How neurons migrate: a dynamic in-silico model of neuronal migration in the developing cortex.

BACKGROUND: Neuronal migration, the process by which neurons migrate from their place of origin to their final position in the brain, is a central process for normal brain development and function. Advances in experimental techniques have revealed much about many of the molecular components involved in this process. Notwithstanding these advances, how the molecular machinery works together to govern the migration process has yet to be fully understood. Here we present a computational model of neuronal migration, in which four key molecular entities, Lis1, DCX, Reelin and GABA, form a molecular program that mediates the migration process. RESULTS: The model simulated the dynamic migration process, consistent with in-vivo observations of morphological, cellular and population-level phenomena. Specifically, the model reproduced migration phases, cellular dynamics and population distributions that concur with experimental observations in normal neuronal development. We tested the model under reduced activity of Lis1 and DCX and found an aberrant development similar to observations in Lis1 and DCX silencing expression experiments. Analysis of the model gave rise to unforeseen insights that could guide future experimental study. Specifically: (1) the model revealed the possibility that under conditions of Lis1 reduced expression, neurons experience an oscillatory neuron-glial association prior to the multipolar stage; and (2) we hypothesized that observed morphology variations in rats and mice may be explained by a single difference in the way that Lis1 and DCX stimulate bipolar motility. From this we make the following predictions: (1) under reduced Lis1 and enhanced DCX expression, we predict a reduced bipolar migration in rats, and (2) under enhanced DCX expression in mice we predict a normal or a higher bipolar migration. CONCLUSIONS: We present here a system-wide computational model of neuronal migration that integrates theory and data within a precise, testable framework. Our model accounts for a range of observable behaviors and affords a computational framework to study aspects of neuronal migration as a complex process that is driven by a relatively simple molecular program. Analysis of the model generated new hypotheses and yet unobserved phenomena that may guide future experimental studies. This paper thus reports a first step toward a comprehensive in-silico model of neuronal migration.

Transcriptome of embryonic and neonatal mouse cortex by high-throughput RNA sequencing

Brain structure and function experience dramatic changes from embryonic to postnatal development. Microarray analyses have detected differential gene expression at different stages and in disease models, but gene expression information during early brain development is limited. We have generated >27 million reads to identify mRNAs from the mouse cortex for>16,000 genes at either embryonic day 18 (E18) or postnatal day 7 (P7), a period of significant synapto-genesis for neural circuit formation. In addition, we devised strategies to detect alternative splice forms and uncovered more splice variants. We observed differential expression of 3,758 genes between the 2 stages, many with known functions or predicted to be important for neural development. Neurogenesis-related genes, such as those encoding Sox4, Sox11, and zinc-finger proteins, were more highly expressed at E18 than at P7. In contrast, the genes encoding synaptic proteins such as synaptotagmin, complexin 2, and syntaxin were up-regulated from E18 to P7. We also found that several neurological disorder-related genes were highly expressed at E18. Our transcriptome analysis may serve as a blueprint for gene expression pattern and provide functional clues of previously unknown genes and disease-related genes during early brain development.

Sequence-Seeking and Counter Streams: A Model for Information Processing in the Cortex

This paper presents a model for the general flow in the neocortex. The basic process, called "sequence-seeking," is a search for a sequence of mappings or transformations, linking source and target representations. The search is bi-directional, "bottom-up" as well as "top-down," and it explores in parallel a large numbe rof alternative sequences. This operation is implemented in a structure termed "counter streams," in which multiple sequences are explored along two separate, complementary pathways which seeking to meet. The first part of the paper discusses the general sequence-seeking scheme and a number of related processes, such as the learning of successful sequences, context effects, and the use of "express lines" and partial matches. The second part discusses biological implications of the model in terms of connections within and between cortical areas. The model is compared with existing data, and a number of new predictions are proposed.

GABAA receptor chloride channels are involved in the neuroprotective role of GABA following oxygen and glucose deprivation in the rat cerebral cortex but not in the hippocampus.

Assays on "ex vivo" sections of rat hippocampus and rat cerebral cortex, subjected to oxygen and glucose deprivation (OGD) and a three-hour reperfusion-like (RL) recovery, were performed in the presence of either GABA or the GABA(A) receptor binding site antagonist, bicuculline. Lactate dehydrogenase (LDH) and propidium iodide were used to quantify cell mortality. We also measured, using real-time quantitative polymerase chain reaction (qPCR), the early transcriptional response of a number of genes of the glutamatergic and GABAergic systems. Specifically, glial pre- and post-synaptic glutamatergic transporters (namely GLAST1a, EAAC-1, GLT-1 and VGLUT1), three GABAA receptor subunits (α1, β2 and γ2), and the GABAergic presynaptic marker, glutamic acid decarboxylase (GAD65), were studied. Mortality assays revealed that GABAA receptor chloride channels play an important role in the neuroprotective effect of GABA in the cerebral cortex, but have a much smaller effect in the hippocampus. We also found that GABA reverses the OGD-dependent decrease in GABA(A) receptor transcript levels, as well as mRNA levels of the membrane and vesicular glutamate transporter genes. Based on the markers used, we conclude that OGD results in differential responses in the GABAergic presynaptic and postsynaptic systems.

How Does the Cerebral Cortex Work? Developement, Learning, Attention, and 3D Vision by Laminar Circuits of Visual Cortex

A key goal of behavioral and cognitive neuroscience is to link brain mechanisms to behavioral functions. The present article describes recent progress towards explaining how the visual cortex sees. Visual cortex, like many parts of perceptual and cognitive neocortex, is organized into six main layers of cells, as well as characteristic sub-lamina. Here it is proposed how these layered circuits help to realize the processes of developement, learning, perceptual grouping, attention, and 3D vision through a combination of bottom-up, horizontal, and top-down interactions. A key theme is that the mechanisms which enable developement and learning to occur in a stable way imply properties of adult behavior. These results thus begin to unify three fields: infant cortical developement, adult cortical neurophysiology and anatomy, and adult visual perception. The identified cortical mechanisms promise to generalize to explain how other perceptual and cognitive processes work.

Linking Visual Cortex to Visual Perception: An Alternative to the Gestalt Bubble

Lehar's lively discussion builds on a critique of neural models of vision that is incorrect in its general and specific claims. He espouses a Gestalt perceptual approach, rather than one consistent with the "objective neurophysiological state of the visual system" (p. 1). Contemporary vision models realize his perceptual goals and also quantitatively explain neurophysiological and anatomical data.

Temporal Dynamics of Decision-Making during Motion Perception in the Visual Cortex

How does the brain make decisions? Speed and accuracy of perceptual decisions covary with certainty in the input, and correlate with the rate of evidence accumulation in parietal and frontal cortical "decision neurons." A biophysically realistic model of interactions within and between Retina/LGN and cortical areas V1, MT, MST, and LIP, gated by basal ganglia, simulates dynamic properties of decision-making in response to ambiguous visual motion stimuli used by Newsome, Shadlen, and colleagues in their neurophysiological experiments. The model clarifies how brain circuits that solve the aperture problem interact with a recurrent competitive network with self-normalizing choice properties to carry out probablistic decisions in real time. Some scientists claim that perception and decision-making can be described using Bayesian inference or related general statistical ideas, that estimate the optimal interpretation of the stimulus given priors and likelihoods. However, such concepts do not propose the neocortical mechanisms that enable perception, and make decisions. The present model explains behavioral and neurophysiological decision-making data without an appeal to Bayesian concepts and, unlike other existing models of these data, generates perceptual representations and choice dynamics in response to the experimental visual stimuli. Quantitative model simulations include the time course of LIP neuronal dynamics, as well as behavioral accuracy and reaction time properties, during both correct and error trials at different levels of input ambiguity in both fixed duration and reaction time tasks. Model MT/MST interactions compute the global direction of random dot motion stimuli, while model LIP computes the stochastic perceptual decision that leads to a saccadic eye movement.

Target Selection by Frontal Cortex During Coordinated Saccadic and Smooth Pursuit Eye Movement

Oculomotor tracking of moving objects is an important component of visually based cognition and planning. Such tracking is achieved by a combination of saccades and smooth pursuit eye movements. In particular, the saccadic and smooth pursuit systems interact to often choose the same target, and to maximize its visibility through time. How do multiple brain regions interact, including frontal cortical areas, to decide the choice of a target among several competing moving stimuli? How is target selection information that is created by a bias (e.g., electrical stimulation) transferred from one movement system to another? These saccade-pursuit interactions are clarified by a new computational neural model, which describes interactions among motion processing areas MT, MST, FPA, DLPN; saccade specification, selection, and planning areas LIP, FEF, SNr, SC; the saccadic generator in the brain stem; and the cerebellum. Model simulations explain a broad range of neuroanatomical and neurophysiological data. These results are in contrast with the simplest parallel model with no interactions between saccades and pursuit than common-target selection and recruitment of shared motoneurons. Actual tracking episodes in primates reveal multiple systematic deviations from predictions of the simplest parallel model, which are explained by the current model.

Spiking Dynamics during Perceptual Grouping in the Laminar Circuits of Visual Cortex

Grouping of collinear boundary contours is a fundamental process during visual perception. Illusory contour completion vividly illustrates how stable perceptual boundaries interpolate between pairs of contour inducers, but do not extrapolate from a single inducer. Neural models have simulated how perceptual grouping occurs in laminar visual cortical circuits. These models predicted the existence of grouping cells that obey a bipole property whereby grouping can occur inwardly between pairs or greater numbers of similarly oriented and co-axial inducers, but not outwardly from individual inducers. These models have not, however, incorporated spiking dynamics. Perceptual grouping is a challenge for spiking cells because its properties of collinear facilitation and analog sensitivity to inducer configurations occur despite irregularities in spike timing across all the interacting cells. Other models have demonstrated spiking dynamics in laminar neocortical circuits, but not how perceptual grouping occurs. The current model begins to unify these two modeling streams by implementing a laminar cortical network of spiking cells whose intracellular temporal dynamics interact with recurrent intercellular spiking interactions to quantitatively simulate data from neurophysiological experiments about perceptual grouping, the structure of non-classical visual receptive fields, and gamma oscillations.

Brain Learning and Recognition: The Large and the Small of It in Inferotemporal Cortex

Anterior inferotemporal cortex (ITa) plays a key role in visual object recognition. Recognition is tolerant to object position, size, and view changes, yet recent neurophysiological data show ITa cells with high object selectivity often have low position tolerance, and vice versa. A neural model learns to simulate both this tradeoff and ITa responses to image morphs using large-scale and small-scale IT cells whose population properties may support invariant recognition.

Grid Cell Hexagonal Patterns Formed by Fast Self-Organized Learning within Entorhinal Cortex

Grid cells in the dorsal segment of the medial entorhinal cortex (dMEC) show remarkable hexagonal activity patterns, at multiple spatial scales, during spatial navigation. How these hexagonal patterns arise has excited intense interest. It has previously been shown how a selforganizing map can convert firing patterns across entorhinal grid cells into hippocampal place cells that are capable of representing much larger spatial scales. Can grid cell firing fields also arise during navigation through learning within a self-organizing map? A neural model is proposed that converts path integration signals into hexagonal grid cell patterns of multiple scales. This GRID model creates only grid cell patterns with the observed hexagonal structure, predicts how these hexagonal patterns can be learned from experience, and can process biologically plausible neural input and output signals during navigation. These results support a unified computational framework for explaining how entorhinal-hippocampal interactions support spatial navigation.

Laminar Cortical Dynamics of Cognitive and Motor Working Memory, Sequence Learning and Performance: Toward a Unified Theory of How the Cerebral Cortex Works

How do the layered circuits of prefrontal and motor cortex carry out working memory storage, sequence learning, and voluntary sequential item selection and performance? A neural model called LIST PARSE is presented to explain and quantitatively simulate cognitive data about both immediate serial recall and free recall, including bowing of the serial position performance curves, error-type distributions, temporal limitations upon recall, and list length effects. The model also qualitatively explains cognitive effects related to attentional modulation, temporal grouping, variable presentation rates, phonemic similarity, presentation of non-words, word frequency/item familiarity and list strength, distracters and modality effects. In addition, the model quantitatively simulates neurophysiological data from the macaque prefrontal cortex obtained during sequential sensory-motor imitation and planned performance. The article further develops a theory concerning how the cerebral cortex works by showing how variations of the laminar circuits that have previously clarified how the visual cortex sees can also support cognitive processing of sequentially organized behaviors.

Multi-Area Visuotopic Map Complexes in Macaque Striate and Extra-striate Cortex

We propose that a simple, closed-form mathematical expression--the Wedge-Dipole mapping--provides a concise approximation to the full-field, two-dimensional topographic structure of macaque V1, V2, and V3. A single map function, which we term a map complex, acts as a simultaneous descriptor of all three areas. Quantitative estimation of the Wedge-Dipole parameters is provided via 2DG data of central-field V1 topography and a publicly available data set of full-field macaque V1 and V2 topography. Good quantitative agreement is obtained between the data and the model presented here. The increasing importance of fMRI-based brain imaging motivates the development of more sophisticated two-dimensional models of cortical visuotopy, in contrast to the one-dimensional approximations that have been in common use. One reason is that topography has traditionally supplied an important aspect of "ground truth", or validation, for brain imaging, suggesting that further development of high-resolution fMRI will be facilitated by this data analysis. In addition, several important insights into the nature of cortical topography follows from this work. The presence of anisotropy in cortical magnification factor is shown to follow mathematically from the shared boundary conditions at the V1-V2 and V2-V3 borders, and therefore may not causally follow from the existence of columnar systems in these areas, as is widely assumed. An application of the Wedge-Dipole model to localizing aspects of visual processing to specific cortical areas--extending previous work in correlating V1 cortical magnification factor to retinal anatomy or visual psychophysics data--is briefly discussed.

Texture Segregation By Visual Cortex: Perceptual Grouping, Attention, and Learning

A neural model is proposed of how laminar interactions in the visual cortex may learn and recognize object texture and form boundaries. The model brings together five interacting processes: region-based texture classification, contour-based boundary grouping, surface filling-in, spatial attention, and object attention. The model shows how form boundaries can determine regions in which surface filling-in occurs; how surface filling-in interacts with spatial attention to generate a form-fitting distribution of spatial attention, or attentional shroud; how the strongest shroud can inhibit weaker shrouds; and how the winning shroud regulates learning of texture categories, and thus the allocation of object attention. The model can discriminate abutted textures with blurred boundaries and is sensitive to texture boundary attributes like discontinuities in orientation and texture flow curvature as well as to relative orientations of texture elements. The model quantitatively fits a large set of human psychophysical data on orientation-based textures. Object boundar output of the model is compared to computer vision algorithms using a set of human segmented photographic images. The model classifies textures and suppresses noise using a multiple scale oriented filterbank and a distributed Adaptive Resonance Theory (dART) classifier. The matched signal between the bottom-up texture inputs and top-down learned texture categories is utilized by oriented competitive and cooperative grouping processes to generate texture boundaries that control surface filling-in and spatial attention. Topdown modulatory attentional feedback from boundary and surface representations to early filtering stages results in enhanced texture boundaries and more efficient learning of texture within attended surface regions. Surface-based attention also provides a self-supervising training signal for learning new textures. Importance of the surface-based attentional feedback in texture learning and classification is tested using a set of textured images from the Brodatz micro-texture album. Benchmark studies vary from 95.1% to 98.6% with attention, and from 90.6% to 93.2% without attention.