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PubMed1984

Corticocortical connections among visual areas in the cat.

The cortical interconnections of 17 visual areas in the cat were studied by making single injections through recording micropipettes of the neuroanatomical tracers 3H-leucine and horseradish peroxidase (HRP) into the visual cortex of 40 adult animals. Coronal sections from each of the brains were analyzed for location of silver grains and HRP-filled neurons. There are five main results: (1) all corticocortical connections among visual areas are reciprocal. (2) Each cortical visual area has a unique set of cortical connections; the cortical targets of no two cortical visual areas are identical. (3) There is a vast and complicated pattern of connections among the visual areas which implies that there are numerous parallel circuits which run through any one visual area. (4) The connections among the cortical visual areas link retinotopically similar loci and are consistent with the visuotopic maps which microelectrode recording experiments have provided. (5) The connections among visual cortical areas often originate from, or terminate in, discontinuous patches within each area; this result obtains not only for areas 17, 18, 19, and posteromedial lateral suprasylvian area (PMLS), but for at least 13 other areas as well. The data reveal many parallel pathways and suggest multiple functional circuits interconnecting visual cortical areas. Since each visual area has multiple inputs and outputs it may have multiple functions, a different one for each of the circuits of which it is a part.

Animals↗
PubMed1996

Hippocampal place cells connected by Hebbian synapses can solve spatial problems.

We propose that a cognitive map can be stored in the synapses between the pyramidal cells of CA3 in the form of the pattern of synaptic strengths connecting them. The model requires only that there are place cells in CA3 and that the connections between them are modifiable in a Hebbian manner. Given these suppositions, the synaptic strengths must evolve to represent the distance between firing centers of synaptically connected place cells. We argue that this arrangement of synaptic weights embodies all the formal properties of a map. We demonstrate that the information stored in such a structure is sufficient to solve several classic spatial problems including finding shortest paths, and negotiating detours. It is clear that much of the physiology and anatomy necessary to more precisely characterize the model is not known at this time. Nevertheless the model is robust under a variety of cell and connection densities. It also performs well under several different functions relating distance to synaptic strength. What is most remarkable in the model is that it is a logical consequence of the several key anatomical and physiological properties of the CA3 region of rats. Whether this information is used by the rat is difficult to assess at this time. Regardless of the outcome of this question, the model has promising applications to the field of robot navigation.

Animals↗
PubMed2004

Reparative mechanisms in the cerebellar cortex.

In the adult brain, different neuronal populations display different degrees of plasticity. Here, we describe the highly different plastic properties of inferior olivary neurones and Purkinje cells. Olivary neurones show a basal expression of growth-associated proteins, such as GAP-43 and Krox24/EGR-1, and remarkable remodelling capabilities of their terminal arbour. They also regenerate their transected neurites into growth-permissive territories and may reinnervate the lost target. Sprouting and regrowing olivary axons are able to follow specific positional information cues to establish new connections according to the original projection map. In addition, they set a strong cell body reaction to injury, which in specific olivary subsets is regulated by inhibitory target-derived cues. In contrast, Purkinje cells do not have a constitutive level of growth-associated genes, and show little cell body reaction, no axonal regeneration after axotomy, and weak sprouting capabilities. Block of myelin-derived signals allows terminal arbour remodelling, but not regeneration, while selective over-expression of GAP-43 induces axonal sprouting along the axonal surface and at the level of the lesion. We suggest that the high constitutive intrinsic plasticity of the inferior olive neurones allows their terminal arbour to sustain the activity-dependent ongoing competition with the parallel fibres in order to maintain the post-synaptic territory, and possibly underlies mechanisms of learning and memory. Such a plasticity is used also as a reparative mechanism following axotomy. In contrast, in Purkinje cells, poor intrinsic regenerative capabilities and myelin-derived signals stabilise the mature connectivity and prevent axonal regeneration after lesion.

Animals↗
PubMed2005

Localization of a disease-associated mutation site in the three-dimensional structure of the cardiac muscle ryanodine receptor.

The cardiac muscle ryanodine receptor (RyR2) functions as a calcium release channel in the heart. Up to 40 mutations in RyR2 have been linked to genetic forms of sudden cardiac death. These mutations are largely clustered in three regions of the sequence of the polypeptide: one near the N terminus, one in the central region, and the third in the C-terminal region. The central region includes 11 mutations, and an isoleucine-proline motif (positions 2427 and 2428) in the same region is predicted to contribute to the binding of FKBP12.6 protein. We have mapped the central mutation site in the three-dimensional structure of RyR2 by green fluorescent protein insertion, cryoelectron microscopy, and single-particle image processing. The central mutation site was mapped to a "bridge" of density that connects cytoplasmic domains 5 and 6, which have been suggested to undergo conformational changes during channel gating. Moreover, the location of this central mutation site is not close to that of the FKBP12.6-binding site mapped previously by cryoelectron microscopy.

Animals↗
PubMed1996

Organization in the somatosensory sector of the cat's thalamic reticular nucleus.

This study describes the organization of cells in the thalamic reticular nucleus (TRN) that project to the somatosensory part of the dorsal thalamus in the cat. Injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) and fluorescent dyes were made into the ventrobasal complex (VB) and the medial division of the posterior complex (POm) of the thalamus. The resultant retrograde labelling in TRN was analyzed. Large injections of a tracer in VB label many reticular cells that are restricted to a centroventral, or somatosensory, sector of TRN. Small injections of a tracer in VB produce narrow zones of labelled cells in this sector. In reconstructions these zones resemble thin "slabs," which lie parallel to the plane of TRN along its oblique rostrocaudal dimension and occupy only a fraction of its thickness. In comparisons of the zones of labelled cells in TRN resulting from tracer injections in different nuclei of VB, inner cells, intermediate cells, and outer cells across the thickness of TRN project to the ventral posteromedial, the medial division of the ventral posterolateral, and the lateral division of the ventral posterolateral nuclei, respectively. Furthermore, shifts in injected areas along the dorsoventral dimension of VB produce similar shifts in zones of labelled cells in TRN. Thus, reticular cells form an accurate map on the basis of their connections with VB. Large injections of a tracer in the ventral subdivision of POm label many reticular cells that are also restricted to the centroventral sector of TRN. Small injections of a tracer in ventral POm produce broad zones of labelled cells in this sector. In comparisons of the zones of labelled cells in TRN resulting from tracer injections in different regions of ventral POm, cells that project to these regions are scattered across the thickness of TRN and occupy overlapping territories. Large injections of a tracer in either VB or ventral POm also label cells in a restricted centroventral region of the perireticular nucleus. Double injections of different tracers in VB and ventral POm produce many cells in TRN that are labelled from both of these dorsal thalamic structures and fewer cells that are labelled from only one or the other of these structures. These results indicate that there is a dual organization in the projections of cells in the somatosensory sector of TRN to dorsal thalamus: Projections to VB are topographically organized whereas those to ventral POm lack a topographical organization. Furthermore, both of these mapped and nonmapped projections can arise from single reticular cells in the somatosensory sector.

Amidines↗
PubMed1987

Interhemispheric connections of the somatosensory cortex in the rabbit.

Corpus callosal connections of somatosensory cortex were studied in rabbits by combining anatomical tracing and electrophysiological mapping in the same animals. The results show that callosal connections are unevenly distributed in SI and SII. In SI, the representations of all body surfaces caudal to the neck and midline structures of the head have dense callosal connections. Conversely, connections are sparse to absent within representations of laterally positioned surfaces of the head, such as the sinus hairs, vibrissae, and nonmidline portions of the lips. Almost all of SII has dense callosal connections; only the representations of the vibrissae and sinus hairs have moderate callosal connections. The laminar distribution of callosal connections in rabbit SI and SII is similar to that observed in other mammals. Callosal terminations extend from the inner portion of layer I to the outer portion of layer VI, are moderately denser in the supragranular layers, and are sparse in layer IV. Callosally projecting cells are found predominantly in layers II, III, and V and are sparse in layers IV and VI. These data further emphasize the direct correspondence between the pattern of callosal connections in SI and the functional importance of particular body surfaces. Hence, representations of body surfaces important in the exploration of the environment are relatively free of callosal connections, whereas representations of midline and more lateral surfaces, less significant in tactile exploration, receive dense callosal connections. Callosal connections in rabbits are distributed extensively throughout responsive koniocortical regions rather than being relegated to distinct, specialized regions of "unresponsive" dysgranular cortex as in rodents.

Animals↗
PubMed2003

Transient activation in a network of coupled map neurons.

The focus of this Letter is on the activity of a network of neurons pairwise coupled by inhibitory connections. Each neuron is represented by a two-dimensional map capable, when isolated, of a rich variety of complex dynamical regimes. It is shown that the network exhibits a stimulus-dependent sequential activation and inactivation of subgroups of neurons. This complex behavior is rather similar to some spatiotemporal features observed in the first stages of the olfaction process in some insects and suggests the possibility of large scale simulation of these processes by using reasonable computational capabilities.

Action Potentials↗
PubMed1998

Large-scale functional connectivity in associative learning: interrelations of the rat auditory, visual, and limbic systems.

Large-scale functional connectivity in associative learning: interrelations of the rat auditory, visual, and limbic systems. J. Neurophysiol. 80: 3148-3162, 1998. Functional relations between specialized parts of the brain may be important determinants of learned behaviors. To study this, we examined the interrelations of the auditory system with several extraauditory structures in two groups of rats having different behavioral histories. Both groups were trained to associate a tone conditional stimulus (CS) with an aversive unconditional stimulus (US). For one group, a light presented with the tone predicted the absence of the US (group TL-). In the other group, the light was a neutral stimulus (group TL0). Fluorodeoxyglucose (FDG) incorporation was measured in the presence of the tone-light compound. Because the tone-light compound was physically identical for both groups, neural differences between groups reflected differences in the learned associative properties of the stimuli. Covariances of FDG uptake in the auditory system and extraauditory structures were examined using partial least squares. Three strong covariance or functional connectivity patterns were identified. The first pattern mainly reflected similarities between groups, with strong interrelations between the subcortical auditory system and the thalamocortical visual system, cerebellum, deep cerebellar nuclei, and midline thalamus. This pattern of interactions may represent part of a common circuit for relaying the associative value of the tone CS to the cerebellum and the midline thalamus. The external nucleus of the inferior colliculus and medial division of the medial geniculate nucleus were associated more strongly with this pattern for group TL-, which was interpreted as representing the change of the associative value of the tone by the light, mediated through extraauditory influences on these two regions. A second pattern involved midbrain auditory regions, superior colliculus, zona incerta, and subiculum and was stronger for group TL0. The relations between midbrain structures may represent the excitatory conditioned response (CR) evoked by the tone in this group. The final pattern was strongest in group TL- and involved interrelations of the thalamocortical auditory system with hippocampus, basolateral amygdala, and hypothalamus. This pattern may represent the learned inhibition of the CR to the tone in the presence of the light. These findings are consistent with behavioral studies suggesting that at least two types of associations are formed during associative learning. One is the sensory relation of the stimuli and another is the relation between the CS and the affective components of the US. These behavioral associations are mapped to the patterns of functional connectivity between auditory and extraauditory regions.

Acoustic Stimulation↗
PubMed2005

Mapping cancer patients' symptoms to UMLS concepts.

A prerequisite for patient-friendly personal health records (PHR) is their ability to allow seamless integration of patient terminology with professional terminologies. In this work, we mapped a set of symptoms/ problems from the self-assessment component of a cancer patient support system to concepts in the Unified Medical Language System (UMLS) Metathesaurus. Our objective was to learn how the UMLS can be used as a tool to connect patient terminology with professional vocabularies. The mapping to UMLS was done with the help of ten expert cancer nurses who evaluated concepts, their synonyms and placement in the source vocabulary hierarchical structure. The UMLS concepts were also compared with terms and phrases found in patient medical records that addressed the same set of symptoms. In this study we observed several problems related to the use of the UMLS Metathesaurus as a tool to connect from patient-level expressions to professional-level classification systems. More work is needed to increase interoperability between layperson health applications and clinical systems.

Feasibility Studies↗
PubMed2002

Transcranial magnetic stimulation: new insights into representational cortical plasticity.

In the last decade, transcranial magnetic stimulation (TMS) has been used increasingly as a tool to explore the mechanisms and consequences of cortical plasticity in the intact human cortex. Because the spatial accuracy of the technique is limited, we refer to this as plasticity at a regional level. Currently, TMS is used to explore regional reorganization in three different ways. First, it can map changes in the pattern of connectivity within and between different cortical areas or their spinal projections. Important examples of this approach can be found in the work on motor cortex representations following a variety of interventions such as immobilization, skill acquisition, or stroke. Second, TMS can be used to investigate the behavioural relevance of these changes. By applying TMS in its "virtual lesion" mode, it is possible to interfere with cortical function and ask whether plastic reorganization within a distinct cortical area improves function. Third, TMS can be used to promote changes in cortical function. This is achieved by using repetitive TMS (rTMS) to induce short-term functional reorganization in the human cortex. The magnitude and the direction of rTMS-induced plasticity depend on extrinsic factors (i.e. the variables of stimulation such as intensity, frequency, and total number of stimuli) and intrinsic factors (i.e. the functional state of the cortex targeted by rTMS). Since conditioning effects of rTMS are not limited to the stimulated cortex but give rise to functional changes in interconnected cortical areas, rTMS is a suitable tool to investigate plasticity within a distributed functional network. Indeed, the lasting effects of rTMS offer new possibilities to study dynamic aspects of the pathophysiology of a variety of diseases and may have therapeutic potential in some neuropsychiatric disorders.

Animals↗
PubMed2006

Probing the integrin-actin linkage using high-resolution protein velocity mapping.

Cell migration is regulated in part by the connection between the substratum and the actin cytoskeleton. However, the very large number of proteins involved in this linkage and their complex network of interactions make it difficult to assess their role in cell migration. We apply a novel image analysis tool, spatio-temporal image correlation spectroscopy (STICS), to quantify the directed movements of adhesion-related proteins and actin in protrusions of migrating cells. The STICS technique reveals protein dynamics even when protein densities are very low or very high, and works in the presence of large, static molecular complexes. Detailed protein velocity maps for actin and the adhesion-related proteins alpha-actinin, alpha5-integrin, talin, paxillin, vinculin and focal adhesion kinase are presented. The data show that there are differences in the efficiency of the linkage between integrin and actin among different cell types and on the same cell type grown on different substrate densities. We identify potential mechanisms that regulate efficiency of the linkage, or clutch, and identify two likely points of disconnect, one at the integrin and the other at alpha-actinin or actin. The data suggests that the efficiency of the linkage increases as actin and adhesions become more organized showing the importance of factors that regulate the efficiency in adhesion signaling and dynamics.

3T3 Cells↗
PubMed1995

Cortical areas within the lateral sulcus connected to cutaneous representations in areas 3b and 1: a revised interpretation of the second somatosensory area in macaque monkeys.

Cortical connections between various body representations in areas 3b and 1 and lateral parietal cortex were examined in 18 macaque monkeys. We injected tracers (Fast Blue, Diamidino Yellow, Horseradish Peroxidase, and Rhodamine Dextran), alone or in combination, into closely related cutaneous responsive sites, e.g., adjacent digits. Separated patches of labeling were found across the parietal operculum and insula for all injected locations. On the basis of cytoarchitectural criteria, the labeled regions include the second somatosensory area (SII), retroinsular area (Ri) and granular insula (Ig). Assuming the connections are homotopical from physiologically identified body representations in primary somatosensory cortex, the labeling patterns in SII include complete anterior and posterior body maps. The orientation of the body is erect in the posterior and supine in the anterior SII region. Area 3b has greater density of connections with anterior SII. The maps are mirror images aligned along the distal extremities. The anterior-posterior (A-P) length of the "SII region" exceeds 7 mm; it extends in the coronal plane from the fundus of the lateral sulcus to surface cortex near the anterior tip of the intraparietal sulcus. Two additional topographically organized maps are likely in Ri. These are "worm-like" body maps oriented along the A-P axis and joined at the head representation. Connections with the center of Ig are not somatotopically organized. The diversity of somatosensory areas in lateral parietal cortex revealed by the labeled connections was discussed in reference to prior mapping of SII in monkeys and was compared to reports of multiple areas in this region of cortex in other species.

Animals↗
PubMed2001

Frequencies contributing to functional connectivity in the cerebral cortex in "resting-state" data.

BACKGROUND AND PURPOSE: In subjects performing no specific cognitive task ("resting state"), time courses of voxels within functionally connected regions of the brain have high cross-correlation coefficients ("functional connectivity"). The purpose of this study was to measure the contributions of low frequencies and physiological noise to cross-correlation maps. METHODS: In four healthy volunteers, task-activation functional MR imaging and resting-state data were acquired. We obtained four contiguous slice locations in the "resting state" with a high sampling rate. Regions of interest consisting of four contiguous voxels were selected. The correlation coefficient for the averaged time course and every other voxel in the four slices was calculated and separated into its component frequency contributions. We calculated the relative amounts of the spectrum that were in the low-frequency (0 to 0.1 Hz), the respiratory-frequency (0.1 to 0.5 Hz), and cardiac-frequency range (0.6 to 1.2 Hz). RESULTS: For each volunteer, resting-state maps that resembled task-activation maps were obtained. For the auditory and visual cortices, the correlation coefficient depended almost exclusively on low frequencies (<0.1 Hz). For all cortical regions studied, low-frequency fluctuations contributed more than 90% of the correlation coefficient. Physiological (respiratory and cardiac) noise sources contributed less than 10% to any functional connectivity MR imaging map. In blood vessels and cerebrospinal fluid, physiological noise contributed more to the correlation coefficient. CONCLUSION: Functional connectivity in the auditory, visual, and sensorimotor cortices is characterized predominantly by frequencies slower than those in the cardiac and respiratory cycles. In functionally connected regions, these low frequencies are characterized by a high degree of temporal coherence.

Adult↗
PubMed2000

Basal cPLA(2) phosphorylation is sufficient for Ca(2+)-induced full activation of cPLA(2) in A549 epithelial cells.

The release of [(3)H] arachidonic acid (AA) and its connection with the triggering of the MAP kinase cascade were studied in the human A549 epithelial cell line upon stimulation with thapsigargin. Thapsigargin can increase AA release along with the increase of intracellular calcium concentration, phosphorylation, and activation of extracellular regulated kinase (ERK) and cytosolic phospholipase A(2) (cPLA(2)). Both ERK and cPLA(2) phosphorylation in response to thapsigargin were inhibited by PD 98059, a specific inhibitor of MAP kinase kinase of the ERK group (MEK), and EGTA. cPLA(2) phosphorylation was not affected by Ro 31-8220 (an inhibitor of all PKC isoforms) or LY 379196 (a PKCbeta selective inhibitor), while both of them indeed attenuated ERK activation. On the other hand, rottlerin (the selective PKCdelta inhibitor), SB 203580 (the selective p38 MAPK inhibitor), and wortmannin (the PI 3-kinase inhibitor) can affect neither cPLA(2) nor ERK phosphorylation. In A549 cells, PKC activator PMA cannot increase either the basal or thapsigargin-induced (3)H-AA release, while it can induce the phosphorylation of ERK and cPLA(2.) The PMA-induced ERK phosphorylation was inhibited by Ro 31-8220, LY 379196, rottlerin, and PD 98059, but unaffected by SB 203580 and wortmannin. Moreover, the phosphorylation by PMA was non-additive with that of thapsigargin. This implies that intracellular Ca(2+) level is the key factor for induction of cPLA(2) activity and thapsigargin-elicited ERK activation itself is substantially sufficient for cPLA(2) activation upon intracellular Ca(2+) increase.

Acetophenones↗
PubMed1983

Topographic analysis of the innervation of the rat neocortex and hippocampus by the basal forebrain cholinergic system.

The basal forebrain-cortex connections of the rat were topographically mapped by retrograde tracer methods; and their contribution to the cholinergic innervation of the cortex was assessed by excitotoxin lesions placed in the rostral and caudal aspects of the complex. Discrete injections of tracer into frontal cortex labeled the prominent multipolar acetylcholinesterase (AchE)-positive cells of the ventromedial globus pallidus. Injections of tracer into the parietal cortex labelled cells in the ventral globus pallidus, the underlying substantia innominata, and the lateral hypothalamus. Separate injections of Fast Blue and Nuclear Yellow in the frontal and in the parietal cortex resulted in double-labeled cells in the ventral globus pallidus, which indicates that at least some of these cells may possess collateralizing axons. The cingulate cortex is innervated predominantly by neurons in the nucleus of the horizontal limb of the diagonal band. The occipital cortex was also shown to receive a projection primarily from the nucleus of the horizontal limb of the diagonal band. The hippocampal formation is innervated primarily by cells located in the vertical limb of the diagonal band and in the medial septum. Consistent with the results of the retrograde tracing studies, excitotoxin lesions affecting the diagonal band and medial septum decreased choline acetyltransferase (CAT) activity up to 40% on the occipital cortex and by 64% in the hippocampus, but did not affect CAT activity in the rostral neocortex. In contrast, ibotenate lesions of the caudal ventral globus pallidus and substantia innominata caused decreases in CAT activity in the frontal cortex of up to 65% without affecting enzyme activity in the hippocampal formation. The results of the present study provide details on the topographic organization of the cortical projections originating in the basal forebrain complex and indicate that these neurons are the predominant source of cortical cholinergic innervation.

Acetylcholine↗
PubMed1985

Growth cone-target interactions in the frog retinotectal pathway.

The growth cones of retinal ganglion cell axons were studied in the optic tract and tectum with horseradish peroxidase (HRP) histochemistry and electron microscopy. The ganglion cell growth cones has many morphological features similar to those described in vitro and in other in vivo systems. However, we found that some processes formed highly differentiated terminal arborizations, while retaining growth cones on many of their branches. In addition, ultrastructural examination of the tectal neuropil revealed that many ganglion cell axonal processes had characteristics of both growth cones and presynaptic endings. These findings are discussed in the context of the hypothesis of shifting connections and the evidence that retinotectal map formation involves several mechanisms, including a process that depends on the action potential activity in the optic fibers.

Animals↗
PubMed1997

Autoepitope-mapping of the U1-70K protein with human-Drosophila chimeric proteins.

The 70K protein is the major autoantigen for anti-RNP autoantibodies directed against the U1 small nuclear ribonucleoprotein complex particle. The U1-70K protein has been epitope-mapped by various groups, and a major antigenic region of about 70 amino acids has been found which overlaps with the RNA binding motif. Attempts to map the major antigenic region further with smaller cloned fragments or with peptides have been hampered by total loss of, or strongly reduced, antigenicity. Thus the major antigenic region is composed of conformational epitopes and a detailed analysis of particular epitopes has not been possible. In the present work, we examine the antigenicity of chimeric proteins assembled from the highly conserved Drosophila melanogaster 70K proteins grafted with human 70K segments. With this approach, the effects on antigenicity of exchanging particular segments can be assayed with the overall structure of the major antigenic domain kept relatively constant. Our results, supported by depletion experiments, show that residues 99-128 from the human protein are essential for recognition by both human and canine anti-RNP autoantibodies. These residues have to be presented in a manner that allows correct conformational interaction between the different protein domains.

Amino Acid Sequence↗
PubMed1997

Three-dimensional structure of Brush Border Myosin-I at approximately 20 A resolution by electron microscopy and image analysis.

Brush Border Myosin-I (BBMI) is a single-headed, unconventional myosin found in the microvilli of intestinal epithelial cells where it forms lateral bridges between the core bundle of actin filaments and the plasma membrane of the microvillus. A three-dimensional (3D) reconstruction of BBMI was made from images of negatively stained, two-dimensional (2D) crystals grown on lipid monolayers formed from mixtures of phosphatidylserine and phosphatidylcholine. The resolution of the 3D map extends to approximately 20 A and allows identification of all of the major structural domains of BBMI. The BBMI molecule is composed of three domains: a globular motor domain, a light-chain-binding domain and a lipid-binding domain. In our map, the putative motor domain is connected to an extended density, which we believe to be the light-chain-binding domain. This long, narrow region has three distinct bends, which may delineate the bound calmodulin light chains. Following the last calmodulin there is density which extends for a short distance across the lipid surface and is presumably the carboxy-terminal lipid-binding domain.

Amino Acid Sequence↗