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PubMed1988

Cortical connections of electrophysiologically and architectonically defined subdivisions of auditory cortex in squirrels.

Multiunit recordings with microelectrodes were used to identify and delimit subdivision of auditory cortex in squirrels. In the same animals, cortical connections of subdivisions of auditory cortex were determined by placing injections of the tracer wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) into electrophysiologically defined locations. The electrophysiological results and patterns of connections were later related to myeloarchitectonic distinctions in brain sections cut parallel to the surface of the artificially flattened cortex. As previously described (Merzenich et al.: J. Comp. Neurol. 166:387-402, '76), a primary auditory field, A-I, was characterized by (1) neurons narrowly tuned to tone frequency; (2) a tonotopic map with high frequencies, which represented caudal to low frequencies; and (3) dense myelination. A-I was reciprocally connected with a rostral field, R, a parietal ventral somatosensory representation, PV, cortex ventral to A-I, and other nearby regions of cortex of the same hemisphere. Callosal connections of A-I were with A-I, R, and two or more other regions of temporal cortex. The less densely myelinated rostral field, R, also had neurons that were frequency tuned, but the neurons were often less securely driven. R appeared to have a tonotopic organization that roughly mirrored that of A-I. Ipsilateral connections of R included A-I, PV, and cortex ventral and caudal to R. Callosal connections were with R, A-I, PV, and cortex ventral and caudal to R. Callosal connections were with R, A-I, PV, and other locations in temporal cortex. Cortex in caudal PV, ventral to A-I, and ventral to R was responsive to auditory stimuli, but responses to pure tones were weak and inconsistent, and habituation to a repeated stimulus was rapid. The cortex responsive to auditory stimuli included some but not all of the cortex connected with A-I and R. The results lead to the conclusion that auditory cortex of squirrels contains at least two tonotopically organized fields, possibly as many as five or more auditory fields, and at least two auditory-somatosensory fields.

Animals↗

PubMed1999

Cloning and characterization of the murine histone deacetylase (HDAC3).

Histone acetylation modifiers have been described to participate as cofactors in mammalian transcriptional complexes involved in the regulation of cellular proliferation and differentiation. The acetylation of core histone proteins is reversible and regulated by two competing enzymatic activities, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Increasing evidence suggests a connection between histone acetylation and the development of cancer and leukemia. We have recently mapped HDAC3 to mouse chromosome 18B3, a region which is syntenic with human chromosome 5q31, where HDAC3 is imbedded in a group of potential tumor suppressor genes and which has been reported to be the smallest commonly deleted segment in malignant myeloid disease. We report herein the identification and characterization of HDAC3, a yeast RPD3 ortholog in the mouse. Studies on murine HDAC3 may yield important insights on the understanding of myeloproliferative disease in humans.

Amino Acid Sequence↗

PubMed1980

[Ontogeny of retinal projections: observation and reflection].

Recent evidence indicates that the retinotectal projection has a field-to-field rather than a point-to-point precision. Therefore, individual fibres can vary their relative position in the fibre pathway to some extent. In addition it is not necessary that retinotopy is maintained throughout the whole pathway; transformations may also occur. In fact, in the chick embryo outgrowing retinal fibres maintain not an absolute but only a high degree of order. Transformations occur at the entrance to the optic nerve and probably also right behind the chiasm. The origin of the map is determined by the fact that central retinal fibres which are formed first connect to tectal neurons near the centre of the optic tectum where neurons mature first. There they immediately invade the cellular tectal layers and form functional synapses soon after. Supernumerary fibres degenerate.

Animals↗

PubMed1987

3-D ventricular myocardial electrical excitation: a minimal orthogonal pathways model.

This study is part of our attempt to develop a fast-responding interactive computer simulator of the left ventricle (LV) which describes the spatial and temporal myocardial characteristics and the global performance of the LV, accounting for the continuous interactions between the electrical activation sequence, fiber mechanics, blood perfusion and transmural metabolism and oxygen demand. Here, the activation propagation front throughout the healthy 3-dimensional LV myocardium is simulated in a macro global level by utilizing an analytical model based on the principle of the propagation of the electric activation signal along minimal pathways in an elliptically assumed LV geometry. The Purkinje network dominates the propagation at the endocardial layer while three orthogonal directions of propagation are assumed within the myocardium. The shortest path consists of the geodetic line at the endocardial layer and the normal that connects the endocardium with the point considered. The generated three-dimensional propagation front maps are in fair agreement with reported experimental data. The study thus presents a new approach that permits a quick reconstruction of the 3-D isochrons in a relatively simple but useful model of the normal heart.

Computer Simulation↗

PubMedDate not supplied

Spike timing-dependent synaptic plasticity in visual cortex: a modeling study.

Recent studies show that synaptic modification depends critically on the relative spike timing of pre- and postsynaptic neurons. Here we explore the functional implications of spike timing-dependent synaptic plasticity in the visual cortex using a model circuit with modifiable intracortical excitatory connections. First we simulated the experiments using two-point stimuli, in which two visual stimuli in a topographically represented feature space were repeatedly presented in quick succession, and found that tuning of the cortical neurons was modified in a manner similar to that observed experimentally. We then explored the dependence of results on the model parameter and identified the intracortical parameters that were critical for the magnitude of the shifts and obtained a simple relationship between the amount of shift and (S=(sigmaEXTCrec_exc)/sigmaINHCrec_inh). Finally we investigated the effects of moving stimuli in a topographically represented visual space and found that they can effectively induce spike timing-dependent modification of the intracortical connections. It suggests the importance of moving stimuli in dynamic modification of the cortical maps through spike timing-dependent synaptic plasticity.

Action Potentials↗

PubMed1995

Neurotransmitter receptor histochemistry: the contribution of in situ hybridization.

Molecular cloning of neurotransmitter receptors has enabled the application of in situ hybridization histochemistry to the study of the regional distribution and cellular localization of receptor mRNAs with an unprecedented degree of selectivity. This has resulted in a large body of information including detailed maps of the distribution of receptor subtype transcripts, the establishment of neurotransmitter phenotype and connectivity of receptor-expressing cells, and the relationship between receptor transcripts and binding sites. In this minireview, we discuss and illustrate with a number of examples the contributions of in situ hybridization histochemistry to the study of receptor distribution in brain tissue.

Animals↗

PubMed2004

Fos-tau-LacZ mice expose light-activated pathways in the visual system.

We have employed fos-tau-LacZ (FTL) transgenic mice to examine functional activation in the visual areas of the nervous system. The FTL mice express the marker gene lacZ in neurons and their processes following many different stimuli, and allow the imaging of activation from the level of the entire brain surface through individual neurons and their projections. Analysis of FTL expression in the retinas of mice following diurnal exposure to light shows that bipolar cells, specific classes of amacrine cells, ganglion cells, and a dense network of processes in the inner plexiform layer are functionally activated. In animals deprived of light, there is almost no activity in the retina. In the lateral geniculate nucleus (LGN), light exposure appears responsible for FTL expression in dorsal nuclei, but not for expression in the ventral nuclei or the intergeniculate leaflet. In the superficial layers of the superior colliculus, FTL expression is highly dependent on light exposure. Similarly, light exposure is required for FTL expression in primary visual cortex (area 17), but some expression remains in area 18 of dark-adapted animals. Finally, using mice with one or both eyes missing, we have determined which parts of the visual system are dependent on the presence of a functional connectivity from the eye. These data demonstrate the usefulness of the FTL mice to map functional activation within the entire visual system. Furthermore, we can capture visual activation in a conscious animal. Our findings give an insight into the architecture of activity within the retina and throughout the visual system.

Animals↗

PubMed2000

The hippocampal lamella hypothesis revisited.

We have re-examined the hippocampal lamellar organization of the CA3-to-CA1 connection. Based on a new technique with electrophysiological quantification of Schaffer collateral density, and a review of recent literature, we conclude that the lamellar organization remains a useful concept for understanding hippocampal connectivity. Using a sheet-like hippocampal preparation, containing the whole CA1 region, we mapped the distribution of Schaffer collaterals by two procedures. First, we recorded the amplitude of the Schaffer compound action potential in various parts of CA1 after stimulation of a point in CA3. Second, we charted the CA1 positions from which we could antidromically excite individual CA3 neurones. Although the Schaffer collaterals radiated from their CA3 cells of origin within a wide, fan-shaped area, covering a large part of the septo-temporal extent of CA1, the amplitude of the compound action potential was largest in a slightly oblique, transverse band across the CA1 towards the subicular region.

Action Potentials↗

PubMed1997

Corpus callosal morphology in treatment-naive pediatric obsessive compulsive disorder.

1. Abnormalities in association circuits have been described in Obsessive Compulsive Disorder (OCD) and may reflect neurodevelopmental abnormalities. Primary and association cortices are topographically mapped in the corpus callosum (CC). The authors hypothesized alterations in CC subdivisions that connect association, but not primary cortices in pediatric OCD. The authors predicted that normal age-related increases in CC area would be absent in OCD. 2. The authors compared the midsagittal magnetic resonance images of 21 psychotropic-naive, nondepressed OCD patients, 7.2-17.7 years, and 21 case-matched healthy controls. Total CC area as well as that of the anterior, middle and posterior genu, anterior and posterior bodies, isthmus, and the anterior, middle and the posterior splenii were measured. 3. All of the CC regions except the isthmus were significantly larger in OCD patients than in controls. CC area correlated significantly with OCD symptom severity but not illness duration. The age-related increase in CC size seen in normal subjects was absent in OCD patients. 4. These findings support theories of abnormal association cortex development in OCD but also suggest possible abnormalities of other primary cortical regions as well.

Adolescent↗

PubMedDate not supplied

A procedure for quantification of precipitate microstructures from three-dimensional atom probe data.

New analysis software for selecting and quantifying particles in three-dimensional atom maps has been designed. The selection of solute-rich regions is performed by connecting solute atoms which lie within a fixed distance (d), and taking clusters above a certain minimum number of solute atoms (N(min)). Other atoms within some distance L greater than d are taken to belong to the cluster. However, this results in the inclusion of a shell of matrix atoms, which must be removed through an erosion step, to define the final cluster. Data filtered in this way can be used for subsequent quantification of parameters such as size, shape, composition, number density and volume fraction with better accuracy than by manual selection. The choice of d, N(min) and L values is discussed and some methods of evaluation of these parameters are proposed. Examples are presented on the application of this new software to the analysis of early stage clustering in an Al-Mg-Si-Cu alloy and a copper-containing steel.

Journal Article↗

PubMed2002

Making connections in the fly visual system.

Understanding the molecular mechanisms that regulate formation of precise patterns of neuronal connections within the central nervous system remains a challenging problem in neurobiology. Genetic studies in worms and flies and molecular studies in vertebrate systems have led to an increasingly sophisticated understanding of how growth cones navigate toward their targets and form topographic maps. Considerably less is known about how growth cones recognize their cellular targets and form synapses with them. Here, we review connection formation in the fly visual system, the methodological approaches used to study it, and recent progress in uncovering the molecular basis of connection specificity.

Animals↗

PubMedDate not supplied

Visual inter-hemispheric processing: constraints and potentialities set by axonal morphology.

The largest bundle of axonal fibers in the entire mammalian brain, namely the corpus callosum, is the pathway through which almost half a billion neurons scattered over all neocortical areas can exert an influence on their contralateral targets. These fibers are thus crucial participants in the numerous cortical functions requiring collaborative processing of information across the hemispheres. One of such operations is to combine the two partial cortical maps of the visual field into a single, coherent representation. This paper reviews recent anatomical, computational and electrophysiological studies on callosal connectivity in the cat visual system. We analyzed the morphology of individual callosal axons linking primary visual cortices using three-dimensional light-microscopic techniques. While only a minority of callosal axons seem to perform a strict 'point-to-point' mapping between retinotopically corresponding sites in both hemispheres, many others have widespread arbors and terminate into a handful of distant, radially oriented tufts. Therefore, the firing of a single callosal neuron might influence several cortical columns within the opposite hemisphere. Computer simulation was then applied to investigate how the intricate geometry of these axons might shape the spatio-temporal distribution of trans-callosal inputs. Based on the linear relation between diameter and conduction velocity of myelinated fibers, the theoretical delays required for a single action potential to reach all presynaptic boutons of a given arbor were derived from the caliber, g-ratio and length of successive axonal segments. This analysis suggests that the architecture of callosal axons is, in principle, suitable to promote the synchronous activation of multiple targets located across distant columns in the opposite hemisphere. Finally, electrophysiological recordings performed in several laboratories have shown the existence of stimulus-dependent synchronization of visual responses across the two hemispheres. Possible implications of these findings are discussed in the context of temporal tagging of neuronal assemblies.

Animals↗

PubMed1998

Structure of the interhelical loops and carboxyl terminus of bacteriorhodopsin by X-ray diffraction using site-directed heavy-atom labeling.

The positions of single amino acids in the interhelical loop regions and the C-terminal tail of bacteriorhodopsin (bR) were investigated by X-ray diffraction using site-directed heavy-atom labeling. Since wild-type bR does not contain any cysteines, appropriate cysteine mutants were produced with a unique sulfhydryl group at specific positions. These sites were then labeled with mercury using the sulfhydryl specific reagent p-chloromercuribenzoate (p-CMB). The cysteine mutants D96A/V101C, V130C, A160C, and G231C were derivatized with labeling stoichiometries of 0.93 +/- 5%, 0.85 +/- 5%, 0.79 +/- 7%, and 0.77 +/- 8%, respectively (Hg per bR). No incorporation was observed with wild-type bR under the same conditions. All mutants and heavy-atom derivatives were fully active as judged by the kinetics of the photocycle and of the proton release and uptake. Moreover, the unit cell dimensions of the two-dimensional P3 lattice were unchanged by the mutations and the derivatization. This allowed the position of the mercury atoms, projected onto the plane of the membrane, to be calculated from the intensity differences in the X-ray diffraction pattern between labeled and unlabeled samples using Fourier difference methods. The X-ray diffraction data were collected at room temperature from oriented purple membrane films at 100% relative humidity without the use of dehydrating solvents. These native conditions of temperature, humidity, and solvent are expected to preserve the structure of the surface-exposed loops. Sharp maxima corresponding to a single mercury atom were found in the difference density maps for D96A/V101C and V130C. Residues 101 and 130 are in the short loops connecting helices C/D and D/E, respectively. No localized difference density was found for A160C and G231C. Residue 160 is in the longer loop connecting helices E and F, whereas residue 231 is in the C-terminal tail. Residues 160 and 231 are apparently in a more disordered and mobile part of the structure.

Alanine↗

PubMed2006

Atom-by-atom analysis of global downhill protein folding.

Protein folding is an inherently complex process involving coordination of the intricate networks of weak interactions that stabilize native three-dimensional structures. In the conventional paradigm, simple protein structures are assumed to fold in an all-or-none process that is inaccessible to experiment. Existing experimental methods therefore probe folding mechanisms indirectly. A widely used approach interprets changes in protein stability and/or folding kinetics, induced by engineered mutations, in terms of the structure of the native protein. In addition to limitations in connecting energetics with structure, mutational methods have significant experimental uncertainties and are unable to map complex networks of interactions. In contrast, analytical theory predicts small barriers to folding and the possibility of downhill folding. These theoretical predictions have been confirmed experimentally in recent years, including the observation of global downhill folding. However, a key remaining question is whether downhill folding can indeed lead to the high-resolution analysis of protein folding processes. Here we show, with the use of nuclear magnetic resonance (NMR), that the downhill protein BBL from Escherichia coli unfolds atom by atom starting from a defined three-dimensional structure. Thermal unfolding data on 158 backbone and side-chain protons out of a total of 204 provide a detailed view of the structural events during folding. This view confirms the statistical nature of folding, and exposes the interplay between hydrogen bonding, hydrophobic forces, backbone conformation and side-chain entropy. From the data we also obtain a map of the interaction network in this protein, which reveals the source of folding cooperativity. Our approach can be extended to other proteins with marginal barriers (less than 3RT), providing a new tool for the study of protein folding.

Entropy↗

PubMed2002

Indications of associations of the porcine FOS proto-oncogene with skeletal muscle fibre traits.

Skeletal muscle fibre characteristics are key determinants of meat quality. High fibre diameters and shifting towards higher white fibre proportions lead to increasing R-values (degree of desamination of adenosine) and lactate-production, resulting in high incidences of pale, soft, exudative (PSE) meat and stress susceptibility in European and American pig breeds. Development of muscle fibres including their enzymes, is regulated by the MyoD-gene family together with transcription factors like FOS. We report on the associations between the chromosomal region of FOS with skeletal muscle fibre and metabolism traits. The BB genotype representing the European Pietrain breed had 10.9% more white fibres with fibre diameters decreased by 6.1%, with 3.9% higher R-values and 8.5% higher lactate levels than the AA genotype of the Chinese Meishan. Lactate levels and R-values per microm of fibre diameter were increased to 18.4 and 11.6% in the BB genotype. The contrast between the two quantitative trait loci (QTL) alleles associated with a polymorphism in the FOS gene explained up to 5.13% of the total variance. A new TaiI-restriction fragment length polymorphism (RFLP) connected to a Asn258/Ser mutation, located in a transcription activator region, was used to map FOS between markers S0115 and Sw581 on SSC7. The QTLs for skeletal muscle fibre and metabolism traits have been mapped to the marker interval around FOS. The present data suggest that variability in FOS gene may underlie phenotypic variation in skeletal muscle fibre and metabolism traits in the pig.

Alleles↗

PubMed1998

Type II protein secretion by Pseudomonas aeruginosa: genetic suppression of a conditional mutation in the pilin-like component XcpT by the cytoplasmic component XcpR.

Pseudomonas aeruginosa exports a number of hydrolytic enzymes and toxins using the type II or general secretion pathway, found in a variety of Gram-negative bacteria and requiring the functions of at least 12 gene products (XcpP-Z and PilD/XcpA in P. aeruginosa). A number of these gene products are homologues of components of the type IV pilus biogenesis system, including four proteins, XcpT-W, which are highly similar to the pilin subunit in their size, localization and post-translational modifications. These proteins, in addition to the pilin subunit, are cleaved and methylated by the PilD/XcpA prepilin peptidase, but their interactions with other components of the export apparatus are unclear. Using a medium developed for the selection of export-proficient P. aeruginosa strains, we have isolated temperature-sensitive mutations in the xcpT gene and extragenic suppressors for one of the mutants. These suppressors fall into two classes, one that maps outside of the xcpP-Z gene cluster and may define additional cellular functions that are required for export, and a second that maps to the xcpR gene product and indicates a potential protein-protein interaction connecting two different cellular compartments and required for the assembly or function of the export apparatus.

Bacterial Outer Membrane Proteins↗

PubMed2001

Generation, description and storage of dendritic morphology data.

It is generally assumed that the variability of neuronal morphology has an important effect on both the connectivity and the activity of the nervous system, but this effect has not been thoroughly investigated. Neuroanatomical archives represent a crucial tool to explore structure-function relationships in the brain. We are developing computational tools to describe, generate, store and render large sets of three-dimensional neuronal structures in a format that is compact, quantitative, accurate and readily accessible to the neuroscientist. Single-cell neuroanatomy can be characterized quantitatively at several levels. In computer-aided neuronal tracing files, a dendritic tree is described as a series of cylinders, each represented by diameter, spatial coordinates and the connectivity to other cylinders in the tree. This 'Cartesian' description constitutes a completely accurate mapping of dendritic morphology but it bears little intuitive information for the neuroscientist. In contrast, a classical neuroanatomical analysis characterizes neuronal dendrites on the basis of the statistical distributions of morphological parameters, e.g. maximum branching order or bifurcation asymmetry. This description is intuitively more accessible, but it only yields information on the collective anatomy of a group of dendrites, i.e. it is not complete enough to provide a precise 'blueprint' of the original data. We are adopting a third, intermediate level of description, which consists of the algorithmic generation of neuronal structures within a certain morphological class based on a set of 'fundamental', measured parameters. This description is as intuitive as a classical neuroanatomical analysis (parameters have an intuitive interpretation), and as complete as a Cartesian file (the algorithms generate and display complete neurons). The advantages of the algorithmic description of neuronal structure are immense. If an algorithm can measure the values of a handful of parameters from an experimental database and generate virtual neurons whose anatomy is statistically indistinguishable from that of their real counterparts, a great deal of data compression and amplification can be achieved. Data compression results from the quantitative and complete description of thousands of neurons with a handful of statistical distributions of parameters. Data amplification is possible because, from a set of experimental neurons, many more virtual analogues can be generated. This approach could allow one, in principle, to create and store a neuroanatomical database containing data for an entire human brain in a personal computer. We are using two programs, L-NEURON and ARBORVITAE, to investigate systematically the potential of several different algorithms for the generation of virtual neurons. Using these programs, we have generated anatomically plausible virtual neurons for several morphological classes, including guinea pig cerebellar Purkinje cells and cat spinal cord motor neurons. These virtual neurons are stored in an online electronic archive of dendritic morphology. This process highlights the potential and the limitations of the 'computational neuroanatomy' strategy for neuroscience databases.

Algorithms↗

PubMed2000

Nonlinear lattice model of viscoelastic mode III fracture.

We study the effect of general nonlinear force laws in viscoelastic lattice models of fracture, focusing on the existence and stability of steady-state mode III cracks. We show that the hysteretic behavior at small driving is very sensitive to the smoothness of the force law. At large driving, we find a Hopf bifurcation to a straight crack whose velocity is periodic in time. The frequency of the unstable bifurcating mode depends on the smoothness of the potential, but is very close to an exact period-doubling instability. Slightly above the onset of the instability, the system settles into a exactly period-doubled state, presumably connected to the aforementioned bifurcation structure. We explicitly solve for this new state and map out its velocity-driving relation.

Journal Article↗