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Stem cells: from epigenetics to microRNAs.

The complexity and cellular diversity of the adult brain arises from the proliferation and differentiation of a small number of stem cells. The intrinsic state of stem cells depends on their spatial and temporal history and affects their responsiveness to extrinsic signals from the microenvironment. Stem cell self-renewal and differentiation along neuronal and glial lineages are defined by the dynamic interplay between transcription, epigenetic control, and posttranscriptional regulators, including microRNAs, whose key role in stem cell biology is just emerging.

Animals↗

High binaural coherence determines successful sound localization and increased activity in posterior auditory areas.

Our brain continuously receives complex combinations of sounds originating from different sources and relating to different events in the external world. Timing differences between the two ears can be used to localize sounds in space, but only when the inputs to the two ears have similar spectrotemporal profiles (high binaural coherence). We used fMRI to investigate any modulation of auditory responses by binaural coherence. We assessed how processing of these cues depends on whether spatial information is task relevant and whether brain activity correlates with subjects' localization performance. We found that activity in Heschl's gyrus increased with increasing coherence, irrespective of whether localization was task relevant. Posterior auditory regions also showed increased activity for high coherence, primarily when sound localization was required and subjects successfully localized sounds. We conclude that binaural coherence cues are processed throughout the auditory cortex and that these cues are used in posterior regions for successful auditory localization.

Acoustic Stimulation↗

Hippocampal c-fos is necessary for long-term memory of a socially transmitted food preference.

The present article examined the requirement of hippocampal c-Fos for learning a socially transmitted food preference (STFP). We reported previously that expression of the c-Fos protein is increased in the dorsal and ventral hippocampus of rats trained on the STFP (Countryman, Orlowski, Brightwell, Oskowitz, & Colombo, 2005). Pretraining intrahippocampal antisense to the immediate early gene c-fos was administered to adult male Long-Evans rats to determine if c-fos expression is necessary for either short- or long-term memory for STFP. Guide cannulae were implanted bilaterally into the dorsal hippocampus. Antisense oligodeoxynucleotides (ODNs) were administered unilaterally either 6.5, 8.5, 10.5, or 12.5 h prior to STFP training while either sense ODNs or saline were infused into the opposite hemisphere. Immunocytochemistry was performed, and cells showing c-Fos immunoreactivity (ir) were counted from the antisense-treated hemisphere and compared to cell counts from the control hemisphere. The results indicated significant suppression of learning-induced c-Fos protein at the 8.5 and 10.5 infusion-train intervals. Additional rats were implanted with cannulae into the dorsal and ventral hippocampus, and antisense ODNs, sense ODNs, or saline were administered bilaterally 8.5h prior to training. Rats were tested immediately and 14 days after training. Rats in all groups showed a significant preference for the demonstrated food at the short-term memory test. At the long-term memory test, however, rats infused with c-fos antisense showed no preference for the demonstrated food whereas rats infused with either sense or saline maintained their preference. The present findings suggest that c-fos is necessary for consolidation of non-spatial hippocampal-dependent memory.

Animals↗

Wistar rats show episodic-like memory for unique experiences.

Human episodic memory refers to the recollection of an unique past experience in terms of its details, its locale, and temporal occurrence. Episodic memory, even in principle, has been difficult to demonstrate in non-verbal mammals. Previously, we provided evidence that mice are able to form an integrated memory for "what," "where," and "when" aspects of single experiences by combining different versions of the novelty-preference paradigm, i.e., object recognition memory, the memory for locations in which objects were explored, and the temporal order memory for objects presented at distinct time points. In the present series of experiments we evaluated whether this paradigm, with minor modifications, also works with rats. We found that rats spent more time exploring an "old familiar" object relative to a "recent familiar" object, suggesting that they recognized objects previously explored during separate trials and remembered their order of presentation. Concurrently, the rats responded differentially to spatial object displacement dependent on whether an "old familiar" or "recent familiar" object was shifted to a location, where it was not encountered previously. These results provide strong evidence that the rats established an integrated memory for "what," "where," and "when." We also found that acute stress impaired the animal's performance in the episodic-like memory task, which, however, could be partially reversed by the N-Methyl-D-aspartate-receptors agonist D-cycloserine.

Animals↗

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain.

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.

Analysis of Variance↗

Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane.

Memantine and neramexane are noncompetitive NMDA receptor antagonists which have been investigated for their promising effects in aiding memory in people with dementia. Memantine is approved for the treatment of Alzheimer's disease, and neramexane is currently under development for this indication. Therefore, the present study provided a comparative assessment of the effects of equimolar doses of memantine and neramexane on spatial (hippocampus-dependent) memory. Adult male rats were given only 3 training trials to learn the location of a hidden platform in a water maze. In control (vehicle-injected) rats, this minimal amount of training produced intact short-term (15 min), but poor long-term (24 h), memory. Pre-training administration of memantine or neramexane produced a dose-dependent enhancement of long-term memory. Pharmacokinetic experiments with equimolar doses of both agents indicated that lower plasma levels of neramexane were more effective than memantine at enhancing memory. The effective doses of both agents in the current study produced plasma levels (and extrapolated brain CSF levels) within a range of activity at NMDA receptors and plasma levels seen in patients with Alzheimer's disease. These findings provide support for the use of neramexane as a pharmacological intervention in the treatment of dementia.

Alzheimer Disease↗

Chromatic induction from S-cone patterns.

Chromatic induction from patterned backgrounds depends on the spatial as well as the chromatic aspects of the background light. Color appearance with patterned and uniform backgrounds was compared using chromaticities distinguished by only the S cones; all backgrounds were equivalent to equal-energy white in terms of L-cone and M-cone stimulation. The measurements showed larger shifts in color appearance with a patterned chromatic background than with a uniform background at any chromaticity within the pattern. The measurements also showed that inducing light within different spatial regions could cause opposite shifts in color appearance: inducing light near a test field shifted appearance toward the inducing chromaticity (assimilation), while the same light some distance from the test shifted appearance away from the inducing chromaticity (simultaneous contrast). The shifts in color appearance were accounted for by a neural receptive field with S-cone spatial antagonism.

Color Perception↗

Chromatic assimilation: spread light or neural mechanism?

Chromatic assimilation is the shift in color appearance of a test field toward the appearance of nearby light. Possible explanations of chromatic assimilation include wavelength independent spread light, wavelength-dependent chromatic aberration and neural summation. This study evaluated these explanations by measuring chromatic assimilation from a concentric-ring pattern into an equal-energy-white background, as a function of the inducing rings' width, separation, chromaticity and luminance. The measurements showed, in the s direction, that assimilation was observed with different inducing-ring widths and separations when the inducing luminance was lower or higher than the test luminance. In general, the thinner the inducing rings and the smaller their separation, the stronger the assimilation in s. In the l direction, either assimilation or contrast was observed, depending on the ring width, separation and luminance. Overall, the measured assimilation could not be accounted for by the joint contributions from wavelength-independent spread light and wavelength-dependent chromatic aberration. Spatial averaging of neural signals explained the assimilation in s reasonably well, but there were clear deviations from neural spatial averaging for the l direction.

Adult↗

What is the signal in noise?

Visual perception is limited by both the strength of the neural signals, and by the noise in the visual nervous system; however, little is known about what aspects of the input noise the human visual system is sensitive to, i.e., what is the signal in noise? In order to investigate this question we asked observers to discriminate differences in the strength of one-dimensional white noise. We measured their response consistency and classification images and compared the results with an ideal energy detector. Our results and modelling show that discrimination of noise is limited by the observer's template (i.e., the weighted combination of energy in each stimulus component) plus higher order nonlinearities (systematic noise), and by sources of random internal noise. We found that systematic noise is present only near detection threshold. Surprisingly, we found that the human template is "adaptive"-- its shape depends on the spatial frequency band of the noise-suggesting that sensitivity to spatial noise is not simply determined via passive filtering.

Discrimination, Psychological↗

The perceived contrast of texture patches embedded in natural images.

The visibility of an isolated simple stimulus is known to depend on its contrast. However, when such a stimulus is surrounded by other geometrically-simple stimuli, its perceived contrast can change markedly. Here, we examined whether such effects contribute to our perception of contrasts when we view real world scenes. We show that the perceived contrast of a luminance texture patch is suppressed when it is surrounded by images of real world scenes. We also show that the amount of this suppression depends on the spatial statistics of the surrounding images. We manipulated the second-order statistics of the images and found minimal suppression of perceived contrast at "un-natural" image statistics and maximal suppression at the characteristic statistics of natural images. This suggests that contrast gain control mechanisms in our visual system are optimally engaged when we view real world images.

Contrast Sensitivity↗

The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis.

The exocrine pancreas synthesizes and secretes large amounts of digestive proteases as inactive precursor zymogens. Under physiological conditions a variety of cellular defense mechanisms protect the pancreatic acinar cell against a premature and intracellular activation of these zymogens. When these defenses fail, pancreatic autodigestion is initiated and acute pancreatitis can develop. A number of experimental observations suggest that extra- as well as intracellular calcium concentrations play an important part in the initiation of pancreatic protease activation, but the intracellular signaling events that regulate this process are unknown. Using a model system in which we used pancreatic acini (freshly prepared functional units of living acinar cells), we were able to simulate the conditions found during experimental pancreatitis in rodents. By means of a cell permeant fluorescent trypsin substrate we could demonstrate in these acini that premature protease activation is initiated at the apical acinar cell pole and occurs only in the presence of secretagogue concentrations that exceed those required for a maximum secretory response. By combining this technique with fluorescence ratio imaging for the Ca(2+)-sensitive dye fura-2, we could further show that this protease activation is highly dependent on the spatial as well as the temporal distribution of the corresponding Ca(2+) release from stores within the same subcellular compartment and that it is not propagated to neighboring acinar cells.

Animals↗

Plant K+ channel alpha-subunits assemble indiscriminately.

In plants a large diversity of inwardly rectifying K+ channels (K(in) channels) has been observed between tissues and species. However, only three different types of voltage-dependent plant K+ uptake channel subfamilies have been cloned so far; they relate either to KAT1, AKT1, or AtKC1. To explore the mechanisms underlying the channel diversity, we investigated the assembly of plant inwardly rectifying alpha-subunits. cRNA encoding five different K+ channel alpha-subunits of the three subfamilies (KAT1, KST1, AKT1, SKT1, and AtKC1) which were isolated from different tissues, species, and plant families (Arabidopsis thaliana and Solanum tuberosum) was reciprocally co-injected into Xenopus oocytes. We identified plant K+ channels as multimers. Moreover, using K+ channel mutants expressing different sensitivities to voltage, Cs+, Ca2+, and H+, we could prove heteromers on the basis of their altered voltage and modulator susceptibility. We discovered that, in contrast to animal K+ channel alpha-subunits, functional aggregates of plant K(in) channel alpha-subunits assembled indiscriminately. Interestingly, AKT-type channels from A. thaliana and S. tuberosum, which as homomers were electrically silent in oocytes after co-expression, mediated K+ currents. Our findings suggest that K+ channel diversity in plants results from nonselective heteromerization of different alpha-subunits, and thus depends on the spatial segregation of individual alpha-subunit pools and the degree of temporal overlap and kinetics of expression.

Arabidopsis Proteins↗

Theory for ligand rebinding at cell membrane surfaces.

Conditions for which a ligand reversibly bound to a cell surface dissociates and then rebinds to the surface have been theoretically examined. The coupled differential equations that describe reaction at the interface between sites on a plane and three-dimensional solution have been described previously (Thompson, N. L., T. P. Burghardt, and D. Axelrod. 1981. Biophys. J. 33:435-454). Here, we use this theoretical formalism to provide an analytical solution for the spatial and temporal dependence of the probabilities of finding a molecule on the surface or in the solution, given initial placement on the surface at the origin. This general analytical solution is used to derive a simple expression for the probability that a molecule rebinds to the surface at a given position and time after release at the origin and time zero. The probability expressions provide fundamental equations that form a basis for subsequent modeling of ligand-receptor interactions in specific geometries.

Binding Sites↗

Dynamics of carbohydrate residues of alpha 1-acid glycoprotein (orosomucoid) followed by red-edge excitation spectra and emission anisotropy studies of Calcofluor White.

Dynamics studies on Calcofluor White bound to the carbohydrate residues of sialylated and asialylated alpha 1-acid glycoprotein (orosomucoid) have been performed. The interaction between the fluorophore and the protein was found to occur preferentially with the glycan residues with a dependence on their spatial conformation. In the presence of sialylated alpha 1-acid glycoprotein, excitation at the red edge of the absorption spectrum of calcofluor does not lead to a shift in the fluorescence emission maximum (440 nm) of the fluorophore. Thus, the emission of calcofluor occurs from a relaxed state. This is confirmed by anisotropy studies as a function of temperature (Perrin plot). In the presence of asialylated alpha 1-acid glycoprotein, red-edge excitation spectra show an important shift (8 nm) of the fluorescence emission maximum of the probe. This reveals that emission of calcofluor occurs before relaxation of the surrounding carbohydrate residues occurs. Emission from a non-relaxed state means that Calcofluor molecules are bound tightly to the carbohydrate residues, a result confirmed by anisotropy studies.

Benzenesulfonates↗

Turning the tables: language and spatial reasoning.

This paper investigates possible influences of the lexical resources of individual languages on the spatial organization and reasoning styles of their users. That there are such powerful and pervasive influences of language on thought is the thesis of the Whorf-Sapir linguistic relativity hypothesis which, after a lengthy period in intellectual limbo, has recently returned to prominence in the anthropological, linguistic, and psycholinguistic literatures. Our point of departure is an influential group of cross-linguistic studies that appear to show that spatial reasoning is strongly affected by the spatial lexicon in everyday use in a community (e.g. Brown, P., & Levinson, S. C. (1993). Linguistic and nonlinguistic coding of spatial arrays: explorations in Mayan cognition (Working Paper No. 24). Nijmegen: Cognitive Anthropology Research Group, Max Planck Institute for Psycholinguistics; Cognitive Linguistics 6 (1995) 33). Specifically, certain groups customarily use an externally referenced spatial-coordinate system to refer to nearby directions and positions ("to the north") whereas English speakers usually employ a viewer-perspective system ("to the left"). Prior findings and interpretations have been to the effect that users of these two types of spatial system solve rotation problems in different ways, reasoning strategies imposed by habitual use of the language-particular lexicons themselves. The present studies reproduce these different problem-solving strategies in speakers of a single language (English) by manipulating landmark cues, suggesting that language itself may not be the key causal factor in choice of spatial perspective. Prior evidence on rotation problem solution from infants (e.g. Acredolo, L.P. (1979). Laboratory versus home: the effect of environment on the 9-month-old infant's choice of spatial reference system. Developmental Psychology, 15 (6), 666-667) and from laboratory animals (e.g. Restle, F. (1975). Discrimination of cues in mazes: a resolution of the place-vs.-response question. Psychological Review, 64, 217-228) suggests a unified interpretation of the findings: creatures approach spatial problems differently depending on the availability and suitability of local landmark cues. The results are discussed in terms of the current debate on the relation of language to thought, with particular emphasis on the question of why different cultural communities favor different perspectives in talking about space.

Adult↗

Electrocardiographic effects of myocardial ischemia induced by atrial pacing in dogs with coronary stenosis. II. Comparison of S-T segment and QRS changes in dogs with left circumflex arterial narrowing.

The effects of tachycardia on the QRS complex in the absence and in the presence of coronary arterial constriction are of possible clinical significance. To study the spatial and temporal distributions of these effects, a canine model simulating progressive coronary occlusion was studied. Tachycardia was induced by atrial pacing, coronary narrowing was produced by implantation of an ameroid constrictor about the left circumflex coronary artery and electrocardiographic effects were studied by isopotential mapping techniques at rates of up to 250 beats per minute, one to three weeks after constrictor implant. In five dogs. pacing without coronary constriction demonstrated the spatial and temporal dependence of QRS changes; tachycardia-induced changes varied from one torso site to another at any instant, and from one moment to another at any one torso location. Patterns in ten dogs with constrictors were dependent upon time after ameroid placement. Resting QRS and S-T segment distributions remained unchanged. One week after surgery, QRS and S-T segment patterns during pacing were as in controls. Two weeks after surgery, QRS patterns were as in controls but flat S-T segment depression resulted at high rates. After three weeks, QRS patterns during pacing were abnormal and S-T segment depression was observed. At each of the later times, the QRS response was similar at rates which did and which did not cause S-T depression. Thus, the effects of tachycardia on excitation and recovery forces in the presence of restricted coronary flow are independent of one another. This suggests that the two responses to ischemia may be due to different basic mechanisms and, hence, that their detection may reflect different myocardial abnormalities.

Animals↗

Effects of macroalgal mats on intertidal sandflats: an experimental study.

The growth of green macroalgal mats is becoming increasingly common in many marine intertidal habitats. While the ecological effects of such growth has previously been experimentally investigated on mudflats, such experiments have rarely been performed on intertidal sandflats. This study investigated the ecological effects of macroalgal cover on a moderately exposed intertidal sandflat, Drum Sands, Firth of Forth, Scotland. Artificially implanted Enteromorpha prolifera (Müller) caused marked changes in the macrobenthos, together with significant changes in all the measured sediment variables. After 6 weeks, the weed significantly increased the macrofaunal diversity. The numbers of Pygospio elegans (Claparède) were significantly reduced under weed mats, while those of Capitella capitata (Fabricius), oligochaetes and gammarids increased. Percent water, organics and silt/clay contents, medium phi and sorting coefficient significantly increased in the sediments under weed mats which also became significantly more reduced between 1 and 8 cm depth. After 20 weeks, a macrofaunal community numerically dominated by C. capitata, with a significantly reduced diversity, was present under weed mats, while sediment variables were no longer significantly different from controls. The negative effect of E. prolifera on P. elegans was mainly due to larval filtering, suggesting that weed is likely to have detrimental effects on population maintenance of most species which rely on planktonic larval recruitment. These results are broadly similar to those obtained from algal manipulation experiments performed in much more sheltered, muddier environments. We suggest that a predictable deterioration in environmental quality results from the growth of macroalgal mats in soft-bottom habitats. However, the longer term effects of such algal growth are less predictable and depend upon the spatial distributions of the most abundant infaunal species and the spatial heterogeneity of weed mat establishment.

Journal Article↗

Alteration of cardiovascular and neuronal function in M1 knockout mice.

We used gene targeting to generate mice lacking the M1 muscarinic acetylcholine receptor. These mice exhibit a decreased susceptibility to pilocarpine-induced seizures, loss of regulation of M-current potassium channel activity and of a specific calcium channel pathway in sympathetic neurons, a loss of the positive chronotropic and inotropic responses to the novel muscarinic agonist McN-A-343, and impaired learning in a hippocampal-dependent test of spatial memory.

Animals↗