Neural field theory of synaptic plasticity

Plasticity is crucial to neural development, learning, and memory. In the common in vivo situation where postsynaptic neural activity results from multiple presynaptic inputs, it is shown that a widely used class of correlation-dependent and spike-timing dependent plasticity rules can be written in a form that can be incorporated into neural field theory, which enables their system-level dynamics to be investigated. It is shown that the resulting plasticity dynamics depends strongly on the stimulus spectrum via overall system frequency responses. In the case of perturbations that are approximately linear, explicit formulas are found for the dynamics in terms of stimulus spectra via system transfer functions. The resulting theory is applied to a simple model system to reveal how collective effects, especially resonances, can drastically modify system-level plasticity dynamics from that implied by single-neuron analyses. The simplified model illustrates the potential relevance of these effects in applications to brain stimulation, synaptic homeostasis, and epilepsy.     

Neural field theory with variance dynamics

Previous neural field models have mostly been concerned with prediction of mean neural activity and with second order quantities such as its variance, but without feedback of second order quantities on the dynamics. Here the effects of feedback of the variance on the steady states and adiabatic dynamics of neural systems are calculated using linear neural field theory to estimate the neural voltage variance, then including this quantity in the total variance parameter of the nonlinear firing rate-voltage response function, and thus into determination of the fixed points and the variance itself. The general results further clarify the limits of validity of approaches with and without inclusion of variance dynamics. Specific applications show that stability against a saddle-node bifurcation is reduced in a purely cortical system, but can be either increased or decreased in the corticothalamic case, depending on the initial state. Estimates of critical variance scalings near saddle-node bifurcation are also found, including physiologically based normalizations and new scalings for mean firing rate and the position of the bifurcation.     

Neural networks for modeling gene-gene interactions in association studies

Background

The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.

Results

We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.

Conclusion

Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.     

Neural systems involved in "theory of mind"

What is the nature of our ability to understand and reason about the beliefs of others--the possession of a "theory of mind", or ToM? Here, we review findings from imaging and lesion studies indicating that ToM reasoning is supported by a widely distributed neural system. Some functional components of this system, such as language-related regions of the left hemisphere, the frontal lobes and the right temporal parietal cortex, are not solely dedicated to the computation of mental states. However, the system also includes a core, domain-specific component that is centred on the amygdala circuitry. We provide a framework in which impairments of ToM can be viewed in terms of abnormalities of the core system, the failure of a co-opted system that is necessary for performance on a particular set of tasks, or the absence of an experiential trigger for the emergence of ToM.     

Prediction of protein-protein association rates from a transition-state theory

We recently developed a theory for the rates of protein-protein association. The theory is based on the concept of a transition state, which separates the bound state, with numerous short-range interactions but restricted translational and rotational freedom, and the unbound state, with, at most, a small number of interactions but expanded configurational freedom. When not accompanied by large-scale conformational changes, protein-protein association becomes diffusion limited. The association rate is then predicted as k(a)=k(a)(0)exp(-DeltaG(el)(double dagger)/k(B)T), where DeltaG(el)(double dagger) is the electrostatic interaction free energy in the transition state, k(a)(0) is the rate in the absence of electrostatic interactions, and k(B)T is thermal energy. Here, this transition-state theory is used to predict the association rates of four protein complexes. The predictions for the wild-type complexes and 23 mutants are found to agree closely with experimental data over wide ranges of ionic strength.     

Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology

Neurons in a small number of brain structures detect rewards and reward-predicting stimuli and are active during the expectation of predictable food and liquid rewards. These neurons code the reward information according to basic terms of various behavioural theories that seek to explain reward-directed learning, approach behaviour and decision-making. The involved brain structures include groups of dopamine neurons, the striatum including the nucleus accumbens, the orbitofrontal cortex and the amygdala. The reward information is fed to brain structures involved in decision-making and organisation of behaviour, such as the dorsolateral prefrontal cortex and possibly the parietal cortex. The neural coding of basic reward terms derived from formal theories puts the neurophysiological investigation of reward mechanisms on firm conceptual grounds and provides neural correlates for the function of rewards in learning, approach behaviour and decision-making.     

Neural Population Structures and Consequences for Neural Coding

Researchers studying neural coding have speculated that populations of neurons would more effectively represent the stimulus if the neurons "cooperated:" by interacting through lateral connections, the neurons would process and represent information better than if they functioned independently. We apply our new theory of information processing to determine the fidelity limits of simple population structures to encode stimulus features. We focus on noncooperative populations, which have no lateral connections. We show that they always exhibit positively correlated responses and that as population size increases, they perfectly represent the information conveyed by their inputs regardless of the individual neuron's coding scheme. Cooperative populations, which do have lateral connections, can, depending on the nature of the connections, perform better or worse than their noncooperative counterparts. We further show that common notions of synergy fail to capture the level of cooperation and to reflect the information processing properties of populations.     

Evolutionary Origins of the Neural Crest and Neural Crest Cells

I evaluate the lines of evidence—cell types, genes, gene pathways, fossils—in putative chordate ancestors—cephalochordates and ascidians—pertaining to the evolutionary origin of the vertebrate neural crest. Given the intimate relationship between the neural crest and the dorsal nervous system during development, I discuss the dorsal nervous system in living (extant) members of the two groups, especially the nature, and genes, and gene regulatory networks of the brain to determine whether any cellular and/or molecular precursors (latent homologues) of the neural may have been present in ancestral cephalochordates or urochordates. I then examine those fossils that have been interpreted as basal chordates or cephalochordates to determine whether they shed any light on the origins of neural crest cell (NCC) derivatives. Do they have, for example, elements of a head skeleton or pharyngeal arches, two fundamental vertebrate characters (synapomorphies)? The third topic recognizes that the origin of the neural crest in the first vertebrates accompanied the evolution of a brain, a muscular pharynx, and paired sensory organs. In a paradigm-breaking hypothesis—often known as the ‘new head hypothesis’—Carl Gans and Glen Northcutt linked these evolutionary innovations to the evolution of the neural crest and ectodermal placodes (Gans and Northcutt Science 220:268-274, 1983. doi:10.1126/science.220.4594.268; Northcutt and Gans The Quarterly Review of Biology 58:1–28, 1983. doi:10.1086/413055). I outline the rationale behind the new head hypothesis before turning to an examination of the pivotal role played by NCCs in the evolution of pharyngeal arches, in the context of the craniofacial skeleton. Integrations between the evolving vertebrate brain, muscular pharynx and paired sensory organs may have necessitated that the pharyngeal arch skeletal system—and subsequently, the skeleton of the jaws and much of the skull (the first vertebrates being jawless)—evolved from NCCs whose developmental connections were to neural ectoderm and neurons rather than to mesoderm and connective tissue; mesoderm produces much of the vertebrate skeleton, including virtually all the skeleton outside the head. The origination of the pharyngeal arch skeleton raises the issue of the group of organisms in which and how cartilage arose as a skeletal tissue. Did cartilage arise in the basal proto-vertebrate from a single germ layer, cell layer or tissue, or were cells and/or genes co-opted from several layers or tissues? Two recent studies utilizing comparative genomics, bioinformatics, molecular fingerprinting, genetic labeling/cell selection, and GeneChip Microarray technologies are introduced as powerful ways to approach the questions that are central to this review.     

Numb与神经发育

不对称性细胞分裂是一个母细胞通过一次分裂,产生两个不同命运的子细胞的分裂方式,是单细胞生物向多细胞生物进化的关键一步。根据现有的证据推论,不称性细胞分裂是在器官发育过程中产生细胞多样化的一种基本方式。Numb是第一个被发现决定多细胞生物不对称细胞分裂的信号蛋白。在果蝇中,Numb通过促进Notch泛素化拮抗Notch信号通路,从而决定子细胞的命运,后来的研究表明Numb是细胞内吞调节蛋白,并用通过内吞参与调节神经细胞的粘附,轴突的生长及细胞迁移等过程;并且发现Numb与肿瘤抑制基因p53、泛素化蛋白HDM2形成三聚体抑制p53的泛素化,从而调节肿瘤的恶性程度。本文系统地分析了Numb发现的历史及后来在脊椎动物中的作用和机制,重点介绍了Numb在神经发育过程中的功能。     

Folding and association of proteins

The acquisition of the native three-dimensional structure of proteins consists of sequential folding reactions with well-populated and well-defined structural intermediates. For small proteins successive stages in the folding have been resolved kinetically; these suggest that H-bonded elements of secondary structure are formed first, followed by folding steps to generate the complete tertiary structure.The rate determining step in the folding of a number of small proteins has been shown to be proline cis tram isomerization. As indicated by experiments using fast kinetics the overall folding mechanism, even in a small single-domain molecule like ribonuclease, involves more than one intermediate.Large protein molecules contain domains which may fold independently. For multi-domain proteins, the pathway of folding therefore involves folding by parts, followed by merging of folded domains.In the case of assembly systems (e.g., oligomeric or multimeric enzymes) folding and association have to be subtly interconnected with respect to the time scale, since the correct assembly of subunits requires their proper folding. In this sense the initial function of oligomeric proteins is their own self-assembly. The corresponding mechanism underlying the spontaneous formation of the native quaternary structure of oligomeric proteins must be the consecutive folding and association of the constituent polypeptide chains.Equilibrium and kinetic studies have been concerned with a number of dimeric, tetrameric and multimeric enzymes, using enzymatic activity to measure structure formation: alcohol dehydrogenase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, lactic dehydrogenase, malic dehydrogenase, pyruvate dehydrogenase, triose phosphate isomerase, tryptophan synthase.These experiments make use of the reversibility of protein denaturation, focusing on refolding and reassociation rather than folding and association, because there is no direct approach to structural investigations of the nascent polypeptide chain in vivo.Optimum conditions of reconstitution yield up to 100% reactivation. After separation of irreversibly denatured protein, reconstituted and native protein turn out to be indistinguishable. The major side reaction leading to wrong aggregation is due to competition between folding and association.Due to the high specificity of the association reaction chimeric species are not observed, and multimeric systems containing different component enzymes show specific assembly.The kinetics of reconstitution generally obey an irreversible sequential first- order/second-order mechanism involving inactive monomers; only in the case of aldolase is subunit activity suggested. For a number of oligomeric enzymes renaturation from various denaturants, in the absence or presence of coenzyme is characterized by identical kinetics. For glyceraldehyde-3-phosphate dehydrogenase, however, free NAD as well as a covalently bound NAD-analog are found to enhance the reconstitution.In the case of assembly structures exceeding the dimer, the observed consecutive folding/association mechanism does not allow us to decide whether the observed second order processes belong to the formation of the dimer or tetramer. Chemical cross-linking and hybridization techniques allow the equilibrium state and the assembly kinetics of oligomeric systems to be analyzed quantitatively. Using this method, e.g., for lactic dehydrogenase, it is obvious that dissociation leads to the homogeneous monomer, while tetramer formation is found to parallel reactivation.In general, equilibrium and kinetic experiments prove that full enzymatic activity requires association.In the case of multisubunit enzymes (multienzyme complexes) heterologous interactions of the component enzymes seem to be involved in the rate determining (first order) reshuffling processes which generate catalytic activity in the overall enzymatic reaction.Dedicated to Professor Ernst M. Helmreich on the occasion of his sixtieth birthday     

Neural Plasticity and Consciousness

We introduce a distinction between cortical dominance andcortical deference, and apply it to various examples ofneural plasticity in which input is rerouted intermodally orintramodally to nonstandard cortical targets. In some cases butnot others, cortical activity `defers' to the nonstandard sourcesof input. We ask why, consider some possible explanations, andpropose a dynamic sensorimotor hypothesis. We believe that thisdistinction is important and worthy of further study, bothphilosophical and empirical, whether or not our hypothesis turnsout to be correct. In particular, the question of how the distinction should be explained is linked to explanatory gapissues for consciousness. Comparative and absolute explanatorygaps should be distinguished: why does neural activity in aparticular area of cortex have this qualitative expressionrather than that, and why does it have any qualitativeexpression at all? We use the dominance/deference distinction toaddress the comparative gaps, both intermodal and intramodal (notthe absolute gap). We do so not by inward scrutiny but rather by expanding our gaze to include relations between brain, body andenvironment.     

Neural chaos and schizophrenia

Recent data indicate that random-like processes are related to the defects in the organization of semantic memory in schizophrenia which is more disorganized and less definable than those of controls with more semantic links and more bizarre and atypical associations. These aspects of schizophrenic cognition are similar to characteristics of chaotic nonlinear dynamical systems. In this context, the hypothesis tested in this study is that dynamic changes of electrodermal activity (EDA) as a measure of brain and autonomic activity may serve as a characteristic which can be used as an indicator of possible neural chaotic process in schizophrenia. In the present study, bilateral EDA in rest conditions were measured in 40 schizophrenic patients and 40 healthy subjects. Results of nonlinear and statistical analysis indicate left-side significant differences of positive largest Lyapunov exponents in schizophrenia patients compared to the control group. This might be interpreted that the neural activity during rest in schizophrenic patients is significantly more chaotic than in the control group. The relationship was confirmed by surrogate data testing. These data suggest that increased neural chaos in patients with schizophrenia may influence brain processes that can cause random-like disorganization of mental processes.     

Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth

In hippocampal neurons and transfected CHO cells, neural cell adhesion molecule (NCAM) 120, NCAM140, and NCAM180 form Triton X-100-insoluble complexes with betaI spectrin. Heteromeric spectrin (alphaIbetaI) binds to the intracellular domain of NCAM180, and isolated spectrin subunits bind to both NCAM180 and NCAM140, as does the betaI spectrin fragment encompassing second and third spectrin repeats (betaI2-3). In NCAM120-transfected cells, betaI spectrin is detectable predominantly in lipid rafts. Treatment of cells with methyl-beta-cyclodextrin disrupts the NCAM120-spectrin complex, implicating lipid rafts as a platform linking NCAM120 and spectrin. NCAM140/NCAM180-betaI spectrin complexes do not depend on raft integrity and are located both in rafts and raft-free membrane domains. PKCbeta2 forms detergent-insoluble complexes with NCAM140/NCAM180 and spectrin. Activation of NCAM enhances the formation of NCAM140/NCAM180-spectrin-PKCbeta2 complexes and results in their redistribution to lipid rafts. The complex is disrupted by the expression of dominant-negative betaI2-3, which impairs binding of spectrin to NCAM, implicating spectrin as the bridge between PKCbeta2 and NCAM140 or NCAM180. Redistribution of PKCbeta2 to NCAM-spectrin complexes is also blocked by a specific fibroblast growth factor receptor inhibitor. Furthermore, transfection with betaI2-3 inhibits NCAM-induced neurite outgrowth, showing that formation of the NCAM-spectrin-PKCbeta2 complex is necessary for NCAM-mediated neurite outgrowth.