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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↗

Functional local connections with differential activity-dependence and critical periods surrounding the primary auditory cortex in rat cerebral slices.

Sensory information is processed in neural networks connecting the primary sensory cortices with surrounding higher areas. Here, we investigated the properties of local connections between the primary auditory cortex (area 41) and surrounding areas (areas 20, 36, 18a and 39) in rat cerebral slices. Neural activities elicited by repetitive electrical stimulation were visualized using the activity-dependent changes in endogenous fluorescence derived from mitochondrial flavoproteins, which mostly reflect activities produced by polysynaptic glutamatergic transmission. Polysynaptic feedforward propagation was dominant compared with the corresponding polysynaptic feedback propagation between the primary (area 41) and secondary (areas 20 and 36) auditory cortices, while such a tendency was less clear in other pathways. Long inter-areal (>1 mm) propagation with the same dominancy was observed after layer V stimulation between areas 41 and 20, and was not affected by cutting the underlying white matter. Activity-dependent changes in neural activities induced by low-frequency stimulation in the presence of 1 microM bicuculline were investigated using Ca2+ imaging. Significant potentiation of the polysynaptic Ca2+ activities was only observed in polysynaptic feedforward pathways from the primary to secondary auditory cortices. Experience-dependence of the connections between areas 41 and 20 was investigated using flavoprotein fluorescence imaging. The activities from areas 41 to 20 were reduced by cochlear lesions produced at P12 but not at P28, while the activities from areas 20 to 41 were reduced by the lesions at P28, suggesting the critical period for the polysynaptic feedforward connection was before P28, while for the polysynaptic feedback connection was after P28.

Animals↗

Partial hippocampal inactivation: effects on spatial memory performance in aged and young rats.

Changes in anatomical or functional connectivity during normal aging are thought to contribute to cognitive alterations over the lifespan. Neural network theories predict that synaptic loss in an aging brain could place the organism near the point of dysfunction in the nonlinear curve defining neural compromise versus performance. The present experiments examined whether aged rats are closer to this point of behavioral dysfunction by reversibly inactivating one or both hippocampal hemispheres. As expected, bilateral tetracaine inactivation of the hippocampus disrupted spatial memory in both age groups. Unilateral left hippocampal inactivation significantly increased errors only in aged rats; however, unilateral inactivation of the right hippocampus had no effect. The present outcome could reflect more extensive synaptic dysfunction in the aged right hippocampus or a greater involvement of the left hippocampus in spatial working memory problems.

Age Factors↗

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↗

An important base triple anchors the substrate helix recognition surface within the Tetrahymena ribozyme active site.

Key to understanding the structural biology of catalytic RNA is determining the underlying networks of interactions that stabilize RNA folding, substrate binding, and catalysis. Here we demonstrate the existence and functional importance of a Hoogsteen base triple (U300.A97-U277), which anchors the substrate helix recognition surface within the Tetrahymena group I ribozyme active site. Nucleotide analog interference suppression analysis of the interacting functional groups shows that the U300.A97-U277 triple forms part of a network of hydrogen bonds that connect the P3 helix, the J8/7 strand, and the P1 substrate helix. Product binding and substrate cleavage kinetics experiments performed on mutant ribozymes that lack this base triple (C A-U, U G-C) or replace it with the isomorphous C(+).G-C triple show that the A97 Hoogsteen triple contributes to the stabilization of both substrate helix docking and the conformation of the ribozyme's active site. The U300. A97-U277 base triple is not formed in the recently reported crystallographic model of a portion of the group I intron, despite the presence of J8/7 and P3 in the RNA construct [Golden, B. L., Gooding, A. R., Podell, E. R. & Cech, T. R. (1998) Science 282, 259-264]. This, along with other biochemical evidence, suggests that the active site in the crystallized form of the ribozyme is not fully preorganized and that substantial rearrangement may be required for substrate helix docking and catalysis.

Animals↗

Synaptic connectivity in cultured hypothalamic neuronal networks.

We have developed a novel approach to analyze the synaptic connectivity of spontaneously active networks of hypothalamic neurons in culture. Synaptic connections were identified by recording simultaneously from pairs of neurons using the whole cell configuration of the patch-clamp technique and testing for evoked postsynaptic current responses to electrical stimulation of one of the neurons. Excitatory and inhibitory responses were distinguished on the basis of their voltage and time dependence. The distribution of latencies between presynaptic stimulation and postsynaptic response showed multiple peaks at regular intervals, suggesting that responses via both monosynaptic and polysynaptic paths were recorded. The probability that an excitatory event is transmitted to another excitatory neuron and results in an above-threshold stimulation was found to be only one in three to four. This low value indicates that in addition to evoked synaptic responses other sources of excitatory drive must contribute to the spontaneous activity observed in these networks. The various types of synaptic connections (excitatory and inhibitory, monosynaptic, and polysynaptic) were counted, and the observations analyzed using a probabilistic model of the network structure. This analysis provides estimates for the ratio of inhibitory to excitatory neurons in the network (1:1.5) and for the ratio of postsynaptic cells receiving input from a single GABAergic or glutamatergic neuron (3:1). The total number of inhibitory synaptic connections was twice that of excitatory connections. Cell pairs mutually connected by an excitatory and an inhibitory synapse occurred significantly more often than predicted by a random process. These results suggests that the formation of neuronal networks in vitro is controlled by cellular mechanisms that favor inhibitory connections in general and specifically enhance the formation of reciprocal connections between pairs of excitatory and inhibitory neurons. These mechanisms may contribute to network formation and function in vivo.

Animals↗

A complex-valued RTRL algorithm for recurrent neural networks.

A complex-valued real-time recurrent learning (CRTRL) algorithm for the class of nonlinear adaptive filters realized as fully connected recurrent neural networks is introduced. The proposed CRTRL is derived for a general complex activation function of a neuron, which makes it suitable for nonlinear adaptive filtering of complex-valued nonlinear and nonstationary signals and complex signals with strong component correlations. In addition, this algorithm is generic and represents a natural extension of the real-valued RTRL. Simulations on benchmark and real-world complex-valued signals support the approach.

Algorithms↗

Strongly anionic sites in peripheral axons of the rat sciatic nerve: light and electron microscopic detection using cationic colloidal iron.

Anionic sites in the rat sciatic nerve were studied by light and electron microscopy using a fine-granular cationic colloidal iron staining method (Murakami et al., 1986). The axon, as well as the endoneurium, the epineurium and the basement membrane of Schwann cells, were all confirmed to react strongly to the cationic colloidal iron even at a pH value of 1.0-2.0. Prior hyaluronidase digestion decreased the colloidal strain of the epineurium; chondroitinase ABC weakened that of the endoneurium and the basement membrane of Schwann cells. However, as axons retained stainability with cationic colloidal iron even after combined digestion with hyaluronidase, chondroitinase ABC, heparitinase and keratanase, the authors consider sulfated glycoconjugates and not those substances which are digestible with such common enzymes. The acid groups ionized at pH 1.0 are most likely sulfate groups. Methylation deprived the axon of the reactivity to cationic colloidal iron staining, and even subsequent saponification could not recover this reactivity to its full extent. In the axon, electron microscopy revealed a deposition of colloidal iron on the external surfaces of microtubules and neurofilaments in the axoplasm and of very fine filaments connecting them. This highly negatively charged intra-axonal network could also serve toward a supportive function in maintaining the spatial distribution of microtubules either mechanically or through electrostatic repulsion or, possibly, serve as an intra-axona cation exchange reservoir.

Animals↗

Emergent properties of layer 2/3 neurons reflect the collinear arrangement of horizontal connections in tree shrew visual cortex.

The superficial layers of primary visual cortex, unlike layer 4, have an extensive network of long-range horizontal connections linking sites of similar orientation preference. To identify possible functional consequences of this distinct anatomy, we compared the receptive field properties of layers 2/3 and 4 neurons in tree shrew primary visual cortex with electrophysiological recordings. We found that elongated receptive fields, strong orientation tuning, and length summation (properties predicted by the anatomy of the horizontal connections) are present in layer 2/3 neurons, but not in layer 4 neurons. We further characterized the summation fields of layer 2/3 neurons and found axis and orientation-specific facilitation that matched the distribution of horizontal connections. The functional signature of horizontal connections was also evident in the population response of layer 2/3 neurons; the intrinsic signal activation pattern elicited by an array of collinear Gabor elements was significantly stronger than that elicited by a noncollinear array. Furthermore, our results showed that this enhancement of population response was achieved without compromising spatial resolution along the collinear axis, providing stimulus-specific facilitation without filling in between stimuli. Taken together, these results suggest that horizontal connections play a significant role in shaping the visual responses of layer 2/3 neurons.

Animals↗

Neural network simulations, cortical connectivity, and schizophrenic psychosis.

Recent studies have suggested that reduced corticocortical connectivity is associated with schizophrenia. My colleagues and I have used neural network simulations to explore parallel, distributed processing systems with reduced connectivity. These systems often behaved in a "schizophrenic-like" manner. Excessively pruned attractor networks became functionally fragmented, suggesting "loose associations," and produced recurrent, intrusive representations suggestive of delusions. Pruning backpropagation simulations of speech perception networks produced spontaneous output, which provided a model of auditory hallucination or "voices." This model also suggested how dopamine-blocking drugs may reduce positive symptoms, and why negative symptoms arise in the wake of positive symptoms.

Bias↗

Attention-dependent changes of activation and connectivity in dichotic listening.

Functional studies of auditory spatial attention generally report enhanced neural responses in auditory cortical regions. However, activity in regions of the spatial attentional network as described in the visual modality is not consistently observed. Data analysis limitations due to oppositely lateralized activity depending on the side of attentional orientation and heterogeneity of paradigms makes it hard to untangle the possible causes of these various activation patterns. In the present article we present a PET study of auditory spatial attention in which we manipulated orientation of attention, attentional load, and difficulty of the task by means of the dichotic listening paradigm. Moreover, we designed a systematic, voxel-specific, method in order to deal with oppositely lateralized activity. The results show that when listeners are involved in auditory spatial attention tasks an interacting network of frontal, temporal, and parietal regions is activated. Selective orientation toward one side mostly yields activity and connectivity modulations in the hemisphere contralateral to the attended side while in divided attention activity is mostly bilateral. Taken together, our observations are consistent with the idea of a multimodal large-scale attentional network.

Adult↗

Architecture must document functional evidence to explain the living rhythm.

The central theme of surgical procedures is to interact structure and function. Two reviews of architecture by Torrent-Guasp and Lunkenheimer provide anatomic observations, and then only deduce, rather than test and verify functional relationships. Lunkenheimer previously showed the reciprocal helical configuration of the connective tissue scaffold, a weave-like network that may be the lattice for the descending and ascending segments of Torrent-Guasp's apical loop formed from the helical band. Lunkenheimer stresses cardiac development from a blood vessel, and exposes the need to disregard heart formation by a band that develops between the pulmonary artery and aorta. Torrent-Guasp's band-like concept is confirmed by MRI and sonomicrometer measurements, together with early systolic filling by ongoing, unopposed contraction of the ascending segment of the apical loop. This muscular component contradicts conventional concepts that elastic recoil causes rapid ventricular filling. However, direct physiologic measurements show that Torrrent-Guasp's physiologic timing sequence must be revised. While presumption is an important first step, proof of the marriage of structure and function happens only with measurement, a critical step before surgical action.

Biomechanical Phenomena↗

The chronoarchitecture of the cerebral cortex.

We review here a new approach to mapping the human cerebral cortex into distinct subdivisions. Unlike cytoarchitecture or traditional functional imaging, it does not rely on specific anatomical markers or functional hypotheses. Instead, we propose that the unique activity time course (ATC) of each cortical subdivision, elicited during natural conditions, acts as a temporal fingerprint that can be used to segregate cortical subdivisions, map their spatial extent, and reveal their functional and potentially anatomical connectivity. We argue that since the modular organisation of the brain and its connectivity evolved and developed in natural conditions, these are optimal for revealing its organisation. We review the concepts, methodology and first results of this approach, relying on data obtained with functional magnetic resonance imaging (fMRI) when volunteers viewed traditional stimuli or a James Bond movie. Independent component analysis (ICA) was used to identify voxels belonging to distinct functional subdivisions, based on their differential spatio-temporal fingerprints. Many more regions could be segregated during natural viewing, demonstrating that the complexity of natural stimuli leads to more differential responses in more functional modules. We demonstrate that, in a single experiment, a multitude of distinct regions can be identified across the whole brain, even within the visual cortex, including areas V1, V4 and V5. This differentiation is based entirely on the differential ATCs of different areas during natural viewing. Distinct areas can therefore be identified without any a priori hypothesis about their function or spatial location. The areas we identified corresponded anatomically across subjects, and their ATCs showed highly area-specific inter-subject correlations. Furthermore, natural conditions led to a significant de-correlation of interregional ATCs compared to rest, indicating an increase in regional specificity during natural conditions. In contrast, the correlation between ATCs of distant regions of known substantial anatomical connections increased and reflected their known anatomical connectivity pattern. We demonstrate this using the example of the language network involving Broca's and Wernicke's area and homologous areas in the two hemispheres. In conclusion, this new approach to brain mapping may not only serve to identify novel functional subdivisions, but to reveal their connectivity as well.

Brain Mapping↗

Aging of myocardial collagen.

The objective of this article was to present a review of the collagen tissue of the heart muscle as a function of age. The myocardial collagen matrix consists of a network of fibrillar collagen which is intimately connected to the myocyte. Most collagen fibers reside in parallel with myocytes. These fibers may have a wavy, taut or coiled appearance. Fibrillar collagen types I and III are the major components of the myocardial collagen matrix. Collagen type I has been found to represent nearly 80% of the total collagen protein, while type III collagen is present in lower proportions (approximately 11%). Cardiac fibroblasts are the cellular source of fibrillar collagen, cardiac myocytes expressing only mRNA for type IV collagen. Collagens types I and III exhibit a high tensile strength which plays an important role in the behavior of the ventricle during the cardiac cycle. The collagen concentration and the intermolecular cross-linking of collagen increase with age. Measurements of collagen content in myocardial tissue suggest that it is the type I collagen fibers that increase in number and thickness in the aged. At the same time, electron microscopic observations have shown an increase in the number of collagen fibrils with a large diameter in the aging heart. The mechanism responsible for the myocardial fibrosis in the senescent myocardium is unclear. The collagen deposition in the myocardium could be due to the regulation of collagen biosynthesis at pre-translational levels. It is possible that the regulatory elements involved in this process are growth factors such as TGF-beta 1 and hormones and neurotransmitters. Details of regulatory mechanism that may come into play during aging may be elucidated by further investigations. The accumulation of collagen within the myocardium increases muscle stiffness. Myocardial function is affected by this process; this is usually reflected by incomplete relaxation during early diastolic filling, and presumably account for the decrease in early left ventricular diastolic compliance.

Collagen↗

Analysis of optimal phenotypic space using elementary modes as applied to Corynebacterium glutamicum.

BACKGROUND: Quantification of the metabolic network of an organism offers insights into possible ways of developing mutant strain for better productivity of an extracellular metabolite. The first step in this quantification is the enumeration of stoichiometries of all reactions occurring in a metabolic network. The structural details of the network in combination with experimentally observed accumulation rates of external metabolites can yield flux distribution at steady state. One such methodology for quantification is the use of elementary modes, which are minimal set of enzymes connecting external metabolites. Here, we have used a linear objective function subject to elementary modes as constraint to determine the fluxes in the metabolic network of Corynebacterium glutamicum. The feasible phenotypic space was evaluated at various combinations of oxygen and ammonia uptake rates. RESULTS: Quantification of the fluxes of the elementary modes in the metabolism of C. glutamicum was formulated as linear programming. The analysis demonstrated that the solution was dependent on the criteria of objective function when less than four accumulation rates of the external metabolites were considered. The analysis yielded feasible ranges of fluxes of elementary modes that satisfy the experimental accumulation rates. In C. glutamicum, the elementary modes relating to biomass synthesis through glycolysis and TCA cycle were predominantly operational in the initial growth phase. At a later time, the elementary modes contributing to lysine synthesis became active. The oxygen and ammonia uptake rates were shown to be bounded in the phenotypic space due to the stoichiometric constraint of the elementary modes. CONCLUSION: We have demonstrated the use of elementary modes and the linear programming to quantify a metabolic network. We have used the methodology to quantify the network of C. glutamicum, which evaluates the set of operational elementary modes at different phases of fermentation. The methodology was also used to determine the feasible solution space for a given set of substrate uptake rates under specific optimization criteria. Such an approach can be used to determine the optimality of the accumulation rates of any metabolite in a given network.

Corynebacterium glutamicum↗

Dual intracellular recording of neocortical neurons in a neuron-glia co-culture system.

Measurement of synchronized activities in neocortical networks is critical for understanding integrated brain function. We describe here a procedure for intracellular recording of activity in two functionally connected neurons using patch electrodes in neuron-glia co-cultures. Rat neocortical neurons survive on monolayers of astrocytes for far longer periods (3-4 weeks) than in their absence. This prolonged survival facilitates the detection of functional synapses which are readily identified in vitro by means of dual intracellular recording using two patch electrodes. The neuron-glia co-culture system appears to be useful not only for studying the formation of neural networks in vitro but also for determining the effects of physiologically active substances and chemicals on synapse formation.

Animals↗

Learning, plasticity, and recovery in the central nervous system.

Cerebral functions can be described by the interaction of different brain regions as parts of distributed networks. Learning is seen as a refinement of the connection between the various parts of these networks. Plastic changes, as illustrated in brain charting techniques, are the result of learning (or use) in normal brains or found as adaptation (active or passive) after peripheral or central lesions. The relation between brain reorganization and recovery of function is investigated by two recent studies relating the training-induced improvement of lost function to changes in the brain. Others search for the effects of passive stimulation and drug influences. Independently of the approach, however, the general idea is that recovery can be seen as a reconnection between the remaining parts of the disturbed network.

Adaptation, Physiological↗