Place Cell Rate Remapping by CA3 Recurrent Collaterals

Episodic-like memory is thought to be supported by attractor dynamics in the hippocampus. A possible neural substrate for this memory mechanism is rate remapping, in which the spatial map of place cells encodes contextual information through firing rate variability. To test whether memories are stored as multimodal attractors in populations of place cells, recent experiments morphed one familiar context into another while observing the responses of CA3 cell ensembles. Average population activity in CA3 was reported to transition gradually rather than abruptly from one familiar context to the next, suggesting a lack of attractive forces associated with the two stored representations. On the other hand, individual CA3 cells showed a mix of gradual and abrupt transitions at different points along the morph sequence, and some displayed hysteresis which is a signature of attractor dynamics. To understand whether these seemingly conflicting results are commensurate with attractor network theory, we developed a neural network model of the CA3 with attractors for both position and discrete contexts. We found that for memories stored in overlapping neural ensembles within a single spatial map, position-dependent context attractors made transitions at different points along the morph sequence. Smooth transition curves arose from averaging across the population, while a heterogeneous set of responses was observed on the single unit level. In contrast, orthogonal memories led to abrupt and coherent transitions on both population and single unit levels as experimentally observed when remapping between two independent spatial maps. Strong recurrent feedback entailed a hysteretic effect on the network which diminished with the amount of overlap in the stored memories. These results suggest that context-dependent memory can be supported by overlapping local attractors within a spatial map of CA3 place cells. Similar mechanisms for context-dependent memory may also be found in other regions of the cerebral cortex.     

The Biological Records Centre–a data centre

The Biological Records Centre collects data on the occurrence of species at a particular time in a particular place. These data are used for the preparation of distribution maps, for lists of species from localities, and lists of localities for species.
The unit of recording at the national level is the 10 km square: from each square a list as complete as possible is collected. For common species presence alone is sufficient, but for rare or critical species more detailed data on locality and source are required.
Mapping data are stored on magnetic tape from which 80-column cards are generated by computer. These cards prepare distribution maps on an electric typewriter through a card reader. Details of locality, habitat, etc. are stored on two sets of 80-column individual record cards, one stored by species and the other by localities.
The Centre is encouraging the collection of data in counties, where the 2times2 km square is used, and for Europe where the 50 times 50 km square is proposed. It is important to establish not only biological records centres but a complete biological recording network.     

Functional connectivity models for decoding of spatial representations from hippocampal CA1 recordings

Hippocampus stores spatial representations, or maps, which are recalled each time a subject is placed in the corresponding environment. Across different environments of similar geometry, these representations show strong orthogonality in CA3 of hippocampus, whereas in the CA1 subfield a considerable overlap between the maps can be seen. The lower orthogonality decreases reliability of various decoders developed in an attempt to identify which of the stored maps is active at the moment. Especially, the problem with decoding emerges with a need to analyze data at high temporal resolution. Here, we introduce a functional-connectivity-based decoder, which accounts for the pairwise correlations between the spiking activities of neurons in each map and does not require any positional information, i.e. any knowledge about place fields. We first show, on recordings of hippocampal activity in constant environmental conditions, that our decoder outperforms existing decoding methods in CA1. Our decoder is then applied to data from teleportation experiments, in which an instantaneous switch between the environment identity triggers a recall of the corresponding spatial representation . We test the sensitivity of our approach on the transition dynamics between the respective memory states (maps). We find that the rate of spontaneous state shifts (flickering) after a teleportation event is increased not only within the first few seconds as already reported, but this instability is sustained across much longer (> 1 min.) periods.     

Aber Lenken Sie Auch? (But do they also guide?)

One of the most intriguing problems in developmental neurobiology is that of how growing axons find the correct way to their proper target cells. Often axonal connections are organized in topographic maps, where neighboring cells of the projecting area are connected to neighboring cells in the target area, thus allowing a faithful transfer of positionally stored information from one area to another. The retinotectal projection is the classical model system for studying topographic projections.     

Transmembrane chloride flux is required for target cell lysis but not for Golgi reorientation in cloned cytolytic effector cells. Golgi reorientation, N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester serine esterase release, and delivery of the lethal hit are separable events in target cell lysis

Cell-mediated cytotoxicity can be inhibited by the replacement of chloride with ions that are incapable of passing through chloride channels or by the presence of stilbene disulfonate derivatives known to interfere with chloride flux. We show that the stilbene disulfonate (4,4-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) inhibits lysis of YAC-1 targets by the cloned cell line NKB61A2. Inhibition of lysis occurs on the level of the effector cell inasmuch as preincubation of effectors but not of targets interferes with subsequent lysis. Moreover, inhibition of chloride flux in the target does not interfere with target cell lysis by cytotoxic granules isolated from killer cells. Target cell binding takes place in the presence of DIDS or absence of external chloride, suggesting that events that follow target cell binding require chloride flux. We show that reorientation of the Golgi apparatus, which occurs subsequent to target cell binding in the effector cell, occurs under conditions that interfere with chloride flux. It is therefore suggested that events in the effector cell taking place subsequent to the Golgi apparatus reorientation reaction are inhibited and that delivery of the lethal hit is a stimulus-induced secretory event that requires transmembrane chloride flux. Delivery of the lethal hit is shown to be independent of the release of N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT) serine esterase, suggesting that cytolytic components and BLT serine esterase are likely packaged in different vesicles.     

A Comparison of Postmigration and Migration-Coupled Mismatch Correction Mechanisms for Branch Migration-Mediated Gene Conversion

We examine several models for nonreciprocal recombination based on the formation of heteroduplex DNA by bidirectional branch migration. We show that the consistency of genetic maps resulting from postmigration mismatch correction is disrupted by the presence of a favored site for initiation of strand exchange, with local inversion of the genetic and physical maps a predicted consequence. We also examine models that allow mismatch correction to take place concurrently with the process of strand exchange and show that the genetic maps resulting from such migration-coupled conversions are substantially free of the anomalies expected of postmigration conversions.     

Mapping gold-labeled IgE receptors on mast cells by scanning electron microscopy: receptor distributions revealed by silver enhancement, backscattered electron imaging, and digital image analysis

Immunogold labeling and silver enhancement techniques are widely used to determine density and distribution of cell membrane receptors by light and transmission electron microscopy. However, these techniques have not been widely used for receptor detection by scanning electron microscopy. We used antigen- or protein A-conjugated colloidal gold particles, together with silver enhancement, sequential secondary and back-scattered electron imaging (SEI and BEI), and digital image processing, to explore cell surface distribution of IgE-receptor complexes on RBL-2H3 cells, a rat leukemia line that provides a model for the study of mucosal mast cells. Cells were first incubated with a monoclonal antidinitrophenol IgE (anti-DNP-IgE) that binds with high affinity to cell surface IgE receptors. The resulting IgE-receptor complexes were cross-linked either with the multivalent antigen, DNP-BSA-gold, or with a polyclonal anti-IgE antibody. Antibody-treated cells were labeled after fixation with protein A-gold. Fixed, gold-labeled cell monolayers were silver enhanced (or not), dehydrated, critical point-dried, and coated with gold-palladium (for SEI analysis) or carbon (for combined SEI/BEI analysis). They were observed in an Hitachi S800 SEM equipped with a field emission tip and a Robinson backscattered electron detector. An image processor (MegaVision 1024XM) digitized images directly from the S800 microscope at 500-1000 line resolution. Silver enhancement significantly improves detection of gold particles in both SEI and BEI modes of SEM. On gold-palladium-coated samples, 20-nm particles are resolved by SEI after enhancement. BEI resolves 15-nm particles without enhancement and 5- or 10-nm particles are resolved by BEI on silver-enhanced, carbon-coated samples. Neither BEI nor SEI alone can yield high resolution topographical maps of receptor distribution (BEI forms images on the basis of atomic number contrast which reveals gold but not surface features). Image analysis techniques were therefore introduced to digitize, enhance, and process BEI and SEI images of the same field of view. The resulting high-contrast, high-resolution images were superimposed, yielding well-resolved maps of the distribution of antigen-IgE-receptor complexes on the surface of RBL-2H3 mast cells. The maps are stored in digital form, as required for computer-based quantitative morphometric analyses. These techniques of silver enhancement, combined BEI/SEI imaging, and digital image analysis can be applied to analyze density and distribution of any gold-labeled ligand on its target cell.     

CTLs contain and use intracellular stores of FasL distinct from cytolytic granules

CTL lyse target cells through the release of cytolytic granule contents and cell surface expression of Fas ligand (FasL). Current models suggest that FasL is stored in cytolytic granules and that FasL cell surface expression would be subject to the same controls as degranulation. We demonstrate that murine CTLs undergo two waves of FasL cell surface expression after stimulation. The first wave is from a pre-existing pool of FasL, and the second wave requires new protein synthesis. Signaling for FasL expression appears to be finely tuned as a weak signal preferentially induced surface translocation of the stored FasL, whereas a strong signal preferentially triggered the expression of de novo synthesized FasL. The early FasL is differentially regulated from degranulation, as there were multiple circumstances whereby rapid FasL cell surface expression and FasL-dependent killing occurred in the absence of detectable degranulation. Furthermore, we found through confocal microscopy that stored FasL resides in vesicles distinct from cytolytic granules. Our data clearly show that CTL degranulation and FasL lytic mechanisms are fully independent with respect to stored component localization and regulation.     

Spatial cognition and neuro-mimetic navigation: a model of hippocampal place cell activity

 A computational model of hippocampal activity during spatial cognition and navigation tasks is presented. The spatial representation in our model of the rat hippocampus is built on-line during exploration via two processing streams. An allothetic vision-based representation is built by unsupervised Hebbian learning extracting spatio-temporal properties of the environment from visual input. An idiothetic representation is learned based on internal movement-related information provided by path integration. On the level of the hippocampus, allothetic and idiothetic representations are integrated to yield a stable representation of the environment by a population of localized overlapping CA3-CA1 place fields. The hippocampal spatial representation is used as a basis for goal-oriented spatial behavior. We focus on the neural pathway connecting the hippocampus to the nucleus accumbens. Place cells drive a population of locomotor action neurons in the nucleus accumbens. Reward-based learning is applied to map place cell activity into action cell activity. The ensemble action cell activity provides navigational maps to support spatial behavior. We present experimental results obtained with a mobile Khepera robot. Received: 02 July 1999 / Accepted in revised form: 20 March 2000     

Integrating the molecular and cellular basis of odor coding in the Drosophila antenna

We investigate how the molecular and cellular maps of the Drosophila olfactory system are integrated. A correspondence is established between individual odor receptors, neurons, and odors. We describe the expression of the Or22a and Or22b receptor genes, show localization to dendritic membranes, and find sexual dimorphism. Or22a maps to the ab3A neuron, which responds to ethyl butyrate. Analysis of a deletion mutant lacking Or22a, along with transgenic rescue experiments, confirms the mapping and demonstrates that an Or gene is required for olfactory function in vivo. Ectopic expression of Or47a in a mutant cell identifies the neuron from which it derives and its odor ligands. Ectopic expression in a wild-type cell shows that two receptors can function in a single cell. The ab3A neuron does not depend on normal odor receptor gene expression to navigate to its target in the CNS.     

KEGG: kyoto encyclopedia of genes and genomes

KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/).     

Spiking Neurons in a Hierarchical Self-Organizing Map Model Can Learn to Develop Spatial and Temporal Properties of Entorhinal Grid Cells and Hippocampal Place Cells

Medial entorhinal grid cells and hippocampal place cells provide neural correlates of spatial representation in the brain. A place cell typically fires whenever an animal is present in one or more spatial regions, or places, of an environment. A grid cell typically fires in multiple spatial regions that form a regular hexagonal grid structure extending throughout the environment. Different grid and place cells prefer spatially offset regions, with their firing fields increasing in size along the dorsoventral axes of the medial entorhinal cortex and hippocampus. The spacing between neighboring fields for a grid cell also increases along the dorsoventral axis. This article presents a neural model whose spiking neurons operate in a hierarchy of self-organizing maps, each obeying the same laws. This spiking GridPlaceMap model simulates how grid cells and place cells may develop. It responds to realistic rat navigational trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with one or more firing fields that match neurophysiological data about these cells and their development in juvenile rats. The place cells represent much larger spaces than the grid cells, which enable them to support navigational behaviors. Both self-organizing maps amplify and learn to categorize the most frequent and energetic co-occurrences of their inputs. The current results build upon a previous rate-based model of grid and place cell learning, and thus illustrate a general method for converting rate-based adaptive neural models, without the loss of any of their analog properties, into models whose cells obey spiking dynamics. New properties of the spiking GridPlaceMap model include the appearance of theta band modulation. The spiking model also opens a path for implementation in brain-emulating nanochips comprised of networks of noisy spiking neurons with multiple-level adaptive weights for controlling autonomous adaptive robots capable of spatial navigation.     

Fine-Grained,Local Maps and Coarse,Global Representations Support Human Spatial Working Memory

While sensory processes are tuned to particular features, such as an object''s specific location, color or orientation, visual working memory (vWM) is assumed to store information using representations, which generalize over a feature dimension. Additionally, current vWM models presume that different features or objects are stored independently. On the other hand, configurational effects, when observed, are supposed to mainly reflect encoding strategies. We show that the location of the target, relative to the display center and boundaries, and overall memory load influenced recall precision, indicating that, like sensory processes, capacity limited vWM resources are spatially tuned. When recalling one of three memory items the target distance from the display center was overestimated, similar to the error when only one item was memorized, but its distance from the memory items'' average position was underestimated, showing that not only individual memory items'' position, but also the global configuration of the memory array may be stored. Finally, presenting the non-target items at recall, consequently providing landmarks and configurational information, improved precision and accuracy of target recall. Similarly, when the non-target items were translated at recall, relative to their position in the initial display, a parallel displacement of the recalled target was observed. These findings suggest that fine-grained spatial information in vWM is represented in local maps whose resolution varies with distance from landmarks, such as the display center, while coarse representations are used to store the memory array configuration. Both these representations are updated at the time of recall.     

Hippocampal Remapping Is Constrained by Sparseness rather than Capacity

Grid cells in the medial entorhinal cortex encode space with firing fields that are arranged on the nodes of spatial hexagonal lattices. Potential candidates to read out the space information of this grid code and to combine it with other sensory cues are hippocampal place cells. In this paper, we investigate a population of grid cells providing feed-forward input to place cells. The capacity of the underlying synaptic transformation is determined by both spatial acuity and the number of different spatial environments that can be represented. The codes for different environments arise from phase shifts of the periodical entorhinal cortex patterns that induce a global remapping of hippocampal place fields, i.e., a new random assignment of place fields for each environment. If only a single environment is encoded, the grid code can be read out at high acuity with only few place cells. A surplus in place cells can be used to store a space code for more environments via remapping. The number of stored environments can be increased even more efficiently by stronger recurrent inhibition and by partitioning the place cell population such that learning affects only a small fraction of them in each environment. We find that the spatial decoding acuity is much more resilient to multiple remappings than the sparseness of the place code. Since the hippocampal place code is sparse, we thus conclude that the projection from grid cells to the place cells is not using its full capacity to transfer space information. Both populations may encode different aspects of space.     

Mechanistic approach to the problem of hybridization efficiency in fluorescent in situ hybridization

In fluorescent in situ hybridization (FISH), the efficiency of hybridization between the DNA probe and the rRNA has been related to the accessibility of the rRNA when ribosome content and cell permeability are not limiting. Published rRNA accessibility maps show that probe brightness is sensitive to the organism being hybridized and the exact location of the target site and, hence, it is highly unpredictable based on accessibility only. In this study, a model of FISH based on the thermodynamics of nucleic acid hybridization was developed. The model provides a mechanistic approach to calculate the affinity of the probe to the target site, which is defined as the overall Gibbs free energy change (DeltaG degrees overall) for a reaction scheme involving the DNA-rRNA and intramolecular DNA and rRNA interactions that take place during FISH. Probe data sets for the published accessibility maps and experiments targeting localized regions in the 16S rRNA of Escherichia coli were used to demonstrate that DeltaG degrees overall is a strong predictor of hybridization efficiency and superior to conventional estimates based on the dissociation temperature of the DNA/rRNA duplex. The use of the proposed model also allowed the development of mechanistic approaches to increase probe brightness, even in seemingly inaccessible regions of the 16S rRNA. Finally, a threshold DeltaG degrees overall of -13.0 kcal/mol was proposed as a goal in the design of FISH probes to maximize hybridization efficiency without compromising specificity.     

A recurrent network for landmark-based navigation

A new type of network is proposed that can be applied to landmark navigation. It solves the guidance task, that is, it finds a nonvisually marked location using knowledge concerning its spatial relation to other, visible landmarks. The path to the searched location is not disturbed if a landmark is not visible for some time. The network can also describe findings obtained by experiments with insects and rodents, where the position of the landmarks has been changed after training. In this net, recognition does not occur by searching for a match between a pattern seen and the same pattern being stored but by searching for a match between a pattern seen with a prediction calculated from different data. A simple extension allows a unique match of the landmarks seen with the items stored in memory. With this extension a recognition of the individual landmark is not necessary. A specific output unit of the network can be interpreted in such a way as to show properties of place cells found in vertebrates and the function of the network proposed here as to determine the input to a place cell. The model can explain the observation that a given place cell can also be active when the animal moves in a different environment. An extension is discussed of how the network could be exploited for recognition-triggered response that allows animals to follow fixed routes.     

Secretory lysosome biogenesis in cytotoxic T lymphocytes from normal and Chediak Higashi syndrome patients

The lytic proteins mediating target cell killing are stored in the lysosomes of activated cytotoxic T lymphocytes (CTL) and are secreted upon recognition of a target cell. These secretory lysosomes cannot be detected in resting T lymphocytes. Interaction of a resting cell with a target cell activates de novo formation of secretory lysosomes. CTL clones in culture mimic this behaviour, and so provide an ideal system for studying secretory lysosome biogenesis and maturation. In the genetic disease, Chediak Higashi syndrome (CHS), all lysosomes in the cells are enlarged and reduced in number compared with wild-type (WT) cells. We have used CTL from this disease to study secretory lysosome biogenesis and maturation. We show that at early stages after activation the secretory lysosomes are identical in WT and mutant cells, and that delivery of proteins to the secretory lysosome along the biosynthetic and endocytic pathways is normal in the mutant cells. With time, the lysosomes in the mutant cells aggregate, become larger and fewer in number and eventually form giant structures. Our results show that the initial steps of secretory lysosome formation are normal in CHS, but that the organelles subsequently fuse together during cell maturation to form the giant secretory lysosomes.     

Stable target-sensitive immunoliposomes.

Interaction of immunoliposomes composed of dioleoylphosphatidylethanolamine (DOPE) (80%), dioleoylphosphatidic acid (DOPA) (20%), and a small amount of specific antibody with Herpes Simplex virus (HSV) were studied by detecting the immune-dependent lysis of liposomes. DOPA was used as the principal stabilizer of the immunoliposomes. Antibodies conjugated with N-glutarylphosphatidylethanolamine or oxidized GM1 served as the target-specific ligands of immunoliposomes. These immunoliposomes (d = 160-180 nm) were stable for at least one month when stored at 4 degrees C. However, they undergo a rapid aggregation and lysis reaction in the presence of a membrane-bound target such as intact HSV virions. We have also employed epitope peptide-containing liposomes (target liposomes) to mimic the virus and showed that the immunoliposomes could be aggregated and lysed by the target liposomes in an antigen-dependent manner. Immunoliposome lysis could be accelerated by increasing the incubation temperature to 60-70 degrees C. No immunoliposome lysis was observed if the target liposomes were absent, indicating the prolonged stability of the immunoliposomes. Liposome lysis was always accompanied by liposome aggregation. However, the aggregation-induced liposome destabilization is unique to the HII phase-forming lipids such as DOPE. DOPC-containing immunoliposomes did not lyse despite the fact that massive liposome aggregation had taken place.     

One axon-multiple functions: Specificity of lateral inhibitory connections by large basket cells

The functional specificity of the projections of single large basket cells of the cat primary visual cortex was studied using novel analytical approaches. The distribution of the labelled axons and that of the target cells were three-dimensionally reconstructed and compared quantitatively to orientation, direction and ocular dominance maps obtained with the intrinsic signal optical imaging technique. Quantitative analysis was carried out (i) for the entire basket cell, (ii) separately, for local and distal projections of the axon and (iii) by dissecting the same axon into two projection fields at the first bifurcation. It was found that although the functional distributions (orientation, direction and ocular dominance) for the entire cell were multi-modal and broadly tuned, individual main branches of the same cell displayed highly specific topography. In the further analysis, 2-dimensional probability density estimates of the target cell distributions revealed clear clustering which may be important for local subfield antagonism. These findings provide support to the idea that the same basket cell mediates several specific receptive field operations depending on the location of the target somata in the functional maps.     

Malaria parasite clag3 genes determine channel-mediated nutrient uptake by infected red blood cells

Development of malaria parasites within vertebrate erythrocytes requires nutrient uptake at the host cell membrane. The plasmodial surface anion channel (PSAC) mediates this transport and is an antimalarial target, but its molecular basis is unknown. We report a parasite gene family responsible for PSAC activity. We used high-throughput screening for nutrient uptake inhibitors to identify a compound highly specific for channels from the Dd2 line of the human pathogen P. falciparum. Inheritance of this compound's affinity in a Dd2 × HB3 genetic cross maps to a single parasite locus on chromosome 3. DNA transfection and in vitro selections indicate that PSAC-inhibitor interactions are encoded by two clag3 genes previously assumed to function in cytoadherence. These genes are conserved in plasmodia, exhibit expression switching, and encode an integral protein on the host membrane, as predicted by functional studies. This protein increases host cell permeability to diverse solutes.