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PubMed1994

Neural network models of cortical functions based on the computational properties of the cerebral cortex.

We describe a biologically plausible modelling framework based on the architectural and processing characteristics of the cerebral cortex. Its key feature is a multicellular processing unit (cortical column) reflecting the modular nature of cortical organization and function. In this framework, we describe a neural network model organization and function. In this framework, we describe a neural network model of the neuronal circuits of the cerebral cortex that learn different functions associated with different parts of the cortex: 1) visual integration for invariant pattern recognition, performed by a cooperation between temporal and parietal areas; 2) visual-to-motor transformation for 3D arm reaching movements, performed by parietal and motor areas; and 3) temporal integration and storage of sensorimotor programs, performed by networks linking the prefrontal cortex to associative sensory and motor areas. The architecture of the network is inspired from the features of the architecture of cortical pathways involved in these functions. We propose two rules which describe neural processing and plasticity in the network. The first rule (adaptive tuning if gating) is an analog of operant conditioning and permits to learn to anticipate an action. The second rule (adaptive timing) is based on a bistable state of activity and permits to learn temporally separate events forming a behavioral sequence.

Cerebral Cortex↗
PubMed2004

Modeling cell signaling networks.

Cell signaling pathways interact with one another to form networks in mammalian systems. Such networks are complex in their organization and exhibit emergent properties such as bistability and ultrasensitivity. Analysis of signaling networks requires a combination of experimental and theoretical approaches including the development and analysis of models. This review focuses on theoretical approaches to understanding cell signaling networks. Using heterotrimeric G protein pathways an example, we demonstrate how interactions between two pathways can result in a network that contains a positive feedback loop and function as a switch. Different mathematical approaches that are currently used to model signaling networks are described, and future challenges including the need for databases as well as enhanced computing environments are discussed.

Animals↗
PubMed2006

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

Amphetamine↗
PubMed2004

Computational multiple steady states for enzymatic esterification of ethanol and oleic acid in an isothermal CSTR.

The capacity of complex biochemical reaction networks (consisting of 11 coupled non-linear ordinary differential equations) to show multiple steady states, was investigated. The system involved esterification of ethanol and oleic acid by lipase in an isothermal continuous stirred tank reactor (CSTR). The Deficiency One Algorithm and the Subnetwork Analysis were applied to determine the steady state multiplicity. A set of rate constants and two corresponding steady states are computed. The phenomena of bistability, hysteresis and bifurcation are discussed. Moreover, the capacity of steady state multiplicity is extended to the family of the studied reaction networks.

Combinatorial Chemistry Techniques↗
PubMed2006

Crosstalk between cAMP-PKA and MAP kinase pathways is a key regulatory design necessary to regulate FLO11 expression.

Signal transduction pathways crosstalk with one another and play a central role in regulation of cellular events. Crosstalk brings complexity to the system, and hence, a systematic analysis of these crosstalks helps in relating the signaling network structure to its function. Here, we present a modular steady state approach to quantify the network comprising of cAMP-PKA and MAP kinase pathways involved in the regulation of FLO11, a gene which is required for pseudohyphae growth in Saccharomyces cerevisiae under nitrogen starvation. These two pathways crosstalk by converging on the same target, i.e., FLO11 and through Ras2p, an upstream activator of both cAMP and MAPK pathway. Analysis of crosstalk at the gene level revealed that cAMP-PKA and MAPK pathways are indispensable to FLO11 expression. The dose response was highly sensitive and primarily controlled by cAMP-PKA pathway. We demonstrate that the highly sensitive response in the cAMP-PKA pathway was due to crosstalk and inhibitor ultrsensitivity, key regulatory designs present at the downstream of cAMP-PKA pathway. The analysis of the role of Ras2p in the crosstalk between the cAMP-PKA and MAPK pathways indicated that crosstalk essentially helped in amplification of the Gpa2p signal, another upstream activator of the cAMP-PKA pathway. However, the effect of crosstalk due to Ras2p on FLO11 expression was minimal under normal activation levels of Ras2p. Whereas, the crosstalk itself can bring about FLO11 expression under the hyperactivated Ras2p conditions thereby eliminating the requirement for the other activator Gpa2p. We also observed the presence of system level properties such as amplification, inhibitor ultrasensitvity and bistability, which can be attributed to the regulatory design present in the FLO11 expression system. These system level properties might help the organism to respond to varying nutritional status.

Adenylyl Cyclases↗
PubMed2006

Switching mechanism for branched biochemical fluxes: graph-theoretical analysis.

A graph-theoretical method is applied to characterize the structure of a simplest switching mechanism of common biochemical importance. This mechanism is based on competition of two coupled substrate-binding pathways for a single substrate. No other regulatory interactions are shown to be needed for the switching phenomenon to be observed. It is shown that switch in branch effluxes is observed as bistability or reciprocal oscillations, depending on the value of steady influx. Frequency of reciprocal efflux oscillations in branches is regulated by steady influx. Therefore, the switching mechanism can function as the coding mechanism in the manner of "influx steady level-efflux frequency". The calculated kinetic equations for the switching mechanism demonstrate very steep transitions in the branch fluxes without using high non-linearity of these equations.

Enzymes↗
PubMed2006

Engineered internal noise stochastic resonator in gene network: a model study.

Based on a genetic bistable switch model coupled with a gene oscillator model, we have constructed a mesoscopic stochastic model for the coupled synthetic gene network, and studied how internal noise would influence the oscillation of such a system. We found that the state-to-state transitions can occur if the internal noise is taken into account, and the performance of resulting oscillation can reach a maximum in a certain internal noise level, which indicates the occurrence of internal noise stochastic resonance (SR) and makes the coupled gene network work as a stochastic resonator. The potential role of such an effect on gene expression systems is also discussed.

Biological Clocks↗
PubMed2006

Multilineage transcriptional priming and determination of alternate hematopoietic cell fates.

Hematopoietic stem cells and their progenitors exhibit multilineage patterns of gene expression. Molecular mechanisms underlying the generation and refinement of these patterns during cell fate determination remain unexplored because of the absence of suitable experimental systems. Using PU.1(-/-) progenitors, we demonstrate that at subthreshold levels, this Ets transcription factor regulates a mixed pattern (macrophage/neutrophil) of gene expression within individual myeloid progenitors. Increased PU.1 levels refine the pattern and promote macrophage differentiation by modulating a novel regulatory circuit comprised of counter antagonistic repressors, Egr-1,2/Nab-2 and Gfi-1. Egr-1 and Egr-2 function redundantly to activate macrophage genes and to repress the neutrophil program. These results are used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and accounts for the onset and resolution of mixed lineage patterns during cell fate determination.

Animals↗
PubMed2004

Psychophysics: catching the old codger's eye.

Some visual stimuli are bistable, with perception alternating irregularly between two alternatives. Recent work suggests that the neural processing of these alternations must occur at low levels of the visual system.

Photic Stimulation↗
PubMed2005

IP3 receptor activity is differentially regulated in endoplasmic reticulum subdomains during oocyte maturation.

Fertilization competency results from hormone-induced remodeling of oocytes into eggs. The signaling pathways that effect this change exemplify bistability, where brief hormone exposure irrevocably switches cell fate. In Xenopus, changes in Ca(2+) signaling epitomize such remodeling: The reversible Ca(2+) signaling phenotype of oocytes rapidly adapts to support irreversible propagation of the fertilization Ca(2+) wave. Here, we simultaneously resolved IP(3) receptor (IP(3)R) activity with endoplasmic reticulum (ER) structure to optically dissect the functional architecture of the Ca(2+) release apparatus underpinning this reorganization. We show that changes in Ca(2+) signaling correlate with IP(3)R redistribution from specialized ER substructures called annulate lamellae (AL), where Ca(2+) release activity is attenuated, into IP(3)R-replete patches in the cortical ER of eggs that support the fertilization Ca(2+) wave. These data show: first, that IP(3)R sensitivity is regulated with high spatial acuity even between contiguous ER regions; and second, that drastic reorganization of Ca(2+) signaling dynamics can be driven by subcellular redistribution in the absence of changes in channel number or molecular or familial Ca(2+) channel diversity. Finally, these results define a novel role for AL in Ca(2+) signaling. Because AL are prevalent in other scenarios of rapid cell division, further studies of their impact on Ca(2+) signaling are warranted.

Animals↗
PubMed2006

Early embryonic programming of neuronal left/right asymmetry in C. elegans.

BACKGROUND: Nervous systems are largely bilaterally symmetric on a morphological level but often display striking degrees of functional left/right (L/R) asymmetry. How L/R asymmetric functional features are superimposed onto an essentially bilaterally symmetric structure and how nervous-system laterality relates to the L/R asymmetry of internal organs are poorly understood. We address these questions here by using the establishment of L/R asymmetry in the ASE chemosensory neurons of C. elegans as a paradigm. This bilaterally symmetric neuron pair is functionally lateralized in that it senses a distinct class of chemosensory cues and expresses a putative chemoreceptor family in a L/R asymmetric manner. RESULTS: We show that the directionality of the asymmetry of the two postmitotic ASE neurons ASE left (ASEL) and ASE right (ASER) in adults is dependent on a L-/R-symmetry-breaking event at a very early embryonic stage, the six-cell stage, which also establishes the L/R asymmetric placement of internal organs. However, the L/R asymmetry of the ASE neurons per se is dependent on an even earlier anterior-posterior (A/P) Notch signal that specifies embryonic ABa/ABp blastomere identities at the four-cell stage. This Notch signal, which functions through two T box genes, acts genetically upstream of a miRNA-controlled bistable feedback loop that regulates the L/R asymmetric gene-expression program in the postmitotic ASE cells. CONCLUSIONS: Our results link adult neuronal laterality to the generation of the A/P axis at the two-cell stage and raise the possibility that neural asymmetries observed across the animal kingdom are similarly established by very early embryonic interactions.

Animals↗
PubMed2005

Seeing in color--warts and all.

In the September 9th issue of Cell, Mikeladze-Dvali et al. show that cell fate decisions needed for color vision are dependent on a bistable negative feedback loop between genes previously implicated in cell proliferation (warts) and growth (melted).

Animals↗
PubMed2006

Synergetics of brain function.

Several brain functions such as movement coordination and visual perception are analysed in terms of synergetics, an interdisciplinary field of research dealing with spontaneous pattern formation. Accordingly, the brain is conceived as a self-organizing system operating close to instabilities where its activities are governed by collective variables, the order parameters, that enslave the individual parts, i.e., the neurons. In this approach, emphasis is laid on qualitative changes of behavioral and neuronal activities. These concepts are substantiated by detailed experimental and theoretical studies of the coordination of finger movements by direct observation of their changes and MEG measurements. In its main part, this paper deals with visual pattern recognition. Using general properties of order parameters, at the phenomenological level bistability, hysteresis and oscillations of visual perception can be modelled. Then, at the microscopic level, a network of pulse-coupled neurons is treated, where the dynamics of the dendritic currents as well as the axonic pulses (spikes) are taken into account. Both pulse-synchronization as well as pattern recognition are treated. In the high pulse frequency limit the attractor network of the synergetic computer is recovered. In the next step, the concept of quasi-attractors is mathematically formulated where due to saturation of attention attractors are closed. Depending on incoming signals, the visual system thus wanders from quasi-attractor to quasi-attractor. The paper includes an interpretation of consciousness in terms of order parameters as well as a discussion on linearity versus nonlinearity, the binding problem, and the psychological "present".

Animals↗
PubMed2003

Sequence-dependent DNA structure: a database of octamer structural parameters.

We have constructed the potential energy surfaces for all unique tetramers, hexamers and octamers in double helical DNA, as a function of the two principal degrees of freedom, slide and shift at the central step. From these potential energy maps, we have calculated a database of structural and flexibility properties for each of these sequences. These properties include: the values of each of the six step parameters (twist roll, tilt, rise, slide and shift), for each step of the sequence; flexibility measures for both decrease and increase in each property value from the minimum energy conformation for the central step; and the deviation from the path of a hypothetical straight octamer. In an analysis of structural change as a function of sequence length, we observe that almost all DNA tends to B-DNA and becomes less flexible. A more detailed analysis of octamer properties has allowed us to determine the structural preferences of particular sequence elements. GGC and GCC sequences tend to confer bistability, low stability and a predisposition to A-form DNA, whereas AA steps strongly prefer B-DNA and inhibit A-structures. There is no correlation between flexibility and intrinsic curvature, but bent DNA is less stable than straight. The most difficult deformation is undertwisting. The TA step stands out as the most flexible sequence element with respect to decreasing twist and increasing roll. However, as with the structural properties, this behavior is highly context-dependent and some TA steps are very straight.

DNA↗
PubMedDate not supplied

Modelling the formation of working memory with networks of integrate-and-fire neurons connected by plastic synapses.

In this paper we review a series of works concerning models of spiking neurons interacting via spike-driven, plastic, Hebbian synapses, meant to implement stimulus driven, unsupervised formation of working memory (WM) states. Starting from a summary of the experimental evidence emerging from delayed matching to sample (DMS) experiments, we briefly review the attractor picture proposed to underlie WM states. We then describe a general framework for a theoretical approach to learning with synapses subject to realistic constraints and outline some general requirements to be met by a mechanism of Hebbian synaptic structuring. We argue that a stochastic selection of the synapses to be updated allows for optimal memory storage, even if the number of stable synaptic states is reduced to the extreme (bistable synapses). A description follows of models of spike-driven synapses that implement the stochastic selection by exploiting the high irregularity in the pre- and post-synaptic activity. Reasons are listed why dynamic learning, that is the process by which the synaptic structure develops under the only guidance of neural activities, driven in turn by stimuli, is hard to accomplish. We provide a 'feasibility proof' of dynamic formation of WM states in this context the beneficial role of short-term depression (STD) is illustrated. by showing how an initially unstructured network autonomously develops a synaptic structure supporting simultaneously stable spontaneous and WM states in this context the beneficial role of short-term depression (STD) is illustrated. After summarizing heuristic indications emerging from the study performed, we conclude by briefly discussing open problems and critical issues still to be clarified.

Action Potentials↗
PubMed2005

The good, the bad and the discriminator--errors in direct and indirect reciprocity.

This paper presents, in a series of simple diagrams, concise results about the replicator dynamics of direct and indirect reciprocity. We consider repeated interactions between donors and recipients, and analyse the relationship between three basic strategies for the donor: unconditional cooperation, all-out defection, and conditional cooperation. In other words, we investigate the competition of discriminating and indiscriminating altruists with defectors. Discriminators and defectors form a bistable community, and hence a population of discriminators cannot be invaded by defectors. But unconditional altruists can invade a discriminating population and 'soften it up' for a subsequent invasion by defectors. The resulting dynamics exhibits various forms of rock-paper-scissors cycles and depends in subtle ways on noise, in the form of errors in implementation. The probability for another round (in the case of direct reciprocity), and information about the co-player (in the case of indirect reciprocity), add further elements to the ecology of reciprocation.

Altruism↗
PubMed2006

A simple time delay model for eukaryotic cell cycle.

We propose a seven variable model with time delay in one of the variables for the cell cycle in higher eukaryotes. The model consists of four important phosphorylation-dephosphorylation (P-D) cycles that govern the cell cycle, namely Pre-MPF-MPF, Cdc25P-Cdc25, Wee1P-Wee1 and APCP-APC. Other variables are cyclin, free cyclin dependent kinase (Cdk) and mass. The mass acts as a G2/M checkpoint and the checkpoint is represented by a saddle node loop bifurcation. The key feature of the model is that a time lag has been introduced in the activation of anaphase promoting complex (APC) by maturation promoting factor (MPF). This is effected by treating MPF as a time-delayed variable in the activation step of APC. The time lag acts as a spindle checkpoint. Absence of time delay induces a bistability in our model. Time delay also brings about variability in G1 phase timings. The model also reproduces the mutant phenotype experiments on wee1 cells. Stochasticity has been introduced in the model to simulate the dependence of the cycle time on cell birth length. Mutant phenotypes in the stochastic model reproduce the experimental observations better than the deterministic model.

Animals↗