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Functional magnetic resonance imaging and cognition at the very early stage of MS.

Dysfunction of high controlled information processing is present in patients with multiple sclerosis (MS) right at the beginning of the disease. One hypothesis is that disruption of communication inside large-scale cortical networks, occurring as a consequence of white matter damage, may constitute the anatomical substrate of cognitive impairment at the very early stage of MS. Disturbance of interregional synchronization might be the main pathogenic factor in controlled information processing deficiency in early MS. Preliminary functional MRI studies (fMRI) have provided important clues to corroborate the connectivity hypotheses. First, brain connectivity assessed by fMRI has brought new data about the influence of diffuse white matter damage on connectivity efficiency inside large-scale networks. These studies have suggested that connectivity disturbances occur inside the working memory network in patients at the very early stage of MS and appear related to the extent of structural white matter damage. Also, fMRI studies have suggested that patients may partially compensate for connectivity impairment by a greater cognitive control. Such a compensatory mechanism could limit the determinant functional impact of diffuse white matter damage on high controlled information processing.

Age of Onset↗

Lateral excitation within the olfactory bulb.

Lateral inhibition is a common feature of cortical networks, serving such functions as contrast enhancement. In the olfactory bulb, inhibition is imbedded in the local connectivity at dendrodendritic synapses between mitral cells and interneurons. However, there is also evidence for excitatory interactions between mitral cells despite the lack of direct synaptic connections. This lateral excitation, although a less well recognized feature of the circuit, provides a potentially powerful mechanism to enhance coordinated activity. We examined lateral excitation in paired recordings between mitral cells projecting to the same glomerulus. Trains of action potentials in one mitral cell evoked autoexcitation in the stimulated cell and a prolonged depolarization in the second cell. This lateral excitation was absent in connexin36(-/-) mice, which lack mitral-mitral cell gap junctions. However, spillover of dendritically released glutamate contributed to lateral excitation during concerted mitral cell excitation or by single-cell activity if glutamate uptake was blocked. Our results suggest that electrical coupling and spillover create a lateral excitatory network within the glomerulus, thus markedly amplifying the sensitivity of each glomerulus to incoming sensory input.

Action Potentials↗

Molecular interaction map of the mammalian cell cycle control and DNA repair systems.

Eventually to understand the integrated function of the cell cycle regulatory network, we must organize the known interactions in the form of a diagram, map, and/or database. A diagram convention was designed capable of unambiguous representation of networks containing multiprotein complexes, protein modifications, and enzymes that are substrates of other enzymes. To facilitate linkage to a database, each molecular species is symbolically represented only once in each diagram. Molecular species can be located on the map by means of indexed grid coordinates. Each interaction is referenced to an annotation list where pertinent information and references can be found. Parts of the network are grouped into functional subsystems. The map shows how multiprotein complexes could assemble and function at gene promoter sites and at sites of DNA damage. It also portrays the richness of connections between the p53-Mdm2 subsystem and other parts of the network.

Animals↗

Unifying measures of gene function and evolution.

Recent genome analyses revealed intriguing correlations between variables characterizing the functioning of a gene, such as expression level (EL), connectivity of genetic and protein-protein interaction networks, and knockout effect, and variables describing gene evolution, such as sequence evolution rate (ER) and propensity for gene loss. Typically, variables within each of these classes are positively correlated, e.g. products of highly expressed genes also have a propensity to be involved in many protein-protein interactions, whereas variables between classes are negatively correlated, e.g. highly expressed genes, on average, evolve slower than weakly expressed genes. Here, we describe principal component (PC) analysis of seven genome-related variables and propose biological interpretations for the first three PCs. The first PC reflects a gene's 'importance', or the 'status' of a gene in the genomic community, with positive contributions from knockout lethality, EL, number of protein-protein interaction partners and the number of paralogues, and negative contributions from sequence ER and gene loss propensity. The next two PCs define a plane that seems to reflect the functional and evolutionary plasticity of a gene. Specifically, PC2 can be interpreted as a gene's 'adaptability' whereby genes with high adaptability readily duplicate, have many genetic interaction partners and tend to be non-essential. PC3 also might reflect the role of a gene in organismal adaptation albeit with a negative rather than a positive contribution of genetic interactions; we provisionally designate this PC 'reactivity'. The interpretation of PC2 and PC3 as measures of a gene's plasticity is compatible with the observation that genes with high values of these PCs tend to be expressed in a condition- or tissue-specific manner. Functional classes of genes substantially vary in status, adaptability and reactivity, with the highest status characteristic of the translation system and cytoskeletal proteins, highest adaptability seen in cellular processes and signalling genes, and top reactivity characteristic of metabolic enzymes.

Animals↗

Model-free functional MRI analysis based on unsupervised clustering.

Conventional model-based or statistical analysis methods for functional MRI (fMRI) are easy to implement, and are effective in analyzing data with simple paradigms. However, they are not applicable in situations in which patterns of neural response are complicated and when fMRI response is unknown. In this paper the "neural gas" network is adapted and rigourosly studied for analyzing fMRI data. The algorithm supports spatial connectivity aiding in the identification of activation sites in functional brain imaging. A comparison of this new method with Kohonen's self-organizing map and with a fuzzy clustering scheme based on deterministic annealing is done in a systematic fMRI study showing comparative quantitative evaluations. The most important findings in this paper are: (1) both "neural gas" and the fuzzy clustering technique outperform Kohonen's map in terms of identifying signal components with high correlation to the fMRI stimulus, (2) the "neural gas" outperforms the two other methods with respect to the quantization error, and (3) Kohonen's map outperforms the two other methods in terms of computational expense. The applicability of the new algorithm is demonstrated on experimental data.

Adult↗

Distributed synaptic modification in neural networks induced by patterned stimulation.

Activity-dependent changes in synaptic efficacy or connectivity are critical for the development, signal processing and learning and memory functions of the nervous system. Repetitive correlated spiking of pre- and postsynaptic neurons can induce a persistent increase or decrease in synaptic strength, depending on the timing of the pre- and postsynaptic excitation. Previous studies on such synaptic modifications have focused on synapses made by the stimulated neuron. Here we examine, in networks of cultured hippocampal neurons, whether and how localized stimulation can modify synapses that are remote from the stimulated neuron. We found that repetitive paired-pulse stimulation of a single neuron for brief periods induces persistent strengthening or weakening of specific polysynaptic pathways in a manner that depends on the interpulse interval. These changes can be accounted for by correlated pre- and postsynaptic excitation at distant synaptic sites, resulting from different transmission delays along separate pathways. Thus, through such a 'delay-line' mechanism, temporal information coded in the timing of individual spikes can be converted into and stored as spatially distributed patterns of persistent synaptic modifications in a neural network.

Animals↗

Exponential stability of Cohen-Grossberg neural networks.

Exponential stabilities of the Cohen-Grossberg neural network with and without delays are analyzed. By Liapunov functions/functionals, sufficient conditions are obtained for general exponential stability, while by using a comparison result from the theory of monotone dynamical systems, componentwise exponential stability is also discussed. All results are established without assuming any symmetry of the connection matrix, and the differentiability and monotonicity of the activation functions.

Neural Networks, Computer↗

Using a hybrid neural system to reveal regulation of neuronal network activity by an intrinsic current.

The generation of rhythmic patterns by neuronal networks is a complex phenomenon, relying on the interaction of numerous intrinsic and synaptic currents, as well as modulatory agents. To investigate the functional contribution of an individual ionic current to rhythmic pattern generation in a network, we constructed a hybrid system composed of a silicon model neuron and a heart interneuron from the heartbeat timing network of the medicinal leech. When the model neuron and a heart interneuron are connected by inhibitory synapses, they produce rhythmic activity similar to that observed in the heartbeat network. We focused our studies on investigating the functional role of the hyperpolarization-activated inward current (I(h)) on the rhythmic bursts produced by the network. By introducing changes in both the model and the heart interneuron, we showed that I(h) determines both the period of rhythmic bursts and the balance of activity between the two sides of the network, because the amount and the activation/deactivation time constant of I(h) determines the length of time that a neuron spends in the inhibited phase of its burst cycle. Moreover, we demonstrated that the model neuron is an effective replacement for a heart interneuron and that changes made in the model can accurately mimic similar changes made in the living system. Finally, we used a previously developed mathematical model (Hill et al. 2001) of two mutually inhibitory interneurons to corroborate these findings. Our results demonstrated that this hybrid system technique is advantageous for investigating neuronal properties that are inaccessible with traditional techniques.

Analysis of Variance↗

Fluctuation functions in aqueous NaCl and urea.

We earlier devised a set of fluctuation functions that provide relative qualitative differences of the amplitude (intensity) and the wavelength (extensity) of fluctuations in entropy and volume and the entropy-volume cross fluctuations. We discuss the mixing schemes in aqueous NaCl and urea using these fluctuation functions. Our earlier studies by using the second and third derivatives of Gibbs energy indicated that their effects on H2O are qualitatively different. An NaCl hydrates 7.5 molecules of H2O but leaves the bulk H2O away from the hydration shell unperturbed. Urea, on the other hand, connects onto the hydrogen bond network of H2O but retards the degree of fluctuation inherent in H2O. The behavior of the fluctuation functions calculated here are consistent with the above mixing schemes. Furthermore, urea was found to reduce the wavelength of fluctuation more strongly than NaCl.

Journal Article↗

[Mechanisms common to biological macromolecules and gels].

Functional Biological macromolecules arising from folding, cross-connection and solvation of long chain biopolymers forming three-dimensional networks may be regarded as Gels. Both involve identical internal competitive forces that are selectively influenced by external conditions and conspire to adjust conformations and modulate activities. In spite of important differences in size, chemical composition, polymer bonding, density and configuration, biological macromolecules indeed manifest some of the essential physical-chemical properties of gels when involved in equilibria and rate processes. This result represents a presumptive evidence for common underlying mechanisms in functional molecules and gels. Thus, the present and highly perfectible model explains why and how, depending on initial conditions, a system may respond differently to an external parameter, and similarly to different parameters. Moreover, the fact that any localized change in one of the competitive forces gives to a pressure in the system as a whole provides an explanation for the mechanism of the transmission of information.

Biopolymers↗

Network organization of interstitial connective tissue cells in the human endolymphatic duct.

The human endolymphatic duct (ED) and sac of the inner ear have been suggested to control endolymph volume and pressure. However, the physiological mechanisms for these processes remain obscure. We investigated the organization of the periductal interstitial connective tissue cells and extracellular matrix (ECM) in four freshly fixed human EDs by transmission electron microscopy and by immunohistochemistry. The unique surgical material allowed a greatly improved structural and epitopic preservation of tissue. Periductal connective tissue cells formed frequent intercellular contacts and focally occurring electron-dense contacts to ECM structures, creating a complex tissue network. The connective tissue cells also formed contacts with the basal lamina of the ED epithelium and the bone matrix, connecting the ED with the surrounding bone of the vestibular aqueduct. The interstitial connective tissue cells were non-endothelial and non-smooth muscle fibroblastoid cells. We suggest that the ED tissue network forms a functional mechanical entity that takes part in the control of inner ear fluid pressure and endolymph resorption.

Connective Tissue Cells↗

Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses.

Locally projecting GABAergic interneurons are the major providers of inhibition in the neocortex and play a crucial role in several brain functions. Neocortical interneurons are connected via electrical and chemical synapses that may be crucial in modulating complex network oscillations. We investigated the properties of spontaneous and evoked IPSCs in two morphologically and physiologically identified interneuron subtypes, the fast-spiking (FS) and low threshold-spiking (LTS) cells in layer V of rodent sensorimotor cortex. We found that IPSCs recorded in FS cells were several orders of magnitude more frequent, larger in amplitude, and had faster kinetics than IPSCs recorded in LTS cells. GABA(A) receptor alpha- and beta-subunit selective modulators, zolpidem and loreclezole, had different effects on IPSCs in FS and LTS interneurons, suggesting differential expression of GABA(A) receptor subunit subtypes. These pharmacological data indicated that the alpha1 subunit subtype is poorly expressed by LTS cells but makes a large contribution to GABA(A) receptors on FS cells. This was confirmed by experiments performed in genetically modified mice in which the alpha1 subunit had been made insensitive to benzodiazepine-like agonists. These results suggest that differences in IPSC waveform are likely attributable to distinctive expression of GABA(A) receptor subunits in FS and LTS cells. The particular properties of GABAergic input on different interneuronal subtypes might have important consequences for generation and pacing of cortical rhythms underlying several brain functions. Moreover, selective pharmacological manipulation of distinct inhibitory circuits might allow regulation of pyramidal cell activities under specific physiological and pathophysiological conditions.

Action Potentials↗

Connectivities and synchronous firing in cortical neuronal networks.

Network connectivities ((-)k) of cortical neural cultures are studied by synchronized firing and determined from measured correlations between fluorescence intensities of firing neurons. The bursting frequency (f) during synchronized firing of the networks is found to be an increasing function of (-)k. With f taken to be proportional to (-)k, a simple random model with a (-)k dependent connection probability p((-)k).has been constructed to explain our experimental findings successfully.

Action Potentials↗

Perceptions and attitudes of land managers in multi-tenure reserve networks and the implications for conservation.

Multi-tenure reserve networks aim to connect areas managed for biodiversity conservation across public and private land and address the impacts of fragmentation on both biotic and social systems. The operation and function of Australian multi-tenure reserve networks as perceived by their land managers was investigated. Overall, the conservation of natural assets was the most frequently reported primary reason for involvement in a network. The perceived aims of the respective networks largely reflected the response identified for involvement and management. Over 88% of managers considered their involvement in multi-tenure reserve networks to be a positive or very positive experience. A lack of resources and time for management were considered major limitations of these networks. The majority (80%) of private land managers within networks were willing to be included in a national reserve system of conservation lands. As the Australian National Reserve System currently incorporates mostly public land, these findings have important and potentially positive implications for a greater role for protected private land.

Agriculture↗

Cognitive deficits and the neurobiology of schizophrenia.

Recent research in schizophrenia has demonstrated widespread abnormalities in patients' brain structure, cognitive function, and physiology. These abnormalities are most probably developmental in origin and involve a network of connected frontal-temporal-limbic structures.

Brain↗

Cerebral mechanisms of prosodic integration: evidence from connected speech.

Using functional Magnetic Resonance Imaging (fMRI) and long connected speech stimuli, we addressed the question of neuronal networks involved in prosodic integration by comparing (1) differences in brain activity when hearing connected speech stimuli with high and low degrees of prosodic expression; (2) differences in brain activity in two different diotic listening conditions (normal speech delivery to both ears, i.e., NN; and low-pass-filtered speech delivery to both ears, i.e., FF); and (3) effects of high and low degrees of prosodic information in the NN and FF conditions. Twelve right-handed French men listened passively to the stimuli. Each stimulus induced a specific cerebral network, the flat one weakening activations, which were mainly reduced to the bilateral STG for both listening conditions. High degrees of prosodic information were found to trigger right specific activations in a wider neuronal network involved in speech integration (such as BA44, BA21-22 and BA39-40) than low degrees of prosodic information did. More precisely, the right BA44 was found to be specifically involved in the process of F(0) modulations, which are the main acoustic correlate of prosody. Not only do the results achieved in the present experiment using 30-s-long connected speech stimuli show the involvement of a bilateral neuronal network but they also strongly suggest that high degrees of prosodic information elicit activations in a wider neuronal network involved in speech perception than low degrees of prosodic information do.

Acoustic Stimulation↗

Cell shape, division and development: the 2002 American Society for Microbiology (ASM) conference on prokaryotic development.

In the last decade, the use of cytological techniques, together with the analysis of complete genomes, has dramatically advanced our understanding of bacterial development. Work on several well-developed model systems such as Bacillus subtilis, Caulobacter crescentus, Myxococcus xanthus and Streptomyces spp., has provided us with an in-depth understanding of processes such as sporulation, multicellular behaviour and the bacterial cell cycle. At the same time, these studies have revolutionized our view of the bacterial cell and shown it to be a highly complex entity with spatial and temporal organization. The recent American Society for Microbiology (ASM) conference on prokaryotic development demonstrated that several laboratories have now started to connect data obtained through functional genomic analysis with subcellular organization, thereby generating three-dimensional regulatory networks. This meeting report highlights new findings in the field, such as regulation of protein localization during sporulation and the cell cycle, control of cell-cell interaction and the initiation of cell division.

Bacillus subtilis↗

Single-channel currents trigger action potentials in small cultured hippocampal neurons.

Spontaneous neuronal impulse activity appears to play a key role in some neural processes, such as the normal establishment of interneuronal connections during development. In addition, spontaneous impulses may be essential for the functional operation of neuronal networks. Mechanisms of spontaneous non-pacemaker impulse generation are, however, not well known. In this work, spontaneous electrical activity in small cultured hippocampal neurons from rat was studied with tight-seal recording techniques. The results demonstrate that spontaneous individual openings of single ion channels can trigger impulse generation in these high-resistance cells. First, impulses recorded in the whole-cell mode were apparently induced by spontaneous plateau-potential events showing the characteristics expected from individual openings and closures of ion channels. Second, patch-clamp recordings in the cell-attached configuration showed that openings of single ion channels in the patch membrane could trigger cellular impulses, detected as biphasic current deflections. These findings suggest that the random gating of ion channel molecules can be used as a mechanism for stochastic triggering of spontaneous impulses in mammalian central neurons.

Action Potentials↗