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PubMed2001

Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus.

We investigated the effects of a single injection and a daily injection of lipopolysaccharide (LPS) on spatial learning and brain-derived neurotrophic factor (BDNF) expression in the rat dentate gyrus. LPS is derived from the cell wall of Gram-negative bacteria and is a potent endotoxin that causes the release of cytokines such as interleukin-1 and tumour necrosis factor. LPS is thought to activate both the neuroimmune and neuroendocrine systems; it also blocks long-term potentiation in the hippocampus. Here, we examined the effects of LPS on a form of hippocampal-dependent learning-spatial learning in the water maze. Rats were injected with LPS intraperitoneally (100 microg/kg) and trained in the water maze. The first group of rats were injected on day 1 of training, 4 h prior to learning the water maze task. Groups 2 and 3 were injected daily, again 4 h prior to the water-maze task; group 2 with LPS and group 3 with saline. A number of behavioural variables were recorded by a computerised tracking system for each trial. The behavioural results showed a single injection of LPS (group 1) impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection of LPS did not significantly impair acquisition or retention. BDNF expression was analysed in the dentate gyrus of all animals. No significant differences in BDNF expression were found between the three groups.

Animals↗

PubMed2006

Modeling a syphilis outbreak through space and time using the Bayesian maximum entropy approach.

PURPOSE: The aim of the study is to describe changes in the spatial distribution of syphilis before, during, and after an outbreak in Baltimore, MD, by using Bayesian maximum entropy (BME), a modern geostatistical technique for space-time analysis and mapping. METHODS: BME was used to conduct simple and composite space-time analyses of the density of syphilis infection based on primary, secondary and early latent syphilis cases reported to the Baltimore City Health Department between January 1, 1994, and December 31, 2002. RESULTS: Spatiotemporal covariance plots indicated that the distribution of the density of syphilis cases showed both spatial and temporal dependence. Temporally dependent disease maps suggested that syphilis increased within two geographic core areas of infection and spread outward. A new core area of infection was established to the northwest. As the outbreak waned, density diminished and receded in all core areas. Morbidity remained elevated in the two original central and new northwestern core areas after the outbreak. CONCLUSIONS: Density of syphilis infection was a simple informative measure easily compared across years. The BME approach was useful for quantitatively and qualitatively describing the spatial development and spread of syphilis. Our results are specific to Baltimore; however, the BME approach is generalizable to other settings and diseases.

Baltimore↗

PubMed1993

Different parameters control motion perception above and below a critical density.

The maximum displacement for the detection of apparent motion (Dmax) is measured using stimuli made up of Gabor function micro-patterns randomly distributed across the stimulus field. Previous studies using high densities of micro-patterns have demonstrated Dmax to be dependent on the spatial frequency content of the stimulus and not the size of the stimulus elements. Here we report that Dmax increases suddenly when the number of micro-patterns in the visual field is reduced beyond some critical point. The number of micro-patterns at which the transition in Dmax occurs is found to be inversely proportional to the width of the micro-patterns along the axis of motion. Beyond this transition, for low density stimuli, Dmax is found to be dependent on both the number and size of micro-patterns in the stimulus field. These results are suggestive of the operation of different motion mechanisms under conditions of low vs high micro-pattern density.

Female↗

PubMed2006

Pharmacological and molecular enhancement of learning in aging and Alzheimer's disease.

When animals learn hippocampus-dependent associative and spatial tasks such as trace eyeblink conditioning and the water maze, CA1 hippocampal neurons become more excitable as a result of reductions in the post-burst, slow afterhyperpolarization. The calcium-activated potassium current that mediates this afterhyperpolarization is activated by the calcium influx that occurs when a series of action potentials fire and serves as a modulator of neuronal firing frequency. As a result, spike frequency accommodation is also reduced after learning. Neuronal calcium buffering processes change and/or voltage-dependent calcium currents increase during aging; leading to enhancements in the slow afterhyperpolarization, increased spike frequency accommodation and age-associated impairments in learning. We describe a series of studies done to characterize this learning-specific enhancement in intrinsic neuronal excitability and its converse in aging brain. We have also combined behavioral pharmacology and biophysics in experiments demonstrating that compounds that increase neuronal excitability in CA1 pyramidal neurons also enhance learning rate of hippocampus-dependent tasks, especially in aging animals. The studies reviewed here include those using nimodipine, an L-type calcium current blocker that tends to cross the blood-brain barrier; metrifonate, a cholinesterase inhibitor; CI1017, a muscarinic cholinergic agonist; and galantamine, a combined cholinesterase inhibitor and nicotinic agonist. Since aging is the chief risk factor for Alzheimer's disease, a disease that targets the hippocampus and associated brain regions and markedly impairs hippocampus-dependent learning, these compounds have potential use as treatments for this disease. Galantamine has been approved by the USDA for this purpose. Finally, we have extended our studies to the TG2576 transgenic mouse model of Alzheimer's disease (AD), that overproduces amyloid precursor protein (APP) and increases levels of toxic beta-amyloid in the brain. Not only do these mice show deficits in hippocampus-dependent learning as they age, but their hippocampal neurons show a reduced capacity to increase their levels of intrinsic excitability with reductions in the slow afterhyperpolarization after application of the muscarinic agonist carbachol. These TG2576 APP overproducing mice were crossed with BACE1 knockout mice, that do not produce beta-amyloid because cleavage of APP by the beta-site APP cleaving enzyme 1 (BACE1) is a critical step in its formation. Not only was hippocampus-dependent learning rescued in the bigenic TG2576-BACE1 mice, but the capacity of hippocampal neurons to show normal enhancements of intrinsic excitability was restored. The series of studies reviewed here support our hypothesis that enhancement in intrinsic excitability by reductions in calcium-activated potassium currents in hippocampal neurons is an important cellular mechanism for hippocampus-dependent learning.

Aging↗

PubMed2001

Activation and repression by the C-terminal domain of Dorsal.

In the Drosophila embryo, Dorsal, a maternally expressed Rel family transcription factor, regulates dorsoventral pattern formation by activating and repressing zygotically active fate-determining genes. Dorsal is distributed in a ventral-to-dorsal nuclear concentration gradient in the embryo, the formation of which depends upon the spatially regulated inhibition of Dorsal nuclear uptake by Cactus. Using maternally expressed Gal4/Dorsal fusion proteins, we have explored the mechanism of activation and repression by Dorsal. We find that a fusion protein containing the Gal4 DNA-binding domain fused to full-length Dorsal is distributed in a nuclear concentration gradient that is similar to that of endogenous Dorsal, despite the presence of a constitutively active nuclear localization signal in the Gal4 domain. Whether this fusion protein activates or represses reporter genes depends upon the context of the Gal4-binding sites in the reporter. A Gal4/Dorsal fusion protein lacking the conserved Rel homology domain of Dorsal, but containing the non-conserved C-terminal domain also mediates both activation and repression, depending upon Gal4-binding site context. A region close to the C-terminal end of the C-terminal domain has homology to a repression motif in Engrailed - the eh1 motif. Deletion analysis indicates that this region mediates transcriptional repression and binding to Groucho, a co-repressor known to be required for Dorsal-mediated repression. As has previously been shown for repression by Dorsal, we find that activation by Dorsal, in particular by the C-terminal domain, is modulated by the maternal terminal pattern-forming system.

Amino Acid Motifs↗

PubMed1996

Effect of intraventricular injections of dihydro-beta-erythroidine (DH beta E) on spatial memory in the rat.

The analysis of the behavioral effect of the nicotinic acetylcholine receptor (nAChR) antagonists has been generally based on drugs which act at the associated ion channel. In contrast dihydro-beta-erythroidine (DH beta E) is a competitive antagonist at the nAChR. Using rats, DH beta E was injected intraventricularly prior to training in two spatial tests, the Morris Water Maze and a Win-Stay radial maze. In addition DH beta E 300 nmol was used to reverse the effect of (-)-nicotine on locomotor activity. In the Morris Water Maze DH beta E (300 nmol) disrupted memory of the platform location as measured by crosses of the area in a probe trial. At 300 nmol DH beta E showed no sensorimotor effects in a visible platform test. In the Win-Stay task there was a significant, dose dependent disruption of spatial memory. A dissociation of nicotine's effects on locomotor activity was observed, in that DH beta E 300 nmol was able to significantly attenuate (-)-nicotine enhancement of horizontal motor activity, but did not affect the initial reduction of vertical activity. Nicotinic processing of memory appears to be involved in these tests of spatial memory.

Animals↗

PubMed1995

Sensory and spatial components of somaesthetic deficits following right brain damage.

We instructed patients with right brain damage (RBD) and somatosensory extinction, hemispatial neglect, or both to verbally report light touches delivered to the left hand, to the right hand, or simultaneously to both hands in two experimental situations. In the "anatomic" situation, each hand was in its homonymous hemispace; in the "crossed" one, each hand was held across the corporeal midline, in its heteronymous hemispace. Under both single and the double stimulation conditions, RBD patients detected stimuli delivered to the contralesional hand with lower accuracy in the anatomic than in the crossed position. This result suggests that somaesthetic deficits can be due not only to sensory but also to attentional factors, depending on the spatial position of the hands. Processing of sensory information in primary areas should not be influenced by the hemispatial position of the stimulated body part. These results suggest that somaesthetic deficits may stem not only from damage of primary sensory areas, as classically held, but also from damage of higher-order areas where information about stimuli, body parts, and extrapersonal space is integrated. Finally, the results show that sensory and attentional components of the deficit can be dissociated by using a very simple clinical test.

Aged↗

PubMed2005

Model-based source localization of extracellular action potentials.

A new model-based analysis method was set up for revealing information encrypted in extracellular spatial potential patterns of neocortical action potentials. Spikes were measured by extracellular linear multiple microelectrode in vivo cat's primary auditory cortex and were analyzed based on current source density (CSD) distribution models. Validity of the monopole and other point source approximations were tested on the measured potential patterns by numerical fitting. We have found, that point source models could not provide accurate description of the measured patterns. We introduced a new model of the CSD distribution on a spiking cell, called counter-current model (CCM). This new model was shown to provide better description of the spatial current distribution of the cell during the initial negative deflection of the extracellular action potential, from the onset of the spike to the negative peak. The new model was tested on simulated extracellular potentials. We proved numerically, that all the parameters of the model could be determined accurately based on measurements. Thus, fitting of the CCM allowed extraction of these parameters from the measurements. Due to model fitting, CSD could be calculated with much higher accuracy as done with the traditional method because distance dependence of the spatial potential patterns was explicitly taken into consideration in our method. Average CSD distribution of the neocortical action potentials was calculated and spatial decay constant of the dendritic trees was determined by applying our new method.

Action Potentials↗

PubMedDate not supplied

The sequential processing of visual motion in the human electroretinogram and visual evoked potential.

Mechanisms of motion vision in the human have been studied extensively by psychophysical methods but less frequently by electrophysiological techniques. It is the purpose of the present investigation to study electrical potentials of the eye (electroretinogram, ERG) and of the brain (visual evoked potential, VEP) in response to moving regular square-wave stripe patterns spanning a wide range of contrasts, spatial frequencies, and speeds. The results show that ERG amplitudes increase linearly with contrast while VEPs, in agreement with the literature, show an amplitude saturation at low contrast. Furthermore, retinal responses oscillate with the fundamental temporal stimulus frequency of the moving pattern while brain responses do not. In both the retina and the brain, the response amplitudes are tuned to certain speeds which is in agreement with the nonlinear correlation-type motion detector. Along the ascending slopes (which means increasing amplitudes) of the tuning functions, the ERG curves overlap at all spatial frequencies if plotted as a function of temporal stimulation frequency. The ascending slopes of the tuning functions of the VEP overlap if plotted as a function of speed. The descending slopes (which means decreasing amplitudes) of the tuning functions show little (ERG) or no (VEP) overlap and the waveforms at high speeds approach pattern-offset-onset responses. These observations suggest that in the retina motion processing along the ascending slopes of the tuning curves takes place by coding the temporal stimulation frequency which depends on the spatial frequency of the moving pattern. In the brain, however, motion processing is by speed independent of spatial frequency. Simple calculations show that the VEP information is decoded from the ERG signal into a speed signal.

Contrast Sensitivity↗

PubMed2000

Spatial, a gene expressed in thymic stromal cells, depends on three-dimensional thymus organization for its expression.

Although the importance of thymic stroma in thymopoiesis has been recognized, the underlying molecular details regarding stromal cell biology remain obscure. To study this area, we have cloned genes expressed in thymic stromal cells. Spatial is alternatively spliced to generate two mRNAs in thymus and lymph node (LN) but it is not expressed in the spleen. In mouse embryos, the short form begins expression at day 10 while the long form is not detected until day 12. Both mRNAs encode proline rich proteins and their closest homology is to homeobox and POU domain transcription factors. Spatial is not expressed in thymocytes, but it is expressed in 2-deoxyguanosine-treated day 14 fetal thymic organ culture (FTOC) and in reaggregated FTOC. These data suggest that a normal three-dimensional organization of stromal cells is required for Spatial expression. An antiserum raised against a C-terminal peptide detected proteins of 38 and 32 kDa in Western blots of total thymus proteins. In frozen thymus sections, subcapsular epithelial cells were stained with the anti-Spatial antiserum. Paracortical subcapsular cells of unknown function were also stained in the LN. Both forms of Spatial fused to the green fluorescent protein (GFP) localize to the nucleus in transfected cells.

5' Untranslated Regions↗

PubMed1989

The effect of intraocular 6-hydroxydopamine on retinal processing of primates.

In previous studies, we showed that in the monkey, systemically administered N-methyl, 4-phenyl, 1-2-3-6 tetrahydropyridine (MPTP) produces a chronic parkinsonian syndrome accompanied by spatial frequency-dependent abnormalities in both the pattern electroretinogram and visual evoked potential. We describe the effect of intravitreally administered 6-hydroxydopamine (6-OH-DA) on the pattern electroretinogram and pattern visual evoked potential of 3 aphakic monkeys. Because of the aphake condition, several complexities of intravitreal injection of 6-OH-DA could be avoided. Nevertheless, following 6-OH-DA treatment, both the phase and the amplitude of pattern electroretinogram and pattern visual evoked potential became abnormal. This abnormality was most pronounced for the higher spatial frequencies (2.5 and 3.5 cycles per degree), whereas lower spatial frequencies (0.5 and 1.2 cycles per degree) were less impaired. The effects of systemically administered MPTP on pattern electroretinogram and pattern visual evoked potential are similar to the effects of intravitreal injections of 6-OH-DA, suggesting that a retinal catecholaminergic system plays an important role in pattern vision of primates.

Animals↗

PubMedDate not supplied

Effects of spatial distribution on proton relaxation enhancement by particulate iron oxide.

The proton relaxation effect of superparamagnetic iron oxide (SPIO) particles under varying conditions of spatial distribution was investigated with use of phantoms. Agar phantoms containing various concentrations of SPIO or gadopentetate dimeglumine, with and without Sephadex beads, were studied. Phantoms with Sephadex had a heterogeneous spatial distribution of iron oxide, comparable to liver tissue in vivo. Relaxometry at 0.47 T showed decreased T2 relaxivity of SPIO in Sephadex phantoms compared with that in agar phantoms without Sephadex. On T2-weighted images obtained at 1.5 T, the signal intensity of Sephadex phantoms showed less SPIO relaxation effect than that of plain agar phantoms. Unlike SPIO, gadopentetate dimeglumine showed the same relaxivities and signal intensity in plain agar and Sephadex phantoms. The results show that the T2 relaxation effect of iron oxide depends on its spatial distribution. A heterogeneous spatial distribution, as in intact liver tissue, diminishes the T2 relaxivity of iron oxide particles.

Agar↗

PubMed2002

The spatial distribution of selective attention assessed using the multifocal visual evoked potential.

To determine the manner in which attention is distributed among numerous locations in the visual space, we used a multifocal recording technique that allowed simultaneous recordings of evoked cortical activity from 12 visual field areas out to 23.6 degrees. We found that multifocal visual evoked potential (mfVEP) amplitude was larger when a region of visual space was attended than when it was not attended. The magnitude of this effect was inversely related to visual field eccentricity and there was no attention-related modulation of VEP amplitude for the most eccentric region. In addition, we found that mfVEP amplitudes in the regions contiguous to the attended region could also be larger, depending upon their spatial relationship to the attended region. Specifically, amplitudes in more central regions on the 'meridian of attention' were larger when the subject attended anywhere along that meridian.

Attention↗

PubMed1988

A dynamic model for water flow in a single tree: evidence that models must account for hydraulic architecture.

A model is presented for the dynamics of water flow in a single eastern white cedar tree (Thuja occidentalis L.). The model takes into account the spatial and temporal dependence of the evaporative flux from leaves in the crown. It also accounts for the quantitative hydraulic architecture of the tree, i.e., the model characterizes the tree as a branched catena of > 4000 stem segments in which account is taken of the segment length, diameter, hydraulic resistance, and the total area of leaves attached to the segment. Input values needed to run the model are measurements of evaporative flux, hydraulic conductance of stems versus stem diameter, and leaf and stem water storage capacitances. Output parameters are the spatial and temporal characterization of stem and leaf water potentials, stem and leaf water deficits, sap flow rate, and relative sap velocity. The input and output values of the branched catena model are compared and contrasted to that of an unbranched catena model. It is shown that the branched catena model fits independently measured field parameters better than an unbranched catena model. Close correspondence is found between model predictions and field measurements of shoot water potential, pressure gradients in stems, hysteresis in sap velocity between the lower and upper parts of the tree, and diurnal changes in stem and leaf water deficits. This model is discussed in terms of both the hydraulic architecture of trees and the potential application of the model to questions of tree morphology, ecology, physiology and evolution.

Journal Article↗

PubMed1999

Integral equation theories for predicting water structure around molecules.

Water plays a crucial role in the structure and function of proteins and other biological macromolecules; thus, theories of aqueous solvation for these molecules are of great importance. However, water is a complex solvent whose properties are still not completely understood. Statistical mechanical integral equation theories predict the density distribution of water molecules around a solute so that all particles are fully represented and thus potentially both molecular and macroscopic properties are included. Here we discuss how several theoretical tools we have developed have been integrated into an integral equation theory designed for globular macromolecular solutes such as proteins. Our approach predicts the three-dimensional spatial and orientational distribution of water molecules around a solute. Beginning with a three-dimensional Ornstein-Zernike equation, a separation is made between a reference part dependent only on the spatial distribution of solvent and a perturbation part dependent also on the orientational distribution of solvent. The spatial part is treated at a molecular level by a modified hypernetted chain closure whereas the orientational part is treated as a Boltzmann prefactor using a quasi-continuum theory we developed for solvation of simple ions. A potential energy function for water molecules is also needed and the sticky dipole models of water, such as our recently developed soft-sticky dipole (SSD) model, are ideal for the proposed separation. Moreover, SSD water is as good as or better than three point models typically used for simulations of biological macromolecules in structural, dielectric and dynamics properties and yet is seven times faster in Monte Carlo and four times faster in molecular dynamics simulations. Since our integral equation theory accurately predicts results from Monte Carlo simulations for solvation of a variety of test cases from a single water or ion to ice-like clusters and ion pairs, the application of this theory to biological macromolecules is promising.

Journal Article↗

PubMed2002

Changes in calcium signaling during postembryonic dendritic growth in Manduca sexta.

Activity-dependent Ca(2+) influx plays crucial roles in adult and developing nervous systems through its influence on signal processing, synaptic plasticity, and neuronal differentiation. The responses to internal Ca(2+) elevations vary depending on the spatial distribution of Ca(2+) accumulation in different cell compartments. In this study, the mechanisms and the distribution of Ca(2+) accumulation are addressed by in situ Ca(2+) imaging of an identified insect motoneuron, MN5, at critical stages of postembryonic life. During metamorphosis of Manduca sexta, MN5 undergoes extensive dendritic regression followed by regrowth. The time course, amplitude, and distribution of Ca(2+) accumulation within MN5 change during development. During the initial stage of rapid dendritic growth and branching, dendritic growth cones are present, and voltage-dependent Ca(2+) currents are small. At this stage, activity-induced elevations of internal Ca(2+) are largest in the distal dendrites, suggesting that the density of voltage-gated Ca(2+) channels is highest in these regions. Later phases of dendritic growth are accompanied by the transient occurrence of prominent Ca(2+) spikes. Single Ca(2+) spikes cause robust Ca(2+) influx of similar amplitudes and time courses in all central compartments of MN5. The resting Ca(2+) levels also increase during development. Ca(2+)-induced Ca(2+) release from intracellular stores did not contribute to the elevations measured at either stage, although Ca(2+) stores are present in the dendrites. These developmental changes of the internal Ca(2+) signaling are consistent with a regulatory role for activity-dependent Ca(2+) influx in postembryonic dendritic growth.

Action Potentials↗

PubMed1990

Binocularity in the little owl, Athene noctua. II. Properties of visually evoked potentials from the Wulst in response to monocular and binocular stimulation with sine wave gratings.

Visually evoked potentials (VEPs) have been recorded from the Wulst surface of the little owl, Athene noctua, in response to counterphase-reversal of sinusoidal gratings with different contrast, spatial frequency and mean luminance, presented either monocularly or binocularly. Monocular full-field stimuli presented to either eye evoked VEPs of similar amplitude, waveform and latency. Under binocular viewing, VEPs approximately doubled in amplitude without waveform changes. VEPs with similar characteristics could be obtained in response to stimulation of the contralateral, but not ipsilateral, hemifield. These results suggest that a 50% recrossing occurs in thalamic efferents and that different ipsilateral and contralateral regions converge onto the same Wulst sites. The VEP amplitude progressively decreased with increase of the spatial frequency beyond 2 cycles/degree, and the high spatial frequency cut-off (VEP acuity) was under binocular viewing (8 cycles/degree) higher than under monocular (5 cycles/degree) viewing (200 cd/m2, 45% contrast). The VEP acuity increased with increase in the contrast and decreased with reduction of the mean luminance. The binocular gain in both VEP amplitude and VEP acuity was largest at the lowest luminance levels. Binocular VEP summation occurred in the medium-high contrast range. With decreased contrast, both monocular and binocular VEPs progressively decreased in amplitude and tended to the same contrast threshold. The VEP contrast threshold depended on the spatial frequency (0.6-1.8% in the range 0.12-2 cycles/degree). Binocular VEPs often showed facilitatory interaction (binocular/monocular amplitude ratio greater than 2), but the binocular VEP amplitude did not change either by changing the stimulus orientation (horizontal vs. vertical gratings) or by inducing different retinal disparities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Effect of positive and negative defocus on contrast sensitivity in myopes and non-myopes.

This study investigated the effect of lens induced defocus on the contrast sensitivity function in myopes and non-myopes. Contrast sensitivity for up to 20 spatial frequencies ranging from 1 to 20 c/deg was measured with vertical sine wave gratings under cycloplegia at different levels of positive and negative defocus in myopes and non-myopes. In non-myopes the reduction in contrast sensitivity increased in a systematic fashion as the amount of defocus increased. This reduction was similar for positive and negative lenses of the same power (p = 0.474). Myopes showed a contrast sensitivity loss that was significantly greater with positive defocus compared to negative defocus (p = 0.001). The magnitude of the contrast sensitivity loss was also dependent on the spatial frequency tested for both positive and negative defocus. There was significantly greater contrast sensitivity loss in non-myopes than in myopes at low-medium spatial frequencies (1-8 c/deg) with negative defocus. Latent accommodation was ruled out as a contributor to this difference in myopes and non-myopes. In another experiment, ocular aberrations were measured under cycloplegia using a Shack-Hartmann aberrometer. Modulation transfer functions were calculated using the second order term for defocus as well as the fourth order Zernike term for spherical aberration. The theoretical maximal contrast sensitivity based on aberration data predicted the measured asymmetry in contrast sensitivity to positive and negative defocus that was observed in myopic subjects. The observed asymmetry in contrast sensitivity with positive and negative defocus in myopes may be linked to the altered accommodative response observed in this group.

Accommodation, Ocular↗