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Ocular perfusion pressure and choroidal blood flow in the rabbit.

PURPOSE: To compare choroidal blood pressure versus flow relationships obtained by three different methods of changing the ocular perfusion pressure. METHODS: Experiments were performed in pentobarbital-anesthetized rabbits with occluders on the aorta and inferior vena cava to control mean arterial pressure (MAP). The central ear artery was cannulated to measure MAP. Two 23-gauge needles were inserted through the pars plana into the vitreous: one connected to a saline-filled syringe to vary the ocular volume and the other to a pressure transducer to measure intraocular pressure (IOP). Choroidal perfusion was measured by laser-Doppler flowmetry with the probe in the vitreous over the posterior pole. In group 1 (n = 15), the MAP was varied while holding the IOP at 10, 15, 20, 25 and 30 mm Hg. In group 2 (n = 19), the IOP was increased while holding the MAP at 80, 70, 60, 50, 40, 30 and 20 mm Hg. In group 3 (n = 21), the MAP was varied without controlling the IOP. RESULTS: Group 1 baseline choroidal flows were similar at the five IOPs. When the flow was plotted against MAP, the curves diverged and extrapolated to intersect the pressure axis when the MAP equaled the set IOP. Group 2 baseline flows were similar at MAPs greater than 40 mm Hg. When the flow was plotted against the IOP, the curves diverged and intersected the pressure axis when the IOP equaled the MAP. In both groups, plotting the flow against the perfusion pressure (i.e., MAP minus IOP) collapsed the data points into single curves. Choroidal autoregulation occurred in all three groups; however, the low end of the autoregulatory perfusion pressure range was approximately 50 mm Hg in group 1, approximately 40 mm Hg in group 2, and approximately 30 mm Hg in group 3. CONCLUSIONS: The results show that the effective choroidal perfusion pressure gradient equals the MAP minus the IOP, and that choroidal autoregulation is most effective when the MAP varies and IOP is not controlled.

Animals↗

Corticocortical connections of area 2 of somatosensory cortex in macaque monkeys: a correlative anatomical and electrophysiological study.

The cortical connections of electrophysiologically identified locations in the body representations in somatosensory cortex of macaque monkeys were investigated after injections of horseradish peroxidase, wheat germ agglutinin (WGA) conjugated with horseradish peroxidase, tritiated WGA, or tritiated proline. After extensive microelectrode mapping of portions of the body representations in areas 3b, 1, 2, and 5 and careful determinations of electrophysiological borders between areas, restricted injections of tracers were placed, usually into the representation of the hand in area 2. Other injections were placed in the foot representation in area 2 or in area 1, in the wrist representation in area 1, and in the forearm and wrist representation in area 5. Connection patterns were related to the physiological mapping results and to cortical cytoarchitecture. Injections confined to a lateral portion of area 2 representing the glabrous digits of the hand revealed reciprocal connections with the digit representations in areas 1 and 3b. Projections to area 2 were largely from layer III neurons in both of these fields, and return projections terminated largely in supragranular layers. Other inputs were from layer III cells in one or more separate locations in area 5 and in one or more closely spaced foci in the expected location of S-II in the lateral sulcus. These connections were also reciprocal with terminations apparent in layers IV and III. A few neurons in area 4 were labeled in some of these cases. Results were similar after an injection in the foot representation in area 2 with the differences that infragranular neurons, in addition to supragranular neurons, formed a substantial part of the projection to area 2, terminations as well as projections were noted from area 4, interconnections were found more rostrally in area 6, and a dense focus of label was apparent in the dorsal bank of cingulate sulcus in the apparent location of the supplementary motor area. Injections in the foot representation in area 1 revealed dense layer IV terminations in the foot representation in area 2, as well as connections with area 3b, the S-II region, and areas 5 and 7. The injection in the wrist representation in area 1 resulted in dense terminations in the portion of area 5 responsive to the distal forearm and hand, sparser connections with a lateral location in part of area 2 related to the hand, and interconnections with 3b and S-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

A WGA-HRP study of the fiber arrangement in the cat optic radiation: a demonstration via three-dimensional reconstruction.

The fiber arrangement of the optic radiation was investigated in fourteen adult cats. The retinotopies of the lateral geniculate nucleus (LGN) were first identified electrophysiologically, and thereafter, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) was iontophoretically injected into defined positions of the LGN. These corresponded to the central (medial LGN), horizontal peripheral (lateral LGN), dorsal (rostral LGN), and ventral (caudal LGN) retina. Geniculocortical fibers from the each position of the LGN and corticogeniculate fibers projecting to these positions were always labeled reciprocally. Labeled terminals were found massively in layer IV with some extending to the lower part of layer III, but layers VI and I also contained substantial numbers. Although most of the labeled neurons were localized in layer VI, some neurons were labeled in layer V and transsynaptically in layer IV. Labeled fibers were superimposed in three-dimensionally reconstructed maps of the white matter for the easy understanding of the pathways connecting the LGN and the visual cortex. They were localized in certain zones in the white matter without wide dispersion; however, we did not obtain any findings which suggested clearly different populations of geniculocortical and corticogeniculate fibers. In agreement with previous studies, fibers from the rostral LGN and the caudal LGN projected to the striate cortex in a regular order, rostrocaudally, and fibers from the medial LGN and the lateral LGN projected to the striate cortex inversely (i.e. lateromedially). This inverse projection resulted because fibers from the lateral LGN traversed fibers from the medial LGN in a lateromedial direction; however, there was only partial crossing of these two pathways. The distribution of geniculocortical fibers together with corticogeniculate fibers formed topographic zones arrayed mediolaterally in the white matter. Thus, fibers of the medial LGN were positioned in the intermediate zone, and fibers of the rostral LGN and the lateral LGN were positioned in the rostral and caudal parts of the lateral zone, respectively. Fibers of the caudal LGN were found in the medial zone. This fiber arrangement displayed a rough centroperipheral retinotopy in that fibers representing the central area were placed between fibers representing the peripheral retina. Finally, this fiber arrangement was compared with that of the optic nerve and optic tract.

Animals↗

Biological systems modeling and analysis: a biomolecular technique of the twenty-first century.

It is proposed that computational systems biology should be considered a biomolecular technique of the twenty-first century, because it complements experimental biology and bioinformatics in unique ways that will eventually lead to insights and a depth of understanding not achievable without systems approaches. This article begins with a summary of traditional and novel modeling techniques. In the second part, it proposes concept map modeling as a useful link between experimental biology and biological systems modeling and analysis. Concept map modeling requires the collaboration between biologist and modeler. The biologist designs a regulated connectivity diagram of processes comprising a biological system and also provides semi-quantitative information on stimuli and measured or expected responses of the system. The modeler converts this information through methods of forward and inverse modeling into a mathematical construct that can be used for simulations and to generate and test new hypotheses. The biologist and the modeler collaboratively interpret the results and devise improved concept maps. The third part of the article describes software, BST-Box, supporting the various modeling activities.

Computational Biology↗

Self-generated disorder and structural glass formation in homopolymer globules.

We have investigated the interrelation between spin glasses and structural glasses. Spin glasses in this case are p-spin interaction spin glasses (at p>2) or Potts glasses that contain quenched disorder, whereas the structural glasses are here exemplified by a homopolymeric globule, which can be viewed as a liquid of connected units on a nanoscale. It is argued that the homopolymeric globule problem can be mapped onto a disorder field theoretical model whose effective Hamiltonian resembles the corresponding one for the spin glass model. In this sense the disorder in the globule is self-generated (in contrast to spin glasses) and can be related to competing interactions (virial coefficients of different signs) and the chain connectivity. The work is aimed at giving a quantitative description of this analogy. We have investigated in the mean-field approximation the phase diagram of the homopolymeric globule where the transition line from the liquid to glassy globule is treated in terms of the replica symmetry breaking paradigm. The configurational entropy temperature dependence is also discussed.

Journal Article↗

A first-draft human protein-interaction map.

BACKGROUND: Protein-interaction maps are powerful tools for suggesting the cellular functions of genes. Although large-scale protein-interaction maps have been generated for several invertebrate species, projects of a similar scale have not yet been described for any mammal. Because many physical interactions are conserved between species, it should be possible to infer information about human protein interactions (and hence protein function) using model organism protein-interaction datasets. RESULTS: Here we describe a network of over 70,000 predicted physical interactions between around 6,200 human proteins generated using the data from lower eukaryotic protein-interaction maps. The physiological relevance of this network is supported by its ability to preferentially connect human proteins that share the same functional annotations, and we show how the network can be used to successfully predict the functions of human proteins. We find that combining interaction datasets from a single organism (but generated using independent assays) and combining interaction datasets from two organisms (but generated using the same assay) are both very effective ways of further improving the accuracy of protein-interaction maps. CONCLUSIONS: The complete network predicts interactions for a third of human genes, including 448 human disease genes and 1,482 genes of unknown function, and so provides a rich framework for biomedical research.

Databases, Protein↗

The representation of the visual field in three extrastriate areas of the ferret (Mustela putorius) and the relationship of retinotopy and field boundaries to callosal connectivity.

We describe representations of the visual field in areas 18, 19 and 21 of the ferret using standard microelectrode mapping techniques. In all areas the azimuths are represented as islands of peripheral visual field surrounded by central visual field representation. The zero meridian was found at the 17/18 and 19/21 borders; at the 18/19 and anterior border of 21 the relative periphery of the visual field was found. In areas 18 and 19, elevations are represented in a smooth medio-lateral progression from lower to upper visual field. In several cases the elevations in area 21 evidenced a similar medio-lateral progression; however, in others the elevations exhibited a split representation of the horizontal meridian. Anatomically determined callosal connections coincided with the representation of azimuths near the zero meridian. Medio-lateral bands of callosal connectivity that straddle the 17/18 and 19/21 borders are connected by bridges of callosally projecting cells. Acallosal cortical islands corresponded to the peripheral visual field and were found straddling the 18/19 border and the anterior border of area 21. The results are discussed in relation to callosal connectivity and retinotopy in extrastriate visual cortex and to proposed homologies of carnivore and primate visual cortex.

Animals↗

Building the component tree in quasi-linear time.

The level sets of a map are the sets of points with level above a given threshold. The connected components of the level sets, thanks to the inclusion relation, can be organized in a tree structure, that is called the component tree. This tree, under several variations, has been used in numerous applications. Various algorithms have been proposed in the literature for computing the component tree. The fastest ones (considering the worst-case complexity) have been proven to run in O(n ln(n)). In this paper, we propose a simple to implement quasi-linear algorithm for computing the component tree on symmetric graphs, based on Tarjan's union-find procedure. We also propose an algorithm that computes the n most significant lobes of a map.

Algorithms↗

Basal ganglia functional connectivity based on a meta-analysis of 126 positron emission tomography and functional magnetic resonance imaging publications.

The striatum receives projections from the entire cerebral cortex. Different, but not mutually exclusive, models of corticostriatal connectivity have been proposed, including connectivity based on proximity, parallel loops, and a model of a tripartite division of the striatum into motor, associative, and limbic areas. All these models were largely based on studies of anatomic connectivity in nonhuman mammals and lesion studies in animals and humans. Functional neuroimaging has the potential to discern patterns of functional connectivity in humans in vivo. We analyzed the functional connectivity between the cortex and the striatum in a meta-analysis of 126 published functional neuroimaging studies. We mapped the peak activations listed in each publication into stereotaxic space and used standard functional imaging statistical methods to determine which cortical areas were most likely to coactivate with different parts of the striatum. The patterns of functional connectivity between the cortex and the different striatal nuclei are broadly consistent with the predictions of the parallel loop model. The rostrocaudal and dorsoventral patterns of corticostriatal functional connectivity are consistent with the tripartite division of the striatum into motor, associative, and limbic zones.

Basal Ganglia↗

Auditory projections to the anterior telencephalon in the budgerigar (Melopsittacus undulatus).

The connections of a higher order auditory area in the neostriatum intermedium pars ventrolateralis (NIVL) were mapped with pathway tracing techniques in order to elucidate possible pathways by which auditory feedback may influence vocal learning in the budgerigar (Melopsittacus undulatus). Previous research has shown that NIVL receives projections from Field 'L' as well as adjacent portions of the dorsolateral neostriatum intermedium (NIDL) and hyperstriatum ventrale (HV) and, therefore, may be homologous to previously described auditory centers in the dorsal and lateral portions of the auditory neostriatum of songbirds. The efferent connections of NIVL terminate within a small portion of the rostromedial archistriatum as well as a more rostrally situated area within the medial neostriatum intermedium (NI) and HV. Near by (but not overlapping) fields in NI and HV receive input from the nucleus dorsomedialis posterior thalami (DMP), the archistriatum and ectostriatum. Interestingly, only the DMP projection field overlaps a neural field known to be related to the vocal motor system. The DMP projection field corresponds to that previously described as the magnocellular nucleus of the anterior neostriatum; this nucleus is known to project to the higher vocal center in the budgerigar. In addition to projections from NIVL to medial NI and HIV, auditory information is relayed to the anterolateral telencephalon directly from the brainstem via the ventrolateral nucleus of the lateral lemniscus (VLV). This latter pathway appears comparable to that described in pigeons derived from the intermediate nucleus of the lateral lemniscus. The projection field of VLV overlaps a restricted portion of the caudal and medial aspect of nucleus basalis. These results support the notion that many aspects of telencephalic auditory pathways in birds are primitive characters, although a direct connection between auditory and vocal motor circuits was not found in the present study.

Animals↗

The deep layers of the superior colliculus.

The evidence is compelling that the deep layers of the SC are involved in the translation of sensory signals into motor commands for the control of saccadic eye movements. The deep layers receive inputs from brain areas involved in the analysis of stimuli (visual, auditory and somatosensory) used to guide orienting movements. Patterns of activity recorded from collicular neurons are appropriate for the initiation and direction of saccades, and neurons carrying these signals are organized topographically, forming a map of motor (saccadic) space. Efferent projections from the deep layers are to brainstem nuclei having direct or indirect connections with motoneuron pools innervating extraocular muscles. Finally, reversible inactivation of neurons in the deep colliculus severely impairs the ability of animals to generate accurate saccades. Major gaps in our knowledge of the anatomical and functional organization of the SC remain. The physiological signals conveyed to the SC over afferent pathways are, for the most part, unknown. The intrinsic organization of the SC is poorly understood; and the question of whether or not there is extensive communication between neurons in the superficial and deep divisions has not yet been resolved. Very little is known about the morphology, location or physiological response properties of the cells of origin of the major efferent pathways; and the neural circuits involved in decoding information about the direction, velocity and amplitude of saccades (contained in the spatial and temporal pattern of neural activity of collicular cells) are still unspecified. In general, the contribution of the sensory responses of deep collicular neurons to the initiation of orienting movements is unknown. There is no experimental evidence that the activity of deep collicular neurons responsive to sensory stimuli is either necessary or sufficient for the generation of the motor signals observed in the SC, and patterns of connections within the SC specifically involved in the translation of sensory signals into motor commands have not been identified. The alignment (in anesthetized or paralysed animals) of auditory, somatosensory and visual maps in the SC has influenced thinking about the process of sensorimotor integration. It is commonly assumed that the deep division of the SC contains topographical maps of sensory space--i.e., a point in the space surrounding the animal is represented by neurons residing at a particular location in the SC. It is assumed, further, that sensory signals from different modalities originating from the same point in space activate a common pool of collicular neurons located within this representation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

QTL analysis of trabecular bone in BXD F2 and RI mice.

UNLABELLED: A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using microCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone. INTRODUCTION: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. microCT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by microCT. MATERIALS AND METHODS: The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n approximately 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by microCT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping. RESULTS: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores 4.3 in the F2 cohort and 1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects. CONCLUSIONS: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions.

Animals↗

Hoxa2- and rhombomere-dependent development of the mouse facial somatosensory map.

In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by rhombomere 3-derived neurons, whereas the rhombomere 2-derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and rhombomere 3-dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.

Afferent Pathways↗

Distortions of visuotopic map match orientation singularities in primary visual cortex.

The map of orientation columns in primary visual cortex (V1) is known to show strong local distortions, with a generally smooth progression of orientation preference across extended regions of cortex, interrupted by sharp jumps (fractures) and point singularities. The map of visual space on V1, in contrast, has been assumed to be locally smooth and isotropic. We find, on the contrary, that the map of visual space on cat V1 shows strong and systematic local distortions in register with inhomogeneities in the orientation map, with the rate of receptive field movement across cortex being largely proportional to the local rate of change of orientation. This suggests possible systematic local variations in the functional connectivity of short-range lateral connections that underlie local cortical processing.

Animals↗

[The spectral rearrangements of the EEG and the organization of the cortical connections during spatial and verbal thinking].

Solution of spatial and verbal tasks was studied in 43 subjects using the advanced version of the method of intracortical interaction mapping (IIM) and analysis of EEG spectra in short (250 ms) intervals. Comparison between the IIM and coherence methods during solving simple motor tasks revealed some advantages of the IIM for studying of labile cortical connections. Several stages were separated in the process of solution of the mental task in accordance with patterns of cortical connections. The duration of the stages was similar in both kinds of tasks and corresponded to that revealed in psychological experiments. Cortical connections in the theta range were generalized and reflected the level of general tension. This unspecific tension was high for the whole period of the spatial task solution while in the verbal task the tension increased to the stage of decision making. Task-specific patterns were revealed in the beta range. The right parietal and temporal regions were the centers of EEG connections during solution of the spatial task while the left central area was essential for the verbal task solution. The left parietal area was involved in solution of both kinds of tasks. The frequency parameters of connections in the beta range were stable during the spatial task solving, and in the process of verbal task solving the dominant frequency changed after the initial (perception) stage probably due to switching to another thinking mechanism.

Adolescent↗

A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network.

The transcriptional activity of the p53 protein is central to its role in tumor suppression. Identification of the complete repertoire of p53-regulated genes is critical for dissecting the complexity of the p53 network. Although several different approaches have been used to characterize the p53 genetic program, we still lack a comprehensive molecular understanding of how p53 prevents cancer. Using a computational approach, we generated a genome-wide map of p53 binding sites (p53BS) to identify novel p53 target genes. We show that the presence of nearby p53BS can identify new proapoptotic members of the Bcl2 family. We show that p53 binds to p53BS identified in the BCL-G/BCL2L14 gene and that induction of this gene contributes to p53-mediated apoptosis. We found that p53 activates the COL18A1 gene encoding the precursor for the antiangiogenic factor endostatin. We also show that p53 up-regulates the MAP4K4 gene and activates the c-Jun NH2-terminal kinase (JNK) pathway to drive apoptosis. Thus, unbiased mapping of the genomic landscape of p53BS provides a systematic and complementary approach to identify novel factors and connections in the p53 genetic network. Our study illustrates how systematic genomic approaches can identify binding sites that are functionally relevant for a p53 transcriptional program. The genetic link among p53, antiangiogenic factors, and the JNK signaling pathway adds new dimensions to understanding p53 function in highly connected genetic networks.

Apoptosis↗

[Peroperative functional mapping using direct electrical stimulations. Methodological considerations].

The interindividual anatomo-functional variability of the central nervous system implies that brain surgery within eloquent regions may induce neurological sequelae. Consequently, several methods of functional mapping were developed, both preoperative non-invasive neurofunctional imaging and intraoperative cortico-subcortical electrical stimulations. While this technique was reported as safe, accurate, reliable and reproducible in the recent literature, a rigorous methodology is nevertheless mandatory in order to avoid any error in the detection of the so-called eloquent structures. Indeed, an erroneous mapping could lead to prematurely interrupting the resection (false positive), or to generate a postoperative permanent deficit due to the removal of critical areas interpreted as non-essential to function (false negative). The goal of the present review is to recall the electrophysiological principles of direct brain stimulations, and to consider the selection of stimulation parameters according to a theoretical approach, in order to adapt in practice the methods to each patient. The results reported in the literature are then analyzed, concerning the clinico-surgical contribution of intraoperative electrical mapping (in terms of extent of surgical indications, minimization of risk of permanent deficit, and quality of resection), their methodological interest (e.g. validation of neurofunctional imaging techniques), and their contribution to neurosciences (better understanding of the pathophysiology of brain structures, of the connectivity, and of the dynamic mechanisms underlying plasticity).

Brain Mapping↗

Biologically plausible models of topographic map formation in the somatosensory and auditory cortices.

Computational models of the somatosensory and auditory systems have been constructed with the neurosimulator GENESIS. The somatosensory model consists of a cortical layer with 1024 pyramidal cells and 512 basket cells connected to a hand surface with 512 tactile receptors. The auditory model consists of a cortical layer with 2256 pyramidal cells and 1128 basket cells connected to a cochlea with 47 receptors. The models reproduce processes related to the formation and maintenance of somatotopic and tonotopic maps and exhibit several features observed in experiments with animals such as variability in the shapes and sizes of areas of cortical representation and, in the case of somatotopy, cortical magnification values in agreement with experimental findings and linear decay of receptive field overlap as a function of cortical distance between recording sites in normal conditions.

Animals↗