were gradually replaced by bone. Chondromodulin-I mRNA was also detected in the thymus and eyes at a lower level. In situ hybridization revealed significant expression in all cartilaginous tissues in the embryos at days 13.5 and 16 of gestation. However, the expression was completely abolished in the hypertrophic cartilage zone prior to calcification. Upon chondrogenic differentiation of mouse ATDC5 cells in vitro, the expression of chondromodulin-I transcripts was induced concomitantly with the formation of type II collagen-expressing chondrocytes. The expression of the transcripts then declined as type X collagen-expressing hypertrophic chondrocytes appeared in the culture. Purified chondromodulin-I protein inhibited the vascular invasion into cartilage ectopically induced by demineralized bone matrix in nude mice, leading to the suppression of bone formation in vivo. These results suggest that chondromodulin-I is involved in the anti-angiogenic property of cartilage, and that the withdrawal of its expression allows the vascular invasion which triggers the replacement of cartilage by bone during endochondral bone development.

Amino Acid Sequence↗

Functional micro-organization of primary visual cortex: receptive field analysis of nearby neurons.

It is well established that multiple stimulus dimensions (e.g., orientation and spatial frequency) are mapped onto the surface of striate cortex. However, the detailed organization of neurons within a local region of striate cortex remains unclear. Within a vertical column, do all neurons have the same response selectivities? And if not, how do they most commonly differ and why? To address these questions, we recorded from nearby pairs of simple cells and made detailed spatiotemporal maps of their receptive fields. From these maps, we extracted and analyzed a variety of response metrics. Our results provide new insights into the local organization of striate cortex. First, we show that nearby neurons seldom have very similar receptive fields, when these fields are characterized in space and time. Thus, there may be less redundancy within a column than previously thought. Moreover, we show that correlated discharge increases with receptive field similarity; thus, the local dissimilarity between neurons may allow for noise reduction by response pooling. Second, we show that several response variables are clustered within striate cortex, including some that have not received much attention such as response latency and temporal frequency. We also demonstrate that other parameters are not clustered, including the spatial phase (or symmetry) of the receptive field. Third, we show that spatial phase is the single parameter that accounts for most of the difference between receptive fields of nearby neurons. We consider the implications of this local diversity of spatial phase for population coding and construction of higher-order receptive fields.

Animals↗

Dynamic patterns of postural sway in ballet dancers and track athletes.

We compared the variability and spatiotemporal profile of postural sway of trained ballet dancers to college varsity track athletes under variations in the availability of vision and rigidity of the support surface. We found no differences between the groups according to the variability measures, but variability increased for both groups with eyes closed and on a foam surface. Recurrence quantification analysis revealed that the postural sway of dancers was less regular (lower recurrence), less stable (lower maxline), less complex (lower entropy), and more stationary (lower absolute trend) than that of track athletes. Dancers, possibly as a result of focused balance training, exhibited different dynamic patterns of postural sway.

Adult↗

Macroscopic optical mapping of excitation in cardiac cell networks with ultra-high spatiotemporal resolution.

Optical mapping of cardiac excitation using voltage- and calcium-sensitive dyes has allowed a unique view into excitation wave dynamics, and facilitated scientific discovery in the cardiovascular field. At the same time, the structural complexity of the native heart has prompted the design of simplified experimental models of cardiac tissue using cultured cell networks. Such reduced experimental models form a natural bridge between single cells and tissue/organ level experimental systems to validate and advance theoretical concepts of cardiac propagation and arrhythmias. Macroscopic mapping (over >1cm(2) areas) of transmembrane potentials and intracellular calcium in these cultured cardiomyocyte networks is a relatively new development and lags behind whole heart imaging due to technical challenges. In this paper, we review the state-of-the-art technology in the field, examine specific aspects of such measurements and outline a rational system design approach. Particular attention is given to recent developments of sensitive detectors allowing mapping with ultra-high spatiotemporal resolution (>5 megapixels/s). Their interfacing with computer platforms to match the high data throughput, unique for this new generation of detectors, is discussed here. This critical review is intended to guide basic science researchers in assembling optical mapping systems for optimized macroscopic imaging with high resolution in a cultured cell setting. The tools and analysis are not limited to cardiac preparations, but are applicable for dynamic fluorescence imaging in networks of any excitable media.

Action Potentials↗

Panoramic measurements of the apex of the cochlea.

Our understanding of cochlear mechanics is impeded by the lack of truly panoramic data. Sensitive mechanical measurements cover only a narrow cochlear region, mostly in the base. The global spatiotemporal pattern of vibrations along the cochlea cannot be inferred from such local measurements but is often extrapolated beyond the measurement spot under the assumption of scaling invariance. Auditory nerve responses give an alternative window on the entire cochlea, but traditional techniques do not allow recovery of the effective vibration pattern. We developed a new analysis technique to measure cochlear amplitude and phase transfer of fibers with characteristic frequencies <5 kHz. Data from six cats yielded panoramic phase profiles along the apex of the cochlea for an approximately 5 octave range of stimulus frequencies. All profiles accumulated systematic phase lags from base to apex. Phase accumulation was not gradual but showed a two-segment character: a steep segment (slow propagation) around the characteristic position of the stimulus, and a shallow segment (fast propagation) basal to it. The transition between the segments occurred in a narrow region and was smooth. Wavelength near characteristic position decreased from approximately 3.5 to approximately 1 mm for frequencies from 200 to 4000 Hz, corresponding to phase velocities of approximately 0.5 to approximately 5 m/s. The accumulated phase lag between the eardrum and characteristic position varied from approximately 1 cycle at 200 Hz to approximately 2.5 cycle at 4 kHz, invalidating scaling invariance. The generic character of our analysis technique and its success in solving the difficult problem of reconstructing the effective sensory input from neural recordings suggest its wider application as a powerful alternative to customary system analysis techniques.

Acoustic Stimulation↗

Critical problems in spatial vision.

In recent years the study of spatial vision seems to have come almost full circle. Localized stimuli (such as lines, bars, and edges) were abandoned in favor of textured patterns (such as sinusoidal gratings), a trend that was accelerated by the discovery that gratings of sufficiently different spatial frequencies or orientations (stimuli localized in the Fourier domain) were detected independently. This led to various attempts to model form vision in terms of spatial frequency analysis. More recently there has been a shift toward models that include, once again, the local aspects of spatial processing; this trend is more consistent with both retinal and cortical physiology. (Still surviving is the notion of a complete set of orthonormal basis functions, but not sinusoidal ones.) Other important developments include attempts to model spatiotemporal interaction, and the discovery that spatial processing takes on an entirely different character in the absence of any temporal variation (i.e., when the retinal image is stabilized). We attempt to trace these developments in terms of a selected group of representative studies, which we examine in some depth.

Biomedical Engineering↗

Probabilistic independent component analysis for functional magnetic resonance imaging.

We present an integrated approach to probabilistic independent component analysis (ICA) for functional MRI (FMRI) data that allows for nonsquare mixing in the presence of Gaussian noise. In order to avoid overfitting, we employ objective estimation of the amount of Gaussian noise through Bayesian analysis of the true dimensionality of the data, i.e., the number of activation and non-Gaussian noise sources. This enables us to carry out probabilistic modeling and achieves an asymptotically unique decomposition of the data. It reduces problems of interpretation, as each final independent component is now much more likely to be due to only one physical or physiological process. We also describe other improvements to standard ICA, such as temporal prewhitening and variance normalization of timeseries, the latter being particularly useful in the context of dimensionality reduction when weak activation is present. We discuss the use of prior information about the spatiotemporal nature of the source processes, and an alternative-hypothesis testing approach for inference, using Gaussian mixture models. The performance of our approach is illustrated and evaluated on real and artificial FMRI data, and compared to the spatio-temporal accuracy of results obtained from classical ICA and GLM analyses.

Algorithms↗

Development of high-throughput tools to unravel the complexity of gene expression patterns in the mammalian brain.

Genomes of animals contain between 15000 (e.g. Drosophila) and 50000 (human, mouse) genes, many of which encode proteins involved in regulatory processes. The availability of sequence data for many of these genes opens up opportunities to study complex genetic and protein interactions that underlie biological regulation. Many examples demonstrate that an understanding of regulatory networks consisting of multiple components is significantly advanced by a detailed knowledge of the spatiotemporal expression pattern of each of the components. Gene expression patterns can readily be determined by RNA in situ hybridization. The unique challenge emerging from the knowledge of the sequence of entire genomes is that assignment of biological functions to genes needs to be carried out on an appropriately large scale. In terms of gene expression analysis by RNA in situ hybridization, efficient technologies need to be developed that permit determination and representation of expression patterns of thousands of genes within an acceptable time-scale. We set out to determine the spatial expression pattern of several thousand genes encoding putative regulatory proteins. To achieve this goal we have developed high-throughput technologies that allow the determination and visualization of gene expression patterns by RNA in situ hybridization on tissue sections at cellular resolution. In particular, we have invented instrumentation for robotic in situ hybridization capable of carrying out in a fully automated fashion, all steps required for detecting sites of gene expression in tissue sections. In addition, we have put together hardware and software for automated microscopic scanning of gene expression data that are produced by RNA in situ hybridization. The potential and limitations of these techniques and our efforts to build a Web-based database of gene expression patterns are discussed.

Animals↗

Dynamics of traveling waves under spatiotemporal forcing.

We study dynamics of traveling waves under spatiotemporal forcing in nonequilibrium systems. Based on the model equations where phase separation and chemical reactions take place simultaneously so that traveling waves are formed in a self-organized manner, we apply a space-time dependent external force. Entrainment and modulation of traveling waves are investigated numerically in one dimension. We develop a theoretical analysis to understand the dynamics obtained.

Journal Article↗

Monte carlo simulation of vesicular release, spatiotemporal distribution of glutamate in synaptic cleft and generation of postsynaptic currents.

The release of vesicular glutamate, spatiotemporal changes in glutamate concentration in the synaptic cleft and the subsequent generation of fast excitatory postsynaptic currents at a hippocampal synapse were modeled using the Monte Carlo method. It is assumed that glutamate is released from a spherical vesicle through a cylindrical fusion pore into the synaptic cleft and that S-alpha-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid (AMPA) receptors are uniformly distributed postsynaptically. The time course of change in vesicular concentration can be described by a single exponential, but a slow tail is also observed though only following the release of most of the glutamate. The time constant of decay increases with vesicular size and a lower diffusion constant, and is independent of the initial concentration, becoming markedly shorter for wider fusion pores. The cleft concentration at the fusion pore mouth is not negligible compared to vesicular concentration, especially for wider fusion pores. Lateral equilibration of glutamate is rapid, and within approximately 50 micros all AMPA receptors on average see the same concentration of glutamate. Nevertheless the single-channel current and the number of channels estimated from mean-variance plots are unreliable and different when estimated from rise- and decay-current segments. Greater saturation of AMPA receptor channels provides higher but not more accurate estimates. Two factors contribute to the variability of postsynaptic currents and render the mean-variance nonstationary analysis unreliable, even when all receptors see on average the same glutamate concentration. Firstly, the variability of the instantaneous cleft concentration of glutamate, unlike the mean concentration, first rapidly decreases before slowly increasing; the variability is greater for fewer molecules in the cleft and is spatially nonuniform. Secondly, the efficacy with which glutamate produces a response changes with time. Understanding the factors that determine the time course of vesicular content release as well as the spatiotemporal changes of glutamate concentration in the cleft is crucial for understanding the mechanism that generates postsynaptic currents.

Animals↗

Are pioneer axons guided by regulatory gene expression domains in the zebrafish forebrain? High-resolution analysis of the patterning of the zebrafish brain during axon tract formation.

Although the principles of axon growth are well understood in vitro the mechanisms guiding axons in vivo are less clear. It has been postulated that growing axons in the vertebrate brain follow borders of neuroepithelial cells expressing specific regulatory genes. In the present study we reexamined this hypothesis by analysing the earliest growing axons in the forebrain of embryonic zebrafish. Confocal laser scanning microscopy was used to determine the spatiotemporal relationship between growing axons and the expression pattern of eight regulatory genes in zebrafish brain. Pioneer axons project either longitudinally or dorsoventrally to establish a scaffold of axon tracts during this developmental period. Each of the regulatory genes was expressed in stereotypical domains and the borders of some were oriented along dorsoventral and longitudinal planes. However, none of these borders clearly defined the trajectories of pioneer axons. In two cases axons coursed in proximity to the borders of shh and pax6, but only for a relatively short portion of their pathway. Only later growing axons were closely apposed to the borders of some gene expression domains. These results suggest that pioneer axons in the embryonic forebrain do not follow continuous pathways defined by the borders of regulatory gene expression domains.

Animals↗

Spatiotemporal dynamics of the functional architecture for gain fields in inferior parietal lobule of behaving monkey.

Intrinsic optical imaging has revealed a representation of eye position smoothly mapped across the surface of the inferior parietal lobule in behaving monkeys. We demonstrate here that blood vessels imaged along with the cortex have large signals tuned sometimes, but not always, to match the surrounding tissue. The relationship between the vessels and surrounding tissue in both space and time was explored using independent component analysis (ICA). Working only with single-trial data, ICA discovered a sequence of regions corresponding to the vascular propagation of activated signals from remote loci into the blood vessels. The vascular signals form a novel map of cortical function--the functional angioarchitecture--superimposed upon the cortical functional architecture. Furthermore, the incorporation of temporal aspects in optical data permitted the tuning of the inferior parietal lobule to be tracked in time through the task, demonstrating the expression of unusual tuning properties that might be exploited for higher cognitive functions.

Animals↗

In vivo analysis of 3-phosphoinositide dynamics during Dictyostelium phagocytosis and chemotaxis.

Phagocytosis and chemotaxis are receptor-mediated processes that require extensive rearrangements of the actin cytoskeleton, and are controlled by lipid second messengers such as phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2]. We used a panel of pleckstrin homology (PH) domains with distinct binding specificities for PtdIns(3,4,5)P3 and PtdIns(3,4)P2 to study the spatiotemporal dynamics of these phosphoinositides in vivo. During phagocytosis and macropinocytosis PtdIns(3,4,5)P3 levels transiently increased at sites of engulfment, followed by a rapid PtdIns(3,4)P2 production round the phagosome/macropinosome upon its internalisation, suggesting that PtdIns(3,4,5)P3 is degraded to PtdIns(3,4)P2. PTEN null mutants, which are defective in phagocytosis, showed normal rates of PtdIns(3,4,5)P3 degradation, but unexpectedly an accelerated PtdIns(3,4)P2 degradation. During chemotaxis to cAMP only PtdIns(3,4,5)P3 was formed in the plasma membrane, and no PtdIns(3,4)P2 was detectable, showing that all PtdIns(3,4,5)P3 was degraded by PTEN to PtdIns(4,5)P2. Furthermore, we showed that different PtdIns(3,4,5)P3 binding PH domains gave distinct spatial and temporal readouts of the same underlying PtdIns(3,4,5)P3 signal, enabling distinct biological responses to one signal.

Animals↗

cDNA cloning of myosin heavy chain genes from medaka Oryzias latipes embryos and larvae and their expression patterns during development.

Several sarcomeric myosin heavy chains (MYHs) were cloned from embryos and larvae of medaka Oryzias latipes. Three genes encoding medaka MYHs (mMYHs) predominantly expressed in embryos (mMYH(emb1)) and larvae (mMYH(L1) and mMYH(L2)), all belonged to fast skeletal MYHs, showing spatiotemporally different expression patterns during development. Besides these mMYHs, a few novel mMYHs were cloned from embryos and larvae at hatching. Whereas mMYH(emb2), mMYH(emb3), and mMYH(L3) belonged to fast skeletal MYH, mMYH(C1) and mMYH(C2) did to slow/cardiac MYH. mMYH(emb1) was expressed ahead of mMYH(L1) and mMYH(L2). In situ hybridization analysis demonstrated that the transcripts of mMYH(emb1) and mMYH(C1) were located in the horizontal myoseptum, whereas those of mMYH(L1) and mMYH(L2) in the inner part of myotomes and pharyngeal muscles, and those of mMYH(C2) in the heart rudiment. In silico cloning based on the medaka genome database showed another mMYHs of the slow/cardiac types, mMYH(C3) and mMYH(C4).

Animals↗

Effects of AIF4- and ATP on intracellular calcium dynamics of crypt epithelial cells in mouse small intestine.

Previous digital imaging analysis of intracellular calcium ion ([Ca2+]i) dynamics in the crypt of the small intestine showed little response by most columnar cells to cholinergic and adrenergic agonists. The objective of the present study was to demonstrate whether G-protein activators and other transmitters elicit [Ca2+]i changes in crypt cells. We used digital imaging to analyze spatiotemporal dynamics of [Ca2+]i in Fura-2/AM-loaded isolated crypts of mouse duodenum and ileum. A1F4- increased [Ca2+]i in crypt columnar cells. In many cases, we observed [Ca2+]i oscillations, which were synchronized throughout the entire crypt. The oscillations were blocked by octanol. ATP, but not adenosine, caused a [Ca2+]i increase in middle crypt-regions of the duodenum and upper regions of the ileum, and the [Ca2+]i wave propagated towards the crypt bottom. The ATP-induced [Ca2+]i increase was prevented by pretreatment with thapsigargin or suramin, but not by La3+ or an extracellular Ca(2+)-free environment. Neither dopamine, 5-hydroxytryptamine (5-HT), histamine, vasoactive intestinal peptide, substance P. cholera toxin, nor guanylin had significant effects. The [Ca2+]i dynamics of Paneth cells were independent of the AlF4(-)-induced synchronous oscillations of columnar cells and of the ATP-induced [Ca2+]i wave. In conclusion, crypt columnar cells have [Ca2+]i-dependent intracellular signaling mechanisms that are linked with G proteins, and by which the cells communicate with each other. ATP elicited [Ca2+]i mobilization from columnar cells via P2 receptors, although some regional differences were noted between the duodenum and ileum.

Adenosine Triphosphate↗

WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair.

Wnt-1-induced secreted protein 1 (WISP-1) is a member of the CCN (connective tissue growth factor, Cyr61, NOV) family of growth factors. Experimental evidence suggests that CCN family members are involved in skeletogenesis and bone healing. To investigate the role of WISP-1 in osteogenic processes, we characterized its tissue and cellular expression and evaluated its activity in osteoblastic and chondrocytic cell culture models. During embryonic development, WISP-1 expression was restricted to osteoblasts and to osteoblastic progenitor cells of the perichondral mesenchyme. In vitro, we showed that WISP-1 expression in differentiating osteoblasts promotes BMP-2-induced osteoblastic differentiation. Using in situ and cell binding analysis, we demonstrated WISP-1 interaction with perichondral mesenchyme and undifferentiated chondrocytes. We evaluated the effect of WISP-1 on chondrocytes by generating stably transfected mouse chondrocytic cell lines. In these cells, WISP-1 increased proliferation and saturation density but repressed chondrocytic differentiation. Because of the similarity between skeletogenesis and bone healing, we also analyzed WISP-1 spatiotemporal expression in a fracture repair model. We found that WISP-1 expression recapitulates the pattern observed during skeletal development. Our data demonstrate that WISP-1 is an osteogenic potentiating factor promoting mesenchymal cell proliferation and osteoblastic differentiation while repressing chondrocytic differentiation. Therefore, we propose that WISP-1 plays an important regulatory role during bone development and fracture repair.

Animals↗

Oscillatory synchronization requires precise and balanced feedback inhibition in a model of the insect antennal lobe.

In the insect olfactory system, odor-evoked transient synchronization of antennal lobe (AL) projection neurons (PNs) is phase-locked to the oscillations of the local field potential. Sensory information is contained in the spatiotemporal synchronization pattern formed by the identities of the phase-locked PNs. This article investigates the role of feedback inhibition from the local neurons (LNs) in this coding. First, experimental biological results are reproduced with a reduced computational spiking neural network model of the AL. Second, the low complexity of the model leads to a mathematical analysis from which a lower bound on the phase-locking probability is derived. Parameters involved in the bound indicate that PN phase locking depends not only on the number of LN-evoked inhibitory postsynaptic potentials (IPSPs) previously received, but also on their temporal jitter. If the inhibition received by a PN at the current oscillatory cycle is both perfectly balanced (i.e., equal to the mean inhibitory drive) and precise (without any jitter), then the PN will be phase-locked at the next oscillatory cycle with probability one.

Animals↗