RESUMEN
Gene networks for disorders of social behavior provide the mechanisms critical for identifying therapeutic targets and biomarkers. Large behavioral phenotypic effects of small human deletions make the positive sociality of Williams syndrome (WS) ideal for determining transcriptional networks for social dysfunction currently based on DNA variations for disorders such as autistic spectrum disorder (ASD) and schizophrenia (SCHZ). Consensus on WS networks has been elusive due to the need for larger cohort size, sensitive genome-wide detection and analytic tools. We report a core set of WS network perturbations in a cohort of 58 individuals (34 with typical, 6 atypical deletions and 18 controls). Genome-wide exon-level expression arrays robustly detected changes in differentially expressed gene (DEG) transcripts from WS deleted genes that ranked in the top 11 of 12 122 transcripts, validated by quantitative reverse transcription PCR, RNASeq and western blots. WS DEG's were strictly dosed in the full but not the atypical deletions that revealed a breakpoint position effect on non-deleted CLIP2, a caveat for current phenotypic mapping based on copy number variants. Network analyses tested the top WS DEG's role in the dendritic spine, employing GeneMANIA to harmonize WS DEGs with comparable query gene-sets. The results indicate perturbed actin cytoskeletal signaling analogous to the excitatory dendritic spines. Independent protein-protein interaction analyses of top WS DEGs generated a 100-node graph annotated topologically revealing three interacting pathways, MAPK, IGF1-PI3K-AKT-mTOR/insulin and actin signaling at the synapse. The results indicate striking similarity of WS transcriptional networks to genome-wide association study-based ASD and SCHZ risk suggesting common network dysfunction for these disorders of divergent sociality.
Asunto(s)
Actinas/metabolismo , Trastorno del Espectro Autista/patología , Redes Reguladoras de Genes , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Actinas/genética , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genéticaRESUMEN
High-level cognitive and emotional experience arises from brain activity, but the specific brain substrates for religious and spiritual euphoria remain unclear. We demonstrate using functional magnetic resonance imaging scans in 19 devout Mormons that a recognizable feeling central to their devotional practice was reproducibly associated with activation in nucleus accumbens, ventromedial prefrontal cortex, and frontal attentional regions. Nucleus accumbens activation preceded peak spiritual feelings by 1-3 s and was replicated in four separate tasks. Attentional activation in the anterior cingulate and frontal eye fields was greater in the right hemisphere. The association of abstract ideas and brain reward circuitry may interact with frontal attentional and emotive salience processing, suggesting a mechanism whereby doctrinal concepts may come to be intrinsically rewarding and motivate behavior in religious individuals.
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Atención/fisiología , Encéfalo/fisiología , Iglesia de Jesucristo de los Santos de los Últimos Días/psicología , Recompensa , Espiritualidad , Adulto , Percepción Auditiva/fisiología , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Emociones/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiología , Descanso , Percepción Visual/fisiologíaRESUMEN
Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.
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Encéfalo/patología , Síndrome de Williams/patología , Adolescente , Adulto , Apoptosis , Calcio/metabolismo , Diferenciación Celular , Forma de la Célula , Reprogramación Celular , Corteza Cerebral/patología , Cromosomas Humanos Par 7/genética , Dendritas/patología , Femenino , Receptores Frizzled/deficiencia , Receptores Frizzled/genética , Haploinsuficiencia/genética , Humanos , Células Madre Pluripotentes Inducidas/patología , Masculino , Modelos Neurológicos , Células-Madre Neurales/patología , Neuronas/patología , Fenotipo , Reproducibilidad de los Resultados , Sinapsis/patología , Síndrome de Williams/genética , Adulto JovenRESUMEN
Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner.
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Imagen de Difusión Tensora/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Animales , Encéfalo/anatomía & histología , Simulación por Computador , Imagen de Difusión Tensora/estadística & datos numéricos , Macaca/anatomía & histología , Conceptos Matemáticos , Relación Señal-RuidoRESUMEN
Williams syndrome (WS) is a genetic condition characterized by a hypersocial personality and desire to form close relationships, juxtaposed with significant anxieties of nonsocial events. The neural underpinnings of anxiety in individuals with WS are currently unknown. Aberrations in the anatomical and microstructural integrity of the uncinate fasciculus (UF) have been recently implicated in social and generalized anxiety disorders. Based on these findings, we tested the hypothesis that the reported anxieties in individuals with WS share similar neuropathological correlates. Toward this end, diffusion tensor imaging (DTI) methods were employed to examine the microstructural integrity (fractional anisotropy, mean diffusivity, longitudinal diffusivity) of the UF in 18 WS and 15 typically developing adults (TD). Anxiety and sociability questionnaires were administered to determine associations with DTI indices of UF across groups. Results revealed comparable white matter integrity of the UF across groups, yet elevated subjective experience of anxiety in those with WS. Additionally, sociability and UF microstructural properties were dissociated across both groups. Whereas no relationships were found between DTI indices and anxiety in TD participants, strong negative associations were observed between these constructs in individuals with WS. Findings indicated that increased anxiety manifested by individuals with WS was associated with DTI measures of the UF and may signal structural or possibly physiological aberration involving this tract within the prefrontal-temporal network.
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Ansiedad/patología , Trastornos del Conocimiento/patología , Sistema Límbico/patología , Vías Nerviosas/patología , Corteza Prefrontal/patología , Adolescente , Adulto , Análisis de Varianza , Ansiedad/etiología , Trastornos del Conocimiento/etiología , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Encuestas y Cuestionarios , Síndrome de Williams/complicaciones , Síndrome de Williams/patología , Adulto JovenRESUMEN
Williams syndrome (WS) is a genetic condition characterized by an overly gregarious personality, including high empathetic concern for others. Although seemingly disparate from the profile of autism spectrum disorder (ASD), both are associated with deficits in social communication/cognition. Notably, the mirror neuron system (MNS) has been implicated in social dysfunction for ASD; yet, the integrity of this network and its association with social functioning in WS remains unknown. Magnetic resonance imaging (MRI) methods were used to examine the structural integrity of the MNS of adults with WS versus typically developing (TD) individuals. The Social Responsiveness Scale (SRS), a tool typically used to screen for social features of ASD, was also employed to assess the relationships between social functioning with the MNS morphology in WS participants. WS individuals showed reduced cortical surface area of MNS substrates yet relatively preserved cortical thickness as compared to TD adults. Increased cortical thickness of the inferior parietal lobule (IPL) was associated with increased deficits in social communication, social awareness, social cognition, and autistic mannerisms. However, social motivation was not related to anatomical features of the MNS. Our findings indicate that social deficits typical to both ASD and WS may be attributed to an aberrant MNS, whereas the unusual social drive marked in WS is subserved by substrates distinct from this network.
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Neuronas Espejo/patología , Síndrome de Williams/patología , Adulto , Análisis de Varianza , Trastorno del Espectro Autista/patología , Femenino , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastorno de la Conducta Social/diagnóstico por imagen , Trastorno de la Conducta Social/etiología , Síndrome de Williams/diagnóstico por imagen , Síndrome de Williams/psicología , Adulto JovenRESUMEN
Diffusion tensor imaging and high angular resolution diffusion imaging are often used to analyze the fiber complexity of tissues. In these imaging techniques, the most commonly calculated metric is anisotropy, such as fractional anisotropy (FA), generalized anisotropy (GA), and generalized fractional anisotropy (GFA). The basic idea underlying these metrics is to compute the deviation from free or spherical diffusion. However, in many cases, the question is not really to know whether it concerns spherical diffusion. Instead, the main concern is to describe and quantify fiber complexity such as fiber crossing in a voxel. In this context, it would be more direct and effective to compute the deviation from a single fiber bundle instead of a sphere. We propose a new metric, called PEAM (PEAnut Metric), which is based on computing the deviation of orientation diffusion functions (ODFs) from a single fiber bundle ODF represented by a peanut. As an example, the proposed PEAM metric is used to classify intravoxel fiber configurations. The results on simulated data, physical phantom data and real brain data consistently showed that the proposed PEAM provides greater accuracy than FA, GA and GFA and enables parallel and complex fibers to be better distinguished.
Asunto(s)
Algoritmos , Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , AnisotropíaRESUMEN
BACKGROUND: The ability to recognize and respond appropriately to threat is critical to survival, and the neural substrates subserving attention to threat may be probed using depictions of media violence. Whether neural responses to potential threat differ in Down syndrome is not known. METHODS: We performed functional MRI scans of 15 adolescent and adult Down syndrome and 14 typically developing individuals, group matched by age and gender, during 50 min of passive cartoon viewing. Brain activation to auditory and visual features, violence, and presence of the protagonist and antagonist were compared across cartoon segments. fMRI signal from the brain's dorsal attention network was compared to thematic and violent events within the cartoons between Down syndrome and control samples. RESULTS: We found that in typical development, the brain's dorsal attention network was most active during violent scenes in the cartoons and that this was significantly and specifically reduced in Down syndrome. When the antagonist was on screen, there was significantly less activation in the left medial temporal lobe of individuals with Down syndrome. As scenes represented greater relative threat, the disparity between attentional brain activation in Down syndrome and control individuals increased. There was a reduction in the temporal autocorrelation of the dorsal attention network, consistent with a shortened attention span in Down syndrome. Individuals with Down syndrome exhibited significantly reduced activation in primary sensory cortices, and such perceptual impairments may constrain their ability to respond to more complex social cues such as violence. CONCLUSIONS: These findings may indicate a relative deficit in emotive perception of violence in Down syndrome, possibly mediated by impaired sensory perception and hypoactivation of medial temporal structures in response to threats, with relative preservation of activity in pro-social brain regions. These findings indicate that specific genetic differences associated with Down syndrome can modulate the brain's response to violence and other complex emotive ideas.
RESUMEN
In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.
Asunto(s)
Cromosomas Humanos Par 7/genética , Cognición/fisiología , Red Nerviosa/fisiología , Desempeño Psicomotor/fisiología , Conducta Social , Síndrome de Williams/genética , Síndrome de Williams/fisiopatología , Encéfalo/patología , Cromosomas Artificiales Bacterianos , Tomografía Computarizada de Haz Cónico , Humanos , Hibridación Fluorescente in Situ , Pruebas Neuropsicológicas , Eliminación de Secuencia/genéticaRESUMEN
We propose a generic method for the statistical analysis of collections of anatomical shape complexes, namely sets of surfaces that were previously segmented and labeled in a group of subjects. The method estimates an anatomical model, the template complex, that is representative of the population under study. Its shape reflects anatomical invariants within the dataset. In addition, the method automatically places control points near the most variable parts of the template complex. Vectors attached to these points are parameters of deformations of the ambient 3D space. These deformations warp the template to each subject's complex in a way that preserves the organization of the anatomical structures. Multivariate statistical analysis is applied to these deformation parameters to test for group differences. Results of the statistical analysis are then expressed in terms of deformation patterns of the template complex, and can be visualized and interpreted. The user needs only to specify the topology of the template complex and the number of control points. The method then automatically estimates the shape of the template complex, the optimal position of control points and deformation parameters. The proposed approach is completely generic with respect to any type of application and well adapted to efficient use in clinical studies, in that it does not require point correspondence across surfaces and is robust to mesh imperfections such as holes, spikes, inconsistent orientation or irregular meshing. The approach is illustrated with a neuroimaging study of Down syndrome (DS). The results demonstrate that the complex of deep brain structures shows a statistically significant shape difference between control and DS subjects. The deformation-based modelingis able to classify subjects with very high specificity and sensitivity, thus showing important generalization capability even given a low sample size. We show that the results remain significant even if the number of control points, and hence the dimension of variables in the statistical model, are drastically reduced. The analysis may even suggest that parsimonious models have an increased statistical performance. The method has been implemented in the software Deformetrica, which is publicly available at www.deformetrica.org.
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Encéfalo/anatomía & histología , Interpretación Estadística de Datos , Interpretación de Imagen Asistida por Computador/métodos , Modelos Anatómicos , Neuroimagen/métodos , Encéfalo/patología , Síndrome de Down/patología , Humanos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
In the Ts65Dn/DnJ mouse model of Down syndrome (DS), hippocampal deficits of learning and memory are the most robust features supporting this mouse as a valid cognitive model of DS. Although dentate gyrus (DG) dysfunction is suggested by excessive GABAergic inhibition, its role in perturbing DG functions in DS is unknown. We hypothesize that in the Ts65Dn/DnJ mouse, the specific role of the DG is disturbed in its support of contextual and spatial information. Support for this hypothesis comes from rats with DG lesions that show similar deficits. In order to test this hypothesis, we have developed a novel series of spontaneous exploratory tasks that emphasize the importance of recognizing spatial and contextual cues and that involve DG function. The results with this exploratory battery show that Ts65Dn/DnJ mice are impaired in DG-dependent short-term recognition tests involving object recognition with contextual cues, in place recognition and in metric distance recognition relative to wild type littermate controls. Further, whereas Ts65Dn/DnJ mice can recognize object novelty in the absence of contextual cues after a 5-min delay, they cannot do so after a delay of 24 h, suggesting a problem with CA1-mediated consolidation. The results also show that Ts65Dn/DnJ mice are not impaired in tasks (object recognition and configural object recognition) that are mediated by the perirhinal cortex (PRh). These results implicate the DG as a specific therapeutic target and the PRh as a potential therapeutic strength for future research to ameliorate learning and memory in DS.
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Cognición/fisiología , Giro Dentado/fisiopatología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Trastornos de la Memoria/fisiopatología , Reconocimiento en Psicología , Conducta Espacial/fisiología , Animales , Animales Congénicos , Síndrome de Down/psicología , Hipocampo/fisiopatología , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Lóbulo Temporal/fisiopatología , Translocación Genética , TrisomíaRESUMEN
Down Syndrome is the most common genetic cause for intellectual disability, yet the pathophysiology of cognitive impairment in Down Syndrome is unknown. We compared fMRI scans of 15 individuals with Down Syndrome to 14 typically developing control subjects while they viewed 50 min of cartoon video clips. There was widespread increased synchrony between brain regions, with only a small subset of strong, distant connections showing underconnectivity in Down Syndrome. Brain regions showing negative correlations were less anticorrelated and were among the most strongly affected connections in the brain. Increased correlation was observed between all of the distributed brain networks studied, with the strongest internetwork correlation in subjects with the lowest performance IQ. A functional parcellation of the brain showed simplified network structure in Down Syndrome organized by local connectivity. Despite increased interregional synchrony, intersubject correlation to the cartoon stimuli was lower in Down Syndrome, indicating that increased synchrony had a temporal pattern that was not in response to environmental stimuli, but idiosyncratic to each Down Syndrome subject. Short-range, increased synchrony was not observed in a comparison sample of 447 autism vs. 517 control subjects from the Autism Brain Imaging Exchange (ABIDE) collection of resting state fMRI data, and increased internetwork synchrony was only observed between the default mode and attentional networks in autism. These findings suggest immature development of connectivity in Down Syndrome with impaired ability to integrate information from distant brain regions into coherent distributed networks.
RESUMEN
Williams syndrome (WS) offers an exciting model for social neuroscience because its genetic basis is well-defined, and the unique phenotype reflects dimensions of prosocial behaviors. WS is associated with a strong drive to approach strangers, a gregarious personality, heightened social engagement yet difficult peer interactions, high nonsocial anxiety, unusual bias toward positive affect, and diminished sensitivity to fear. New neurobiological evidence points toward alterations in structure, function, and connectivity of the social brain (amygdala, fusiform face area, orbital-frontal regions). Recent genetic studies implicate gene networks in the WS region with the dysregulation of prosocial neuropeptides. The study of WS has implications for understanding human social development, and may provide insight for translating genetic and neuroendocrine evidence into treatments for disorders of social behavior.
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Encéfalo/fisiopatología , Conducta Social , Síndrome de Williams/psicología , Femenino , Humanos , Masculino , Fenotipo , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologíaRESUMEN
Although individuals with Williams syndrome (WS) typically demonstrate an increased appetitive social drive, their social profile is characterized by dissociations, including socially fearless behavior coupled with anxiousness, and distinct patterns of "peaks and valleys" of ability. The aim of this study was to compare the processing of social and non-social visually and aurally presented affective stimuli, at the levels of behavior and autonomic nervous system (ANS) responsivity, in individuals with WS contrasted with a typically developing (TD) group, with the view of elucidating the highly sociable and emotionally sensitive predisposition noted in WS. Behavioral findings supported previous studies of enhanced competence in processing social over non-social stimuli by individuals with WS; however, the patterns of ANS functioning underlying the behavioral performance revealed a surprising profile previously undocumented in WS. Specifically, increased heart rate (HR) reactivity, and a failure for electrodermal activity to habituate were found in individuals with WS contrasted with the TD group, predominantly in response to visual social affective stimuli. Within the auditory domain, greater arousal linked to variation in heart beat period was observed in relation to music stimuli in individuals with WS. Taken together, the findings suggest that the pattern of ANS response in WS is more complex than previously noted, with increased arousal to face and music stimuli potentially underpinning the heightened behavioral emotionality to such stimuli. The lack of habituation may underlie the increased affiliation and attraction to faces characterizing individuals with WS. Future research directions are suggested.
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Video games capture the rapt attention of an individual player's mind and body, providing new opportunities for personalized health care. An example of therapeutic interactive technologies is an incentive-based video game that translates physical exercise into mental empowerment via motivational metaphoric visualization in order to help patients psychologically overcome cancer. Such nonpharmacological interventions may enhance patients' resilience toward various chronic disorders via neuronal mechanisms that activate positive emotions and the reward system.
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Pacientes , Poder Psicológico , Juegos de Video , Encéfalo/fisiopatología , Humanos , Juegos de Video/economíaRESUMEN
The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ~28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.
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Oxitocina/fisiología , Conducta Social , Vasopresinas/fisiología , Síndrome de Williams/fisiopatología , Adulto , Femenino , Humanos , MasculinoRESUMEN
In the context of long-range digital neural circuit reconstruction, this paper investigates an approach for registering axons across histological serial sections. Tracing distinctly labeled axons over large distances allows neuroscientists to study very explicit relationships between the brain's complex interconnects and, for example, diseases or aberrant development. Large scale histological analysis requires, however, that the tissue be cut into sections. In immunohistochemical studies thin sections are easily distorted due to the cutting, preparation, and slide mounting processes. In this work we target the registration of thin serial sections containing axons. Sections are first traced to extract axon centerlines, and these traces are used to define registration landmarks where they intersect section boundaries. The trace data also provides distinguishing information regarding an axon's size and orientation within a section. We propose the use of these features when pairing axons across sections in addition to utilizing the spatial relationships among the landmarks. The global rotation and translation of an unregistered section are accounted for using a random sample consensus (RANSAC) based technique. An iterative nonrigid refinement process using B-spline warping is then used to reconnect axons and produce the sought after connectivity information.
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Axones/fisiología , Bases de Datos Factuales , Red Nerviosa/citología , Red Nerviosa/fisiología , Animales , Encéfalo/citología , Encéfalo/fisiología , Macaca , Microscopía Confocal/métodosRESUMEN
Statistical analysis of shapes, performed by constructing an atlas composed of an average model of shapes within a population and associated deformation maps, is a fundamental aspect of medical imaging studies. Usual methods for constructing a shape atlas require point correspondences across subjects, which are difficult in practice. By contrast, methods based on currents do not require correspondence. However, existing atlas construction methods using currents suffer from two limitations. First, the template current is not in the form of a topologically correct mesh, which makes direct analysis on shapes difficult. Second, the deformations are parametrized by vectors at the same location as the normals of the template current which often provides a parametrization that is more dense than required. In this paper, we propose a novel method for constructing shape atlases using currents where topology of the template is preserved and deformation parameters are optimized independently of the shape parameters. We use an L1-type prior that enables us to adaptively compute sparse and low dimensional parameterization of deformations. We show an application of our method for comparing anatomical shapes of patients with Down's syndrome and healthy controls, where the sparse parametrization of diffeomorphisms decreases the parameter dimension by one order of magnitude.
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Algoritmos , Encéfalo/patología , Síndrome de Down/patología , Interpretación de Imagen Asistida por Computador/métodos , Modelos Anatómicos , Reconocimiento de Normas Patrones Automatizadas/métodos , Simulación por Computador , Humanos , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders.
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Moléculas de Adhesión Celular/metabolismo , Colágeno Tipo VI/genética , Cardiopatías Congénitas/genética , Herencia Multifactorial , Animales , Adhesión Celular/genética , Moléculas de Adhesión Celular/genética , Línea Celular , Cromosomas Humanos Par 21/genética , Colágeno Tipo VI/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Corazón/anatomía & histología , Corazón/fisiología , Humanos , Ratones , Ratones Transgénicos , Miocardio/metabolismo , FenotipoRESUMEN
Although genetics is the most significant known determinant of human intelligence, specific gene contributions remain largely unknown. To accelerate understanding in this area, we have taken a new approach by studying the relationship between quantitative gene expression and intelligence in a cohort of 65 patients with Williams Syndrome (WS), a neurodevelopmental disorder caused by a 1.5 Mb deletion on chromosome 7q11.23. We find that variation in the transcript levels of the brain gene STX1A correlates significantly with intelligence in WS patients measured by principal component analysis (PCA) of standardized WAIS-R subtests, r = 0.40 (Pearson correlation, Bonferroni corrected p-value = 0.007), accounting for 15.6% of the cognitive variation. These results suggest that syntaxin 1A, a neuronal regulator of presynaptic vesicle release, may play a role in WS and be a component of the cellular pathway determining human intelligence.