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Results for “functional network connectivity”

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PubMed2003

[Research advances on p53 gene network].

The p53 tumor suppressor gene integrates numerous signals to control cell life and death. p53 and its function-related genes consists of a complicated gene network. When a highly connected node in the network breaks down, the disruption of p53 has severe consequences. p53 gene locates in human chromosome 17q13.1. Its encoding wild-type p53 protein is composed of four parts: N-terminal activation domain, DNA-binding domain, oligomerization domain, and C-terminal regulation domain. As the gene structures of p73, p51, p63 are similar with p53, they are regarded as members of p53 gene family. p53 play an intermediate role connecting varied stress signals with the reactions of cells. DNA damage caused by ionizing radiation, aberrant growth signals, or chemotherapeutic drugs may activate the p53 network. When expression of p53 elevated, p53-mdm2 and p14(ARF)-mdm2 feedback loops can accurately regulate the expression level of p53, and the cooperation of p33ING1b gene is also needed in the process of p53 exerting normal function. Phosphorylation and acelylation are two important mechanisms to modulate p53 activity in vivo. Several dozen downstream genes are controlled directly by p53, and the activity of p53 falls into four categories: cell cycle inhibition, apoptosis, genetic stability, and inhibition of blood vessel formation. Elucidation of the function of p53 gene network will help to clarify the interaction mechanisms of p53 gene and its function-related genes.

DNA-Binding Proteins↗

PubMed1997

Short-term reverberant memory model of hippocampal field CA3.

Synaptic plasticity mechanisms for associative learning require near-simultaneous pairs of inputs to target cells. Sensory cues encountered behaviorally, however, are typically staggered in time, implying the need for active short-term memory traces of antecedent cues. The dense recurrent connectivity within regions of hippocampal field CA3 is suggestive of the kind of re-entrant network that could subserve this kind of "holding" memory. Consequently, we have investigated whether an abstract model of this region incorporating its major anatomical and physiological features could function as a reverberatory memory network. The continuous-time model describes the behavior of highly connected groups of CA3 pyramidal cells, or "patches," in response to brief, rhythmic, sensory stimulation. Time constants for excitatory and inhibitory postsynaptic potentials and axonal transmission delays for local and distal connections were estimated from empirical data. When the inhibitory units in these patches were connected to an oscillator intended to model the theta wave activity of the medial septum, the network entered reverberatory states and maintained second-long memory traces of the cortical input, after which it lost its coherent behavior. Noise analysis indicated that the network's operation was moderately resistant to random fluctuations proportional to patch activity. These results suggest that field CA3 could function as a holding memory that assists the integration of disjoint stimuli found in innumerable associative tasks, and that the duration of its coherent operation might determine the temporal limits in their performance.

Animals↗

PubMed1990

Anti-Hebbian learning in a non-linear neural network.

The Hebbian rule (Hebb 1949), coupled with an appropriate mechanism to limit the growth of synaptic weights, allows a neuron to learn to respond to the first principal component of the distribution of its input signals (Oja 1982). Rubner and Schulten (1990) have recently suggested the use of an "anti-Hebbian" rule in a network with hierarchical lateral connections. When applied to neurons with linear response functions, this model allows additional neurons to learn to respond to additional principal components (Rubner and Tavan 1989). Here we apply the model to neurons with non-linear response functions characterized by a threshold and a transition width. We propose local, unsupervised learning rules for the threshold and the transition width, and illustrate the operation of these rules with some simple examples. A network using these rules sorts the input patterns into classes, which it identifies by a binary code, with the coarser structure coded by the earlier neurons in the hierarchy.

Brain↗

PubMed2006

Adaptive reconfiguration of fractal small-world human brain functional networks.

Brain function depends on adaptive self-organization of large-scale neural assemblies, but little is known about quantitative network parameters governing these processes in humans. Here, we describe the topology and synchronizability of frequency-specific brain functional networks using wavelet decomposition of magnetoencephalographic time series, followed by construction and analysis of undirected graphs. Magnetoencephalographic data were acquired from 22 subjects, half of whom performed a finger-tapping task, whereas the other half were studied at rest. We found that brain functional networks were characterized by small-world properties at all six wavelet scales considered, corresponding approximately to classical delta (low and high), , alpha, beta, and gamma frequency bands. Global topological parameters (path length, clustering) were conserved across scales, most consistently in the frequency range 2-37 Hz, implying a scale-invariant or fractal small-world organization. Dynamical analysis showed that networks were located close to the threshold of order/disorder transition in all frequency bands. The highest-frequency gamma network had greater synchronizability, greater clustering of connections, and shorter path length than networks in the scaling regime of (lower) frequencies. Behavioral state did not strongly influence global topology or synchronizability; however, motor task performance was associated with emergence of long-range connections in both beta and gamma networks. Long-range connectivity, e.g., between frontal and parietal cortex, at high frequencies during a motor task may facilitate sensorimotor binding. Human brain functional networks demonstrate a fractal small-world architecture that supports critical dynamics and task-related spatial reconfiguration while preserving global topological parameters.

Brain↗

PubMed2006

beta-Spectrin functions independently of Ankyrin to regulate the establishment and maintenance of axon connections in the Drosophila embryonic CNS.

alpha- and beta-Spectrin are major components of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins. Besides its structural role in red blood cells, the Spectrin network is thought to function in non-erythroid cells during protein targeting and membrane domain formation. Here, we demonstrate that beta-Spectrin is required in neurons for proper midline axon guidance in the Drosophila embryonic CNS. In beta-spectrin mutants many axons inappropriately cross the CNS midline, suggesting a role for beta-Spectrin in midline repulsion. Surprisingly, neither the Ankyrin-binding nor the pleckstrin homology (PH) domains of beta-Spectrin are required for accurate guidance decisions. alpha-Spectrin is dependent upon beta-Spectrin for its normal subcellular localization and/or maintenance, whereas alpha-spectrin mutants exhibit a redistribution of beta-Spectrin to the axon scaffold. beta-spectrin mutants show specific dose-dependent genetic interactions with the midline repellent slit and its neuronal receptor roundabout (robo), but not with other guidance molecules. The results suggest that beta-Spectrin contributes to midline repulsion through the regulation of Slit-Robo pathway components. We propose that the Spectrin network is playing a role independently of Ankyrin in the establishment and/or maintenance of specialized membrane domains containing guidance molecules that ensure the fidelity of axon repulsion at the midline.

Animals↗

PubMed2004

Neuronal network models of ADHD -- lateralization with respect to interhemispheric connectivity reconsidered.

BACKGROUND: Recent research on structural and functional anatomy related to ADHD has concentrated on fronto-striatocerebellar circuits. These findings and resultant neurobiological models of ADHD may explain some of the disturbances. On the other hand, there is some evidence that the restricted look at anterior-posterior anomalies might neglect the important additional information of lateralization problems related to hemispheric connectivity. OBJECTIVE: Hence, the role of lateralization in the pathophysiology of ADHD should be reconsidered. METHOD: After a short review of imaging studies in ADHD the special role of the corpus callosum (including the influence of its anomalies on general brain development, lateralization and functioning) is outlined and the first case of total agenesis of corpus callosum in a child with ADHD is presented and discussed within this context. CONCLUSIONS: In view of the remaining inconsistencies concerning structural and functional brain anomalies in ADHD, attention should be paid not only to anterior- posterior but also to left-right aspects of functional and structural brain anomalies. This should include disturbances probably related to anomalies of the corpus callosum, especially in regard to co-existing problems like dyslexia and developmental coordination disorder.

Agenesis of Corpus Callosum↗

PubMed2000

[Neuronal and synaptic properties: fundamentals of network plasticity].

Neurons, within the nervous system, are organized in different neural networks through synaptic connections. Two fundamental components are dynamically interacting in these functional units. The first one are the neurons themselves, and far from being simple action potential generators, they are capable of complex electrical integrative properties due to various types, number, distribution and modulation of voltage-gated ionic channels. The second elements are the synapses where a similar complexity and plasticity is found. Identifying both cellular and synaptic intrinsic properties is necessary to understand the links between neural networks behavior and physiological function, and is a useful step towards a better control of neurological diseases.

Animals↗

PubMed1997

Inactivation of two Dictyostelium discoideum genes, DdPIK1 and DdPIK2, encoding proteins related to mammalian phosphatidylinositide 3-kinases, results in defects in endocytosis, lysosome to postlysosome transport, and actin cytoskeleton organization.

Phosphatidylinositide 3-kinases (PI3-kinases) have been implicated in controlling cell proliferation, actin cytoskeleton organization, and the regulation of vesicle trafficking between intracellular organelles. There are at least three genes in Dictyostelium discoideum. DdPIK1, DdPIK2, and DdPIK3, encoding proteins most closely related to the mammalian 110-kD PI-3 kinase in amino acid sequence within the kinase domain. A mutant disrupted in DdPIK1 and DdPIK2 (delta ddpik1/ddpik2) grows slowly in liquid medium. Using FITC-dextran (FD) as a fluid phase marker, we determined that the mutant strain was impaired in pinocytosis but normal in phagocytosis of beads or bacteria. Microscopic and biochemical approaches indicated that the transport rate of fluid-phase from acidic lysosomes to non-acidic postlysosomal vacuoles was reduced in mutant cells resulting in a reduction in efflux of fluid phase. Mutant cells were also almost completely devoid of large postlysosomal vacuoles as determined by transmission EM. However, delta ddpik1/ddpik2 cells functioned normally in the regulation of other membrane traffic. For instance, radiolabel pulse-chase experiments indicated that the transport rates along the secretory pathway and the sorting efficiency of the lysosomal enzyme alpha-mannosidase were normal in the mutant strain. Furthermore, the contractile vacuole network of membranes (probably connected to the endosomal pathway by membrane traffic) was functionally and morphologically normal in mutant cells. Light microscopy revealed that delta ddpik1/ddpik2 cells appeared smaller and more irregularly shaped than wild-type cells; 1-3% of the mutant cells were also connected by a thin cytoplasmic bridge. Scanning EM indicated that the mutant cells contained numerous filopodia projecting laterally and vertically from the cell surface, and fluorescent microscopy indicated that these filopodia were enriched in F-actin which accumulated in a cortical pattern in control cells. Finally, delta ddpik1/ddpik2 cells responded and moved more rapidly towards cAMP. Together, these results suggest that Dictyostelium DdPIK1 and DdPIK2 gene products regulate multiple steps in the endosomal pathway, and function in the regulation of cell shape and movement perhaps through changes in actin organization.

Actins↗

PubMed2002

Effects of verbal working memory load on corticocortical connectivity modeled by path analysis of functional magnetic resonance imaging data.

We investigated the hypothesis that there are load-related changes in the integrated function of frontoparietal working memory networks. Functional magnetic resonance imaging time-series data from 10 healthy volunteers performing a graded n-back verbal working memory task were modeled using path analysis. Seven generically activated regions were included in the model: left/right middle frontal gyri (L/R MFG), left/right inferior frontal gyri (L/R IFG), left/right posterior parietal cortex (L/R PPC), and supplementary motor area (SMA). The model provided a good fit to the 1-back (chi(2) = 7.04, df = 8, P = 0.53) and 2-back conditions (chi(2) = 9.35, df = 8, P = 0.31) but not for the 3-back condition (chi(2) = 20.60, df = 8, P = 0.008). Model parameter estimates were compared overall among conditions: there was a significant difference overall between 1-back and 2-back conditions (chi(2)(diff) = 74.77, df = 20, P < 0.001) and also between 2-back and 3-back conditions (chi(2)(diff) = 96.28, df = 20, P < 0.001). Path coefficients between LIFG and LPPC were significantly different from zero in both 1-back and 2-back conditions; in the 2-back condition, additional paths from LIFG to LPPC via SMA and to RMFG from LMFG and LPPC were also nonzero. This study demonstrated a significant change in functional integration of a neurocognitive network for working memory as a correlate of increased load. Enhanced inferior frontoparietal and prefrontoprefrontal connectivity was observed as a correlate of increasing memory load, which may reflect greater demand for maintenance and executive processes, respectively.

Adult↗

PubMed1999

The surface-connected canalicular system in the sinus endothelial cells of rat spleen.

The existence of a surface-connected canalicular system in the splenic sinus endothelial cells of the rat has been demonstrated by transmission electron microscopy with lanthanum nitrate acting as a tracer for the extracellular space. In addition, the three-dimensional arrangement of the canaliculi has been revealed by computer-aided reconstruction. The surface-connected canalicular system of the sinus endothelial cells consists of slender canaliculi that are branched, anastomosed, and that show continuity with the plasma membrane. They twist in and out among the organelles and are often found in close apposition to the spherical invaginations of the plasma membrane and run alongside them. Canaliculi which are not infiltrated by lanthanum nitrate take the form of electron-lucent tubules and are accompanied by numerous spherical invaginations of the plasma membrane. From a computer-aided reconstruction, the canaliculi, which invaginate from various sites of the plasma membrane, have been found to be continuous with each other and to penetrate to the surface of the sinus endothelial cell; they also branch and anastomose to form a complex network in the cytoplasm. Although the surface-connected canalicular system in blood platelets and thrombocytes is believed to function as the main route for the discharge of granules and the uptake of foreign materials and also to take part in the storage and transport of calcium, it is unclear at present whether the network of the surface-connected canalicular system in splenic sinus endothelial cells has any physiological significance.

Animals↗

PubMed2005

Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi.

BACKGROUND: The trypanosomatids Leishmania major, Trypanosoma brucei and Trypanosoma cruzi cause some of the most debilitating diseases of humankind: cutaneous leishmaniasis, African sleeping sickness, and Chagas disease. These protozoa possess complex life cycles that involve development in mammalian and insect hosts, and a tightly coordinated cell cycle ensures propagation of the highly polarized cells. However, the ways in which the parasites respond to their environment and coordinate intracellular processes are poorly understood. As a part of an effort to understand parasite signaling functions, we report the results of a genome-wide analysis of protein kinases (PKs) of these three trypanosomatids. RESULTS: Bioinformatic searches of the trypanosomatid genomes for eukaryotic PKs (ePKs) and atypical PKs (aPKs) revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major, most of which are orthologous across the three species. This is approximately 30% of the number in the human host and double that of the malaria parasite, Plasmodium falciparum. The representation of various groups of ePKs differs significantly as compared to humans: trypanosomatids lack receptor-linked tyrosine and tyrosine kinase-like kinases, although they do possess dual-specificity kinases. A relative expansion of the CMGC, STE and NEK groups has occurred. A large number of unique ePKs show no strong affinity to any known group. The trypanosomatids possess few ePKs with predicted transmembrane domains, suggesting that receptor ePKs are rare. Accessory Pfam domains, which are frequently present in human ePKs, are uncommon in trypanosomatid ePKs. CONCLUSION: Trypanosomatids possess a large set of PKs, comprising approximately 2% of each genome, suggesting a key role for phosphorylation in parasite biology. Whilst it was possible to place most of the trypanosomatid ePKs into the seven established groups using bioinformatic analyses, it has not been possible to ascribe function based solely on sequence similarity. Hence the connection of stimuli to protein phosphorylation networks remains enigmatic. The presence of numerous PKs with significant sequence similarity to known drug targets, as well as a large number of unusual kinases that might represent novel targets, strongly argue for functional analysis of these molecules.

Animals↗

PubMed2002

Seizures in paediatric Chiari type I malformation: the role of single-photon emission computed tomography.

UNLABELLED: Chiari type I malformation is one of the posterior fossa maldevelopments with which different clinical manifestations have been associated. Seizures have only recently been associated with Chiari type I malformation. This study reports on 4 children with epilepsy (2M, 2F; age range 8-15 y) diagnosed with Chiari type I malformation by brain magnetic resonance imaging (MRI), in whom no cortical structural involvement was observed. In these patients an interictal ethylcysteinate-dimer-single-photon emission computed tomographic (ECD-SPECT) study was performed to define more precisely the relationship between Chiari type I malformation and seizures. In these patients the hypoperfusion area correlated with electroencephalographic (EEG) focal abnormalities. These hypoperfusions may represent the functional aspect of a cerebral microdysgenesis; seizures and EEG epileptic anomalies may also be linked to the complex network connection between cortices and cerebellar hemispheres. A cerebellar hypoperfusion was also detected in two of the four examined patients, indicating a functional or structural involvement. CONCLUSION: Interictal SPECT scans are helpful for the clarification of seizures in patients with Chiari type I malformation.

Adolescent↗

PubMed1988

[Social networks and mental disease].

This is a three-purpose study: (a) Furthering a definition of social network analysis since such a theoretical and methodological approach is of great interest to studying social interaction, (b) Analyzing the social networks within one psychiatric case study in order to build up a network interaction model aiming at fostering future research, this interaction model being used as a concept framework, and (c) Discussing how fruitful research on social networks can prove to be in connection with the treatment of the mentally ill, as well as considering the protective and supportive functions of these networks.

Humans↗

PubMed2006

How can corticospinal tract neurons contribute to ipsilateral movements? A question with implications for recovery of motor functions.

In this review, the authors discuss some recent findings that bear on the issue of recovery of function after corticospinal tract lesions. Conventionally the corticospinal tract is considered to be a crossed pathway, in keeping with the clinical findings that damage to one hemisphere, for example, in stroke, leads to a contralateral paresis and, if the lesion is large, a paralysis. However, there has been great interest in the possibility of compensatory recovery of function using the undamaged hemisphere. There are several substrates for this including ipsilaterally descending corticospinal fibers and bilaterally operating neuronal networks. Recent studies provide important evidence bearing on both of these issues. In particular, they reveal networks of neurons interconnecting two sides of the gray matter at both brainstem and spinal levels, as well as intrahemispheric transcallosal connections. These may form "detour circuits" for recovery of function, and here the authors will consider some possibilities for exploiting these networks for motor control, even though their analysis is still at an early stage.

Animals↗

PubMed2002

Disruption of coherent oscillations in inhibitory networks with anesthetics: role of GABA(A) receptor desensitization.

The effect of anesthetic drugs at central synapses can be described quantitatively by developing kinetic models of ligand-gated ion channels. Experiments have shown that the hypnotic propofol and the sedative benzodiazepine midazolam have similar effects on single inhibitory postsynaptic potentials (IPSPs) but very different effects on slow desensitization that are not revealed by examining single responses. Synchronous oscillatory activity in networks of interneurons connected by inhibitory synapses has been implicated in many hippocampal functions, and differences in the kinetics of the GABAergic response observed with anesthetics can affect this activity. Thus we have examined the effect of propofol and midazolam-enhanced IPSPs using mathematical models of self-inhibited one- and two-cell inhibitory networks. A detailed kinetic model of the GABA(A) channel incorporating receptor desensitization is used at synapses in our models. The most dramatic effect of propofol is the modulation of slow desensitization. This is only revealed when the network is driven at frequencies that are thought to be relevant to cognitive tasks performed in the hippocampus. The level of desensitization at synapses with propofol is significantly reduced compared to control synapses. In contrast, midazolam increases macroscopic desensitization at network synapses by altering receptor affinity without concurrently modifying desensitization rates. These differences in gating between the two drugs are shown to alter network activity in stereotypically different ways. Specifically, propofol dramatically increases the amount of excitatory drive necessary for synchronized behavior relative to control, which is not the case for midazolam. Moreover, the range of parameters for which synchrony occurs is larger for propofol but smaller for midazolam, relative to control. This is an important first step in linking alterations in channel kinetics with behavioral changes.

Algorithms↗

PubMed2003

Protein complexes and functional modules in molecular networks.

Proteins, nucleic acids, and small molecules form a dense network of molecular interactions in a cell. Molecules are nodes of this network, and the interactions between them are edges. The architecture of molecular networks can reveal important principles of cellular organization and function, similarly to the way that protein structure tells us about the function and organization of a protein. Computational analysis of molecular networks has been primarily concerned with node degree [Wagner, A. & Fell, D. A. (2001) Proc. R. Soc. London Ser. B 268, 1803-1810; Jeong, H., Tombor, B., Albert, R., Oltvai, Z. N. & Barabasi, A. L. (2000) Nature 407, 651-654] or degree correlation [Maslov, S. & Sneppen, K. (2002) Science 296, 910-913], and hence focused on single/two-body properties of these networks. Here, by analyzing the multibody structure of the network of protein-protein interactions, we discovered molecular modules that are densely connected within themselves but sparsely connected with the rest of the network. Comparison with experimental data and functional annotation of genes showed two types of modules: (i) protein complexes (splicing machinery, transcription factors, etc.) and (ii) dynamic functional units (signaling cascades, cell-cycle regulation, etc.). Discovered modules are highly statistically significant, as is evident from comparison with random graphs, and are robust to noise in the data. Our results provide strong support for the network modularity principle introduced by Hartwell et al. [Hartwell, L. H., Hopfield, J. J., Leibler, S. & Murray, A. W. (1999) Nature 402, C47-C52], suggesting that found modules constitute the "building blocks" of molecular networks.

Biophysical Phenomena↗

PubMed2006

Functional maturation of adult-generated granule cells.

The excitability and connectivity of adult-generated granule cells dictate to what extent newborn neurons participate in the hippocampal network. These functional parameters evolve as newborn cells mature and interact with the existing circuit. The progression of granule cell maturation during neonatal development appears to be reiterated in the adult, but with some caveats. New approaches to identify and track newborn neurons are revealing the timing of this process, as well as its sensitivity to activity-dependent regulation.

Aging↗

PubMed2006

Effective connectivity within the distributed cortical network for face perception.

Face perception elicits activation within a distributed cortical network in the human brain. The network includes visual ("core") regions, as well as limbic and prefrontal ("extended") regions, which process invariant facial features and changeable aspects of faces, respectively. We used functional Magnetic Resonance Imaging and Dynamic Causal Modeling to investigate effective connectivity and functional organization between and within the core and the extended systems. We predicted a ventral rather than dorsal connection between the core and the extended systems during face viewing and tested whether valence and fame would alter functional coupling within the network. We found that the core system is hierarchically organized in a predominantly feed-forward fashion, and that the fusiform gyrus (FG) exerts the dominant influence on the extended system. Moreover, emotional faces increased the coupling between the FG and the amygdala, whereas famous faces increased the coupling between the FG and the orbitofrontal cortex. Our results demonstrate content-specific dynamic alterations in the functional coupling between visual-limbic and visual-prefrontal face-responsive pathways.

Adult↗