Cell groups reveal structure of stimulus space

An important task of the brain is to represent the outside world. It is unclear how the brain may do this, however, as it can only rely on neural responses and has no independent access to external stimuli in order to “decode” what those responses mean. We investigate what can be learned about a space of stimuli using only the action potentials (spikes) of cells with stereotyped—but unknown—receptive fields. Using hippocampal place cells as a model system, we show that one can (1) extract global features of the environment and (2) construct an accurate representation of space, up to an overall scale factor, that can be used to track the animal's position. Unlike previous approaches to reconstructing position from place cell activity, this information is derived without knowing place fields or any other functions relating neural responses to position. We find that simply knowing which groups of cells fire together reveals a surprising amount of structure in the underlying stimulus space; this may enable the brain to construct its own internal representations.     

Stochastic model of the overdispersion in the place cell discharge

The spontaneous firing activity of the place cells reflects the position of an experimental animal in its arena. The firing rate is high inside a part of the arena, called the firing field, and low outside. It is generally accepted concept that this is the way in which the hippocampus stores a map of the environment. This well known fact was recently reinvestigated [Fenton, A.A., Muller, R.U., 1998. Proc. Natl. Acad. Sci. USA 95, 3182-3187] and it was found that while the activity was highly reliable in position, it did not retain the same reliability in time. The number of action potentials fired during different passes through the firing field were substantially different (overdispersion). We present a mathematical model based on a doubly stochastic Poisson process which is able to reproduce the experimental findings. Further, it enables us to propose specific statistical inference on the experiments in aim to verify data and model compatibility. The model permits to speculate about the neural mechanisms leading to the overdispersion in the activity of the hippocampal place cells. Namely, the statistical variation of the intensity of firing can be achieved, for example, by introducing a hierarchical structure into the local neural network.     

A Kalman filtering approach to the representation of kinematic quantities by the hippocampal-entorhinal complex

Several regions of the brain which represent kinematic quantities are grouped under a single state-estimator framework. A theoretic effort is made to predict the activity of each cell population as a function of time using a simple state estimator (the Kalman filter). Three brain regions are considered in detail: the parietal cortex (reaching cells), the hippocampus (place cells and head-direction cells), and the entorhinal cortex (grid cells). For the reaching cell and place cell examples, we compute the perceived probability distributions of objects in the environment as a function of the observations. For the grid cell example, we show that the elastic behavior of the grids observed in experiments arises naturally from the Kalman filter. To our knowledge, the application of a tensor Kalman filter to grid cells is completely novel.     

Dissociation of exteroceptive and idiothetic orientation cues: effect on hippocampal place cells and place navigation.

Navigation by means of cognitive maps appears to require the hippocampus; hippocampal place cells (PCs) appear to store spatial memories because their discharge is confined to cell-specific places called firing fields (FFs). Experiments with rats manipulated idiothetic and landmark-related information to understand the relationship between PC activity and spatial cognition. Rotating a circular arena in the light caused a discrepancy between these cues. This discrepancy caused most FFs to disappear in both the arena and room reference frames. However, FFs persisted in the rotating arena frame when the discrepancy was reduced by darkness or by a card in the arena. The discrepancy was increased by ''field clamping'' the rat in a room-defined FF location by rotations that countered its locomotion. Most FFs dissipated and reappeared an hour or more after the clamp. Place-avoidance experiments showed that navigation uses independent idiothetic and exteroceptive memories. Rats learned to avoid the unmarked footshock region within a circular arena. When acquired on the stable arena in the light, the location of the punishment was learned by using both room and idiothetic cues; extinction in the dark transferred to the following session in the light. If, however, extinction occurred during rotation, only the arena-frame avoidance was extinguished in darkness; the room-defined location was avoided when the lights were turned back on. Idiothetic memory of room-defined avoidance was not formed during rotation in light; regardless of rotation, there was no avoidance when the lights were turned off, but room-frame avoidance reappeared when the lights were turned back on. The place-preference task rewarded visits to an allocentric target location with a randomly dispersed pellet. The resulting behaviour alternated between random pellet searching and target-directed navigation, making it possible to examine PC correlates of these two classes of spatial behaviour. The independence of idiothetic and exteroceptive spatial memories and the disruption of PC firing during rotation suggest that PCs may not be necessary for spatial cognition; this idea can be tested by recordings during the place-avoidance and preference tasks.     

Crayfish (Cherax destructor) use Tactile Cues to Detect and Learn Topographical Changes in Their Environment

When placed in a rectangular aquarium (arena) containing no objects, blindfolded freshwater crayfish ( Cherax destructor ) explore by walking along the walls of the arena. Animals taken from their home tanks and placed in the arena for a 40-min trial each day habituate and exhibit a reduction in their exploratory activity over 4 trials, despite their lack of continuous exposure to the arena. Dishabituation (i.e. an immediate increase in exploratory activity) occurs when animals were placed in the arena after the introduction of short partitions projecting at right angles from the walls. The dishabituation was interpreted as indicating that the animal can detect differences in the spatial configuration of the arena topography. Using dishabituation as a measure, we found that animals responded not only to the presence or absence of the partitions but also to changes in the position of the partitions. Animals with immobilized or lesioned second antennae no longer responded to configurational changes in the spatial arrangement of the partitions in the arena. We conclude that Cherax destructor relies upon the tactile input from its second antennae to detect topographical changes in the environment and that such topographical changes can be retained for at least 24 h. For an organism that forages in and defends a home territory on a daily basis, this seems to be an ecologically relevant time scale.     

Dynamic Grouping of Hippocampal Neural Activity During Cognitive Control of Two Spatial Frames

Cognitive control is the ability to coordinate multiple streams of information to prevent confusion and select appropriate behavioral responses, especially when presented with competing alternatives. Despite its theoretical and clinical significance, the neural mechanisms of cognitive control are poorly understood. Using a two-frame place avoidance task and partial hippocampal inactivation, we confirmed that intact hippocampal function is necessary for coordinating two streams of spatial information. Rats were placed on a continuously rotating arena and trained to organize their behavior according to two concurrently relevant spatial frames: one stationary, the other rotating. We then studied how information about locations in these two spatial frames is organized in the action potential discharge of ensembles of hippocampal cells. Both streams of information were represented in neuronal discharge—place cell activity was organized according to both spatial frames, but almost all cells preferentially represented locations in one of the two spatial frames. At any given time, most coactive cells tended to represent locations in the same spatial frame, reducing the risk of interference between the two information streams. An ensemble''s preference to represent locations in one or the other spatial frame alternated within a session, but at each moment, location in the more behaviorally relevant spatial frame was more likely to be represented. This discharge organized into transient groups of coactive neurons that fired together within 25 ms to represent locations in the same spatial frame. These findings show that dynamic grouping, the transient coactivation of neural subpopulations that represent the same stream of information, can coordinate representations of concurrent information streams and avoid confusion, demonstrating neural-ensemble correlates of cognitive control in hippocampus.     

Boundary coding in the rat subiculum

The spatial mapping function of the hippocampal formation is likely derived from two sets of information: one based on the external environment and the other based on self-motion. Here, we further characterize ‘boundary vector cells’ (BVCs) in the rat subiculum, which code space relative to one type of cue in the external environment: boundaries. We find that the majority of cells with fields near the perimeter of a walled environment exhibit an additional firing field when an upright barrier is inserted into the walled environment in a manner predicted by the BVC model. We use this property of field repetition as a heuristic measure to define BVCs, and characterize their spatial and temporal properties. In further tests, we find that subicular BVCs typically treat drop edges similarly to walls, including exhibiting field repetition when additional drop-type boundaries are added to the testing environment. In other words, BVCs treat both kinds of edge as environmental boundaries, despite their dissimilar sensory properties. Finally, we also report the existence of ‘boundary-off cells’, a new class of boundary-coding cells. These cells fire everywhere except where a given BVC might fire.     

The nuclear orphan receptor TR4 promotes proliferation of myeloid progenitor cells.

Nuclear receptors represent key regulators in cell proliferation, differentiation, and development. Here we demonstrate that the nuclear orphan receptor TR4 is highly expressed in hematopoietic cells and tissues and have analyzed the impact of TR4 in this cell compartment. We show that TR4, when ectopically expressed in bone marrow cells via retrovirus vector, promotes proliferation of myeloid progenitor cells. Cells represent promyelocytes as judged by morphological features, expression of cell surface molecules, and specific markers like Mim-1 and CAAT/enhancer binding protein beta. We also demonstrate that the growth promoting activity of TR4 is not exclusively dependent on its association with DNA, because expression of a mutated TR4 version devoid of its DNA binding domain exhibits a similar proliferative potential as wild-type TR4. In conclusion, these data position the orphan receptor TR4 as an important regulator of myeloid progenitor cell proliferation and development.     

The mechanism of rate remapping in the dentate gyrus

Rate remapping is a recently revealed neural code in which sensory information modulates the firing rate of hippocampal place cells. The mechanism underlying rate remapping is unknown. Its characteristic modulation, however, must arise from the interaction of the two major inputs to the hippocampus, the medial entorhinal cortex (MEC), in which grid cells represent the spatial position of the rat, and the lateral entorhinal cortex (LEC), in which cells represent the sensory properties of the environment. We have used computational methods to elucidate the mechanism by which this interaction produces rate remapping. We show that the convergence of LEC and MEC inputs, in conjunction with a competitive network process mediated by feedback inhibition, can account quantitatively for this phenomenon. The same principle accounts for why different place fields of the same cell vary independently as sensory information is altered. Our results show that rate remapping can be explained in terms of known mechanisms.     

Conjoint control of hippocampal place cell firing by two visual stimuli. I. The effects of moving the stimuli on firing field positions

To better understand how hippocampal place cell activity is controlled by sensory stimuli, and to further elucidate the nature of the environmental representation provided by place cells, we have made recordings in the presence of two distinct visual stimuli under standard conditions and after several manipulations of these stimuli. In line with a great deal of earlier work, we find that place cell activity is constant when repeated recordings are made in the standard conditions in which the centers of the two stimuli, a black card and a white card, are separated by 135 degrees on the wall of a cylindrical recording chamber. Rotating the two stimuli by 45 degrees causes equal rotations of place cell firing fields. Removing either card and rotating the other card also causes fields to rotate equally, showing that the two stimuli are individually salient. Increasing or decreasing the card separation (card reconfiguration) causes a topological distortion of the representation of the cylinder floor such that field centers move relative to each other. We also found that either kind of reconfiguration induces a position-independent decrease in the intensity of place cell firing. We argue that these results are not compatible with either of two previously stated views of the place cell representation; namely, a nonspatial theory in which each place cell is tuned to an arbitrarily selected subset of available stimuli or a rigid map theory. We propose that our results imply that the representation is map-like but not rigid; it is capable of undergoing stretches without altering the local arrangement of firing fields.     

Place memory in crickets

Certain insect species are known to relocate nest or food sites using landmarks, but the generality of this capability among insects, and whether insect place memory can be used in novel task settings, is not known. We tested the ability of crickets to use surrounding visual cues to relocate an invisible target in an analogue of the Morris water maze, a standard paradigm for spatial memory tests on rodents. Adult female Gryllus bimaculatus were released into an arena with a floor heated to an aversive temperature, with one hidden cool spot. Over 10 trials, the time taken to find the cool spot decreased significantly. The best performance was obtained when a natural scene was provided on the arena walls. Animals can relocate the position from novel starting points. When the scene is rotated, they preferentially approach the fictive target position corresponding to the rotation. We note that this navigational capability does not necessarily imply the animal has an internal spatial representation.     

A biologically inspired hierarchical goal directed navigation model

We propose an extended version of our previous goal directed navigation model based on forward planning of trajectories in a network of head direction cells, persistent spiking cells, grid cells, and place cells. In our original work the animat incrementally creates a place cell map by random exploration of a novel environment. After the exploration phase, the animat decides on its next movement direction towards a goal by probing linear look-ahead trajectories in several candidate directions while stationary and picking the one activating place cells representing the goal location. In this work we present several improvements over our previous model. We improve the range of linear look-ahead probes significantly by imposing a hierarchical structure on the place cell map consistent with the experimental findings of differences in the firing field size and spacing of grid cells recorded at different positions along the dorsal to ventral axis of entorhinal cortex. The new model represents the environment at different scales by populations of simulated hippocampal place cells with different firing field sizes. Among other advantages this model allows simultaneous constant duration linear look-ahead probes at different scales while significantly extending each probe range. The extension of the linear look-ahead probe range while keeping its duration constant also limits the degrading effects of noise accumulation in the network. We show the extended model’s performance using an animat in a large open field environment.     

Place cells, neocortex and spatial navigation: a short review

Hippocampal place cells are characterized by location-specific firing, that is each cell fires in a restricted region of the environment explored by the rat. In this review, we briefly examine the sensory information used by place cells to anchor their firing fields in space and show that, among the various sensory cues that can influence place cell activity, visual and motion-related cues are the most relevant. We then explore the contribution of several cortical areas to the generation of the place cell signal with an emphasis on the role of the visual cortex and parietal cortex. Finally, we address the functional significance of place cell activity and demonstrate the existence of a clear relationship between place cell positional activity and spatial navigation performance. We conclude that place cells, together with head direction cells, provide information useful for spatially guided movements, and thus provide a unique model of how spatial information is encoded in the brain.     

Dexamethasone selectively regulates the activity of enzymatic markers of cerebral endothelial cell lines

Summary Two endothelial cell lines were derived from grafts of the central nervous system using retrovirus mediated gene transfer to introduce the polyoma middle-T oncogene into fetal rat brain endothelial cells and transplantation of these cells into adult rat brain. In this report, we further characterize these cells and the effect of dexamethasone on the expression of specific enzymatic markers. These cells take up acetylated low density lipoprotein, leucine, and glucose, and express Factor VIII-related antigen, angiotensin converting enzyme, alkaline phosphatase, gamma-glutamyltranspeptidase, and as yet undescribed aminopeptidase A and B-like enzymes. When grown on semi-permeable membranes, these transformed cells do not spontaneously retain small hydrophilic molecules. In culture, one of the lines (EC 193) forms a confluent monolayer of spindle-shaped cells homogenously expressing gamma-glutamyltranspeptidase at a level comparable to primary cells. The other cell line (EC 219) grows as clusters of elongated cells, and gamma-glutamyltranspeptidase activity is expressed mainly in cells forming the clusters. This clustered pattern changes to a confluent one after culture on type-I collagen. Dexamethasone increases angiotensin-converting enzyme activity, and decreases the expression of gamma-glutamyltranspeptidase and aminopeptidase A, whereas the aminopeptidase B activity is little modified. Inhibition of aminopeptidase A activity by amastatin, potentiates angiotensin II effects on DNA synthesis. These results indicate that retrovirally transformed brain endothelial cells are a useful model for studying the blood-brain barrier in vitro and that dexamethasone, an agent with the potential to reduce brain edema, directly affects some blood-brain barrier properties in these endothelial cell lines.     

Estimating Location without External Cues

The ability to determine one''s location is fundamental to spatial navigation. Here, it is shown that localization is theoretically possible without the use of external cues, and without knowledge of initial position or orientation. With only error-prone self-motion estimates as input, a fully disoriented agent can, in principle, determine its location in familiar spaces with 1-fold rotational symmetry. Surprisingly, localization does not require the sensing of any external cue, including the boundary. The combination of self-motion estimates and an internal map of the arena provide enough information for localization. This stands in conflict with the supposition that 2D arenas are analogous to open fields. Using a rodent error model, it is shown that the localization performance which can be achieved is enough to initiate and maintain stable firing patterns like those of grid cells, starting from full disorientation. Successful localization was achieved when the rotational asymmetry was due to the external boundary, an interior barrier or a void space within an arena. Optimal localization performance was found to depend on arena shape, arena size, local and global rotational asymmetry, and the structure of the path taken during localization. Since allothetic cues including visual and boundary contact cues were not present, localization necessarily relied on the fusion of idiothetic self-motion cues and memory of the boundary. Implications for spatial navigation mechanisms are discussed, including possible relationships with place field overdispersion and hippocampal reverse replay. Based on these results, experiments are suggested to identify if and where information fusion occurs in the mammalian spatial memory system.     

A computational model of the hippocampus that represents environmental structure and goal location,and guides movement

Hippocampal place cells (PCs) are believed to represent environmental structure. However, it is unclear how and which brain regions represent goals and guide movements. Recently, another type of cells that fire around a goal was found in rat hippocampus (we designate these cells as goal place cells, GPCs). This suggests that the hippocampus is also involved in goal representation. Assuming that the activities of GPCs depend on the distance to a goal, we propose an adaptive navigation model. By monitoring the population activity of GPCs, the model navigates to shorten the distance to the goal. To achieve the distance-dependent activities of GPCs, plastic connections are assumed between PCs and GPCs, which are modified depending on two reward-triggered activities: activity propagation through PC–PC network representing the topological environmental structure, and the activity of GPCs with different durations. The former activity propagation is regarded as a computational interpretation of “reverse replay” phenomenon found in rat hippocampus. Simulation results confirm that after reaching a goal only once, the model can navigate to the goal along almost the shortest path from arbitrary places in the environment. This indicates that the hippocampus might play a primary role in the representation of not only the environmental structure but also the goal, in addition to guiding the movement. This navigation strategy using the population activity of GPCs is equivalent to the taxis strategy, the simplest and most basic for biological systems. Our model is unique because this simple strategy allows the model to follow the shortest path in the topological map of the environment.     

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.     

过表达蛋白激酶CβI亚类NRK细胞模型的建立和初步分析

本实验通过逆转录病毒载体pMV7将大鼠蛋白激酶c(Protein Kinase C,PKC)βⅠ亚类cDNA全长片段导入NRK细胞中,建立了一个过表达PKC-βⅠ亚类的NRK细胞模型,并对此细胞模型在佛波脂TPA进一步诱导激活PKC状态下的生长情况及与c-jun基因表达的相关性进行了初步观察。     

Preferential accumulation of mature NK cells during human immunosenescence.

The major histocompatibility complex-unrestricted, cell-mediated, constitutive anti-tumor cytotoxic function of natural killer cells is highly preserved in healthy elderly. A study of the dynamics of expression of natural killer cell-associated phenotypes during immunosenescence shows that selective, bidirectional, and disproportionate changes in certain natural killer cell subset number and ratio take place during aging. The mean natural killer cell subset ratio (%CD16+CD57+ over %CD56+CD57-) gradually increases from a young adult level of 0.7 to 4.6 with advancing age predominantly due to a tripling of %CD16+57+ cells as opposed to a moderate decrease (-54%) in %CD56+57- phenotype. The parallel increase in natural killer phenotype ratio and cytotoxic activity might represent a shift in the maturity status of these cells. Based on these findings, a model of natural killer cell immunosenescence is proposed. It is concluded that not all immunosenescent changes need be detrimental; some may even improve the potential for survival and represent an adaptational immunosenescent change.