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Glutamate receptor blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex.

The segregation of thalamocortical inputs into eye-specific stripes in the developing cat or monkey visual cortex is prevented by manipulations that perturb or abolish neural activity in the visual pathway. Such findings show that proper development of the functional organization of visual cortex is dependent on normal patterns of neural activity. The generalisation of this conclusion to other sensory cortices has been questioned by findings that the segregation of thalamocortical afferents into a somatotopic barrel pattern in developing rodent primary somatosensory cortex (S1) is not prevented by activity blockade. We show that a temporary block of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in rat S1 during the critical period for barrel development disrupts the topographic refinement of thalamocortical connectivity and columnar organization. These effects are evident well after the blockade is ineffective and thus may be permanent. Our findings show that neural activity and specifically the activation of postsynaptic cortical neurons has a prominent role in establishing the primary sensory map in S1, as well as the topographic organization of higher order synaptic connections.

2-Amino-5-phosphonovalerate↗

Delineating gray and white matter involvement in brain lesions: three-dimensional alignment of functional magnetic resonance and diffusion-tensor imaging.

OBJECT: The role of functional magnetic resonance (fMR) imaging has become increasingly important in the presurgical mapping of gray matter. Neurosurgical interventions often involve fiber bundles that connect critical functional areas. Recently, diffusion-tensor (DT) imaging has enabled the visualization of fiber bundle direction and integrity, thus providing the ability to delineate clearly white matter from gray matter tissue. The main objective of this study was to improve the presurgical assessment of critical functionality in the vicinity of brain lesions by combining DT and fMR imaging methodologies. METHODS: Twenty patients with various space-occupying brain lesions underwent imaging for presurgical evaluation of motor and/or somatosensory functions. The authors focus on five patients with diverse space-occupying brain lesions. Diffusion tensor-based fiber tracking and fMR imaging activation maps were superimposed in three dimensions to visualize pyramidal tracts corresponding to motor and somatosensory regional activation. CONCLUSIONS: The combination of DT and fMR imaging for presurgical functional brain mapping provides valuable information that cannot be extracted using either method alone. The validity and sensitivity of noninvasive functional mapping for surgical guidance could be improved by considering results obtained with both methods. Furthermore, the use of three-dimensional visualization seems crucial and unique for viewing and understanding the complicated spatial relationship among the lesion, gray matter activation, and white matter fiber bundles.

Adolescent↗

Exclusion mapping of the genetic predisposition for cervical artery dissections by linkage analysis.

Skin biopsies from a patient with a dissection of the left internal carotid artery and from four of his children were analyzed by electron microscopy. The index patient and three children showed mild but regular electron microscopic connective tissue aberrations. They were considered as carriers of an unknown autosomal dominant mutation. Thirty-four candidate genes involved in the biosynthesis of the extracellular matrix were excluded by genetic linkage analysis as possible sites of a disease-causing mutation in this family (logarithm of odds [LOD]-score less than -2.0).

Biopsy↗

Visuotopic organization of corticocortical connections in the visual system of the cat.

It has recently been demonstrated that, in contrast with the retinogeniculocortical projection, the corticocortical connections in the cat present a high degree of convergence and divergence. This suggests that some corticocortical connections link nonvisuotopically corresponding regions. Using fine-grain electrophysiological mapping and anatomical tracing, we have set out to test this possibility by placing a small injection of retrograde tracer in area 17 and by comparing the extent of visual field encoded in the region of area 18 containing labeled cells and that represented in the uptake zone. The results demonstrate that the size of the labeled region on the surface of area 18 is independent of eccentricity and that, despite its anisotrophy, this region of labeling encodes a broadly circular region of visual field that is larger than that encoded in the uptake zone of the tracer in area 17. For example, in the representation of lower visual field, a virtual point in area 17 that encodes a visual field region 4 degrees in diameter receives afferents from a region of area 18 encoding a region 11 degrees wide. Examination of the density of labeled cells in the labeled zone in area 18 reveals that the highest density is observed in a region in visuotopic correspondence with the injection site. However, high labeling density is also occasionally found in patches that do not represent the same visual field region as the injection site. Many receptive fields of neurons recorded in the labeled zone in area 18 only partially overlap or fail to overlap the visual field region encoded by the injection site. The results also demonstrate that the extent of visual field encoded in the labeled zone in area 18 is the same as that represented in the region of intrinsic labeling in area 17. It is suggested that cortical afferents coming from several cortical areas and converging on a column of cells in area 17 cover the same extent of visual field and that this cortical network constitutes the structural basis for the modulatory regions of the receptive field as well as the synchronization of neurons in different cortical areas.

Animals↗

Serotonergic afferents to the dorsal raphe nucleus: evdience from HRP and synaptosomal uptake studies.

Afferent connections of the serotonin (5-HT)-containing dorsal raphe nucleus were investigated in the rat utilizing the horseradish peroxidase (HRP) retrograde cell labeling technique. Small quantities (0.1-0.5 mul) of HRP solutions were infused into the dorsal raphe, and the brains were examined 19-72 h later for retrograde transport of the enzyme. Intrinsic connections within the dorsal raphe nucleus were revealed by this mapping technique, as was an input to the dorsal raphe from another serotonergic cell group, the median raphe nucleus. Little evidence was found for projections from other, more remote, brain sites. A serotonergic innervation of the dorsal raphe was also demonstrated by the presence of high affinity uptake of [3H]5-HT (Km=0.17 muM) into synaptosomal suspensions of the dorsal raphe nucleus. Synaptosomal uptake of [3H]5-HT was blocked by selective destruction of serotonergic axon terminals induced by the intraventricular injection of 200 mug of 5,7-dihydroxytryptamine following desipramine HCl pretreatment, but not by destruction of catecholaminergic axon terminals induced by intraventricularly injected 6-hydroxydopamine (2 X 250 mug). The uptake of [3H]-5-HT by synaptosomes of the dorsal raphe was comparable to that of striatal and hypothalamic synaptosomes, and markedly greater than that of synaptosomes from the cerebellum or nearby dorsal central gray or midbrain reticular formation, indicating the presence of a relatively dense serotonergic innervation. These data together indicate that neurons in the dorsal raphe nucleus receive a prominent serotonergic input that is derived, at least in part, from other neurons within the dorsal nucleus and from a neighboring raphe nucleus.

5,6-Dihydroxytryptamine↗

Large-scale modeling of the primary visual cortex: influence of cortical architecture upon neuronal response.

A large-scale computational model of a local patch of input layer 4 [Formula: see text] of the primary visual cortex (V1) of the macaque monkey, together with a coarse-grained reduction of the model, are used to understand potential effects of cortical architecture upon neuronal performance. Both the large-scale point neuron model and its asymptotic reduction are described. The work focuses upon orientation preference and selectivity, and upon the spatial distribution of neuronal responses across the cortical layer. Emphasis is given to the role of cortical architecture (the geometry of synaptic connectivity, of the ordered and disordered structure of input feature maps, and of their interplay) as mechanisms underlying cortical responses within the model. Specifically: (i) Distinct characteristics of model neuronal responses (firing rates and orientation selectivity) as they depend upon the neuron's location within the cortical layer relative to the pinwheel centers of the map of orientation preference; (ii) A time independent (DC) elevation in cortico-cortical conductances within the model, in contrast to a "push-pull" antagonism between excitation and inhibition; (iii) The use of asymptotic analysis to unveil mechanisms which underly these performances of the model; (iv) A discussion of emerging experimental data. The work illustrates that large-scale scientific computation--coupled together with analytical reduction, mathematical analysis, and experimental data, can provide significant understanding and intuition about the possible mechanisms of cortical response. It also illustrates that the idealization which is a necessary part of theoretical modeling can outline in sharp relief the consequences of differing alternative interpretations and mechanisms--with final arbiter being a body of experimental evidence whose measurements address the consequences of these analyses.

Action Potentials↗

Three-dimensional arrangement of the cell wall protein of Sulfolobus acidocaldarius.

The three-dimensional structure of the S-layer that surrounds the bacterium Sulfolobus acidocaldarius is described in detail. Pieces of the S-layer, which are two-dimensional crystals with p6 symmetry, have been studied by crystallographic analysis of electron micrographs of tilted specimens. In the density map, each asymmetric unit appears to consist of several domains connected by strong hinges. On the basis of the ragged appearance of the structure at torn edges, we now suggest that the single species of polypeptide is in a highly extended conformation, with much overlap between different molecules, and show how such molecules might be weaved together to produce the morphological domains. We show that the closed surface lattice of the intact cell wall contains 5-fold and 7-fold vertices and show how the subunit structure appears to be well suited to form 5-fold and 7-fold symmetric rings at these points in place of the 6-fold rings of the hexagonal lattice.

Bacterial Proteins↗

Long-term molecular dynamics simulation of copper plastocyanin in water.

A long molecular dynamics simulation (1.1 ns) of fully hydrated plastocyanin has been performed and analysed to relate protein dynamics to structural elements and functional properties. The solvated structure is described in detail by the analysis of H-bond network. During all the simulation, the crystal H-bond network is maintained in the beta-sheet regions, while several H-bonds are broken or formed on the external surface of the protein. To evaluate whether such changes could be due to conformational rearrangements or to solvent competition, we have examined the average number of H-bonds between protein atoms and water molecules, and the root mean square deviations from crystal structure as a function of protein residues. Protein mobility and flexibility have been examined by positional and dihedral angle rms fluctuations. Finally, cross-correlation maps have revealed the existence of correlated motions among residues connected by hydrogen bonds.

Journal Article↗

Detection of susceptibility effects using simultaneous T(2)* and magnetic field mapping.

Tracking susceptibility effects is a convenient way to detect small inclusions in a bulk tissue matrix by MRI. We propose a quantitative assessment of these susceptibility effects by simultaneously mapping T(2)* and magnetic field from the time course of magnitude and phase using a multiple GE sequence at 4.7 T. A high-pass scheme is also introduced to highlight the mesoscopic magnetic field variations due to local susceptibility differences specifically in the magnetic field map. Applying this method to muscle tissue, we demonstrate that connective tissue generates detectable susceptibility effects through concomitant local magnetic field variation and T(2)* shortening.

Adipose Tissue↗

Evolution and analysis of model CPGs for walking: II. General principles and individual variability.

Are there general principles for pattern generation? We examined this question by analyzing the operation of large populations of evolved model central pattern generators (CPGs) for walking. Three populations of model CPGs were evolved, containing three, four, or five neurons. We identified six general principles. First, locomotion performance increased with the number of interneurons. Second, the top 10 three-, four-, and five-neuron CPGs could be decomposed into dynamical modules, an abstract description developed in a companion article. Third, these dynamical modules were multistable: they could be switched between multiple stable output configurations. Fourth, the rhythmic pattern generated by a CPG could be understood as a closed chain of successive destabilizations of one dynamical module by another. A combinatorial analysis enumerated the possible dynamical modular structures. Fifth, one-dimensional modules were frequently observed and, in some cases, could be assigned specific functional roles. Finally, dynamic dynamical modules, in which the modular structure itself changed over one cycle, were frequently observed. The existence of these general principles despite significant variability in both patterns of connectivity and neural parameters was explained by degeneracy in the maps from neural parameters to neural dynamics to behavior to fitness. An analysis of the biomechanical properties of the model body was essential for relating neural activity to behavior. Our studies of evolved model circuits suggest that, in the absence of other constraints, there is no compelling reason to expect neural circuits to be functionally decomposable as the number of interneurons increase. Analyzing idealized model pattern generators may be an effective methodology for gaining insights into the operation of biological pattern generators.

Algorithms↗

Perspective on the reactions between F- and CH3CH2F: the free energy landscape of the E2 and SN2 reaction channels.

Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F(-) and CH(3)CH(2)F by using a powerful technique within Car-Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and S(N)2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common "E2C-like" transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the S(N)2 channel.

Algorithms↗

Flexible segments modulate co-folding of dUTPase and nucleocapsid proteins.

The homotrimeric fusion protein nucleocapsid (NC)-dUTPase combines domains that participate in RNA/DNA folding, reverse transcription, and DNA repair in Mason-Pfizer monkey betaretrovirus infected cells. The structural organization of the fusion protein remained obscured by the N- and C-terminal flexible segments of dUTPase and the linker region connecting the two domains that are invisible in electron density maps. Small-angle X-ray scattering reveals that upon oligonucleotide binding the NC domains adopt the trimeric symmetry of dUTPase. High-resolution X-ray structures together with molecular modeling indicate that fusion with NC domains dramatically alters the conformation of the flexible C-terminus by perturbing the orientation of a critical beta-strand. Consequently, the C-terminal segment is capable of double backing upon the active site of its own monomer and stabilized by non-covalent interactions formed with the N-terminal segment. This co-folding of the dUTPase terminal segments, not observable in other homologous enzymes, is due to the presence of the fused NC domain. Structural and genomic advantages of fusing the NC domain to a shortened dUTPase in betaretroviruses and the possible physiological consequences are envisaged.

Amino Acid Sequence↗

Robustness and enhancement of neural synchronization by activity-dependent coupling.

We study the synchronization of two model neurons coupled through a synapse having an activity-dependent strength. Our synapse follows the rules of spike-timing dependent plasticity. We show that this plasticity of the coupling between neurons produces enlarged frequency-locking zones and results in synchronization that is more rapid and much more robust against noise than classical synchronization arising from connections with constant strength. We also present a simple discrete map model that demonstrates the generality of the phenomenon.

Animals↗

Three-dimensional finite-difference bidomain modeling of homogeneous cardiac tissue on a data-parallel computer.

In this paper, a data-parallel computer is used to provide the memory and reduction in computer time for solving large finite-difference bidomain problems. The finite-difference grid is mapped effectively to the processors of the parallel computer, simply by mapping one node to one (virtual) processor. Implemented on the connection machines (CM's) CM-200 and CM-5, the data-parallel finite-difference algorithm has allowed the solution of finite-difference bidomain problems with over 2 million nodes. Details on the algorithm are presented together with computational performance results.

Algorithms↗

On the precision of the conditionally autoregressive prior in spatial models.

Bayesian analyses of spatial data often use a conditionally autoregressive (CAR) prior, which can be written as the kernel of an improper density that depends on a precision parameter tau that is typically unknown. To include tau in the Bayesian analysis, the kernel must be multiplied by tau(k) for some k. This article rigorously derives k = (n - I)/2 for the L2 norm CAR prior (also called a Gaussian Markov random field model) and k = n - I for the L1 norm CAR prior, where n is the number of regions and I the number of "islands" (disconnected groups of regions) in the spatial map. Since I = 1 for a spatial structure defining a connected graph, this supports Knorr-Held's (2002, in Highly Structured Stochastic Systems, 260-264) suggestion that k = (n - 1)/2 in the L2 norm case, instead of the more common k = n/2. We illustrate the practical significance of our results using a periodontal example.

Bayes Theorem↗

Topology and dimensions of pig coronary capillary network.

To provide a morphometric basis for any mathematical modeling of the coronary vasculature, data on the network of coronary capillary blood vessels and the topology of the arteriolar supply and venular drainage relative to the capillaries are presented. The diameters, lengths, and branching patterns of the coronary capillary blood vessels in the right and left ventricles of four pigs were measured. The locations of the coronary arterioles and venules were identified, topological maps were constructed, and the mean functional length of capillaries connecting an arteriole to an adjacent venule was measured. The vasculature was fixed by perfusing the coronary vessels with a catalyzed polymer. After the polymer hardened, plugs of the myocardium were removed, sectioned, dehydrated, and cleared to render the capillary network visible in a light microscope. The capillaries then were traced by optical sectioning. We designated the capillaries as blood vessels of order number zero; we further designated the capillaries as those fed directly by arterioles (C0a), those drained directly into venules (C0v), and those capillary vessels connected to C0a and C0v. The capillaries are connected in patterns identified as Y, T, H, or hairpin and anastomosed through capillary cross-connections (Ccc). The Ccc vessels may connect adjacent capillaries or capillaries originating from different arterioles. The connection among the capillaries, arteries, and veins is presented in terms of a connectivity matrix. Combining the present data with those for the arterial and venous trees, we have obtained a complete set of statistical data of all the blood vessels of the heart of the pig. Such a data set will serve as the basis of coronary hemodynamics.

Anatomy, Comparative↗

Mapping of movement in the isometrically contracting human soleus muscle reveals details of its structural and functional complexity.

It is becoming increasingly apparent that precise knowledge of the anatomic features of muscle, aponeurosis, and tendons is necessary for understanding how a muscle-tendon complex generates force and accomplishes length changes. This report presents both anatomic and functional data from the human soleus muscle acquired by using magnetic resonance imaging. The results show a strong relationship between the complex three-dimensional structure of the muscle-tendon system and the intramuscular distribution of tissue velocities during in vivo isometric contractions. The proximal region of the muscle is unipennate, whereas the midregion has a radially bipennate hemicylindrical structure, and the distal region is quadripennate. Tissue velocity mapping shows that the highest velocity regions overlay the aponeuroses connected to the Achilles tendon. These are located on the anterior and posterior surfaces of the muscle. The lowest velocities overlay the aponeuroses connected to the origin of the muscle and are generally located intramuscularly.

Adult↗