Large-scale extraction of brain connectivity from the neuroscientific literature.

MOTIVATION: In neuroscience, as in many other scientific domains, the primary form of knowledge dissemination is through published articles. One challenge for modern neuroinformatics is finding methods to make the knowledge from the tremendous backlog of publications accessible for search, analysis and the integration of such data into computational models. A key example of this is metascale brain connectivity, where results are not reported in a normalized repository. Instead, these experimental results are published in natural language, scattered among individual scientific publications. This lack of normalization and centralization hinders the large-scale integration of brain connectivity results. In this article, we present text-mining models to extract and aggregate brain connectivity results from 13.2 million PubMed abstracts and 630 216 full-text publications related to neuroscience. The brain regions are identified with three different named entity recognizers (NERs) and then normalized against two atlases: the Allen Brain Atlas (ABA) and the atlas from the Brain Architecture Management System (BAMS). We then use three different extractors to assess inter-region connectivity. RESULTS: NERs and connectivity extractors are evaluated against a manually annotated corpus. The complete in litero extraction models are also evaluated against in vivo connectivity data from ABA with an estimated precision of 78%. The resulting database contains over 4 million brain region mentions and over 100 000 (ABA) and 122 000 (BAMS) potential brain region connections. This database drastically accelerates connectivity literature review, by providing a centralized repository of connectivity data to neuroscientists.

Local perfusion of corticosterone in the rat medial hypothalamus potentiates D-fenfluramine-induced elevations of extracellular 5-HT concentrations.

The dorsomedial hypothalamus (DMH) plays an important role in coordinating physiological and behavioral responses to stress-related stimuli. In vertebrates, DMH serotonin (5-HT) concentrations increase rapidly in response to acute stressors or corticosterone (CORT). Recent studies suggest that CORT inhibits postsynaptic clearance of 5-HT from the extracellular fluid in the DMH by blocking organic cation transporter 3 (OCT3), a polyspecific CORT-sensitive transport protein. Because OCTs are low-affinity, high-capacity transporters, we hypothesized that CORT effects on extracellular 5-HT are most pronounced in the presence of elevated 5-HT release. We predicted that local application of CORT into the DMH would potentiate the effects of d-fenfluramine, a 5-HT-releasing agent, on extracellular 5-HT. These experiments were conducted using in vivo microdialysis in freely-moving male Sprague-Dawley rats implanted with a microdialysis probe into the medial hypothalamus (MH), which includes the DMH. In Experiment 1, rats simultaneously received intraperitoneal (i.p.) injections of 1 mg/kg D-fenfluramine or saline and either 200 ng/mL CORT or dilute ethanol (EtOH) vehicle delivered to the MH by reverse-dialysis for 40 min. In Experiment 2, 5 microM D-fenfluramine and either 200 ng/mL CORT or EtOH vehicle were concurrently delivered to the MH for 40 min using reverse-dialysis. CORT potentiated the increases in extracellular 5-HT concentrations induced by either i.p. or intra-MH administration of D-fenfluramine. Furthermore, CORT and D-fenfluramine interacted to alter home cage behaviors. Our results support the hypothesis that CORT inhibition of OCT3-mediated 5-HT clearance from the extracellular fluid contributes to stress-induced increases in extracellular 5-HT and 5-HT signaling.

The Human Brain Project: Creating a European Research Infrastructure to Decode the Human Brain.

Decoding the human brain is perhaps the most fascinating scientific challenge in the 21st century. The Human Brain Project (HBP), a 10-year European Flagship, targets the reconstruction of the brain's multi-scale organization. It uses productive loops of experiments, medical, data, data analytics, and simulation on all levels that will eventually bridge the scales. The HBP IT architecture is unique, utilizing cloud-based collaboration and development platforms with databases, workflow systems, petabyte storage, and supercomputers. The HBP is developing toward a European research infrastructure advancing brain research, medicine, and brain-inspired information technology.

Personal attributes of authors and reviewers, social bias and the outcomes of peer review: a case study.

Peer review is the "gold standard" for evaluating journal and conference papers, research proposals, on-going projects and university departments. However, it is widely believed that current systems are expensive, conservative and prone to various forms of bias. One form of bias identified in the literature is "social bias" linked to the personal attributes of authors and reviewers. To quantify the importance of this form of bias in modern peer review, we analyze three datasets providing information on the attributes of authors and reviewers and review outcomes: one from Frontiers - an open access publishing house with a novel interactive review process, and two from Spanish and international computer science conferences, which use traditional peer review. We use a random intercept model in which review outcome is the dependent variable, author and reviewer attributes are the independent variables and bias is defined by the interaction between author and reviewer attributes. We find no evidence of bias in terms of gender, or the language or prestige of author and reviewer institutions in any of the three datasets, but some weak evidence of regional bias in all three. Reviewer gender and the language and prestige of reviewer institutions appear to have little effect on review outcomes, but author gender, and the characteristics of author institutions have moderate to large effects. The methodology used cannot determine whether these are due to objective differences in scientific merit or entrenched biases shared by all reviewers.

Computing the size and number of neuronal clusters in local circuits.

The organization of connectivity in neuronal networks is fundamental to understanding the activity and function of neural networks and information processing in the brain. Recent studies show that the neocortex is not only organized in columns and layers but also, within these, into synaptically connected clusters of neurons (Ko et al., 2011; Perin et al., 2011). The recently discovered common neighbor rule, according to which the probability of any two neurons being synaptically connected grows with the number of their common neighbors, is an organizing principle for this local clustering. Here we investigated the theoretical constraints for how the spatial extent of neuronal axonal and dendritic arborization, heretofore described by morphological reach, the density of neurons and the size of the network determine cluster size and numbers within neural networks constructed according to the common neighbor rule. In the formulation we developed, morphological reach, cell density, and network size are sufficient to estimate how many neurons, on average, occur in a cluster and how many clusters exist in a given network. We find that cluster sizes do not grow indefinitely as network parameters increase, but tend to characteristic limiting values.

BrainSnail: a dynamic information display system for the sciences.

Scientific reference management has become crucial in rapidly expanding fields of biology. Many of the reference management systems currently employed are reference centric and not object/process focused. BrainSnail is a reference management/knowledge representation application that tries to bridge disconnect between subject and reference in the fields of neuropharmacology, neuroanatomy and neurophysiology. BrainSnail has been developed with considering both individual researcher and research group efforts.

OntoSlug: a dynamic visual front-end program for ontologies.

The display of ontological information has become a crucial factor over the last decade in systems biology. The possibility to compare different ontological systems in a single application has however not been answered with an appropriate application. OntoSlug is an easy to use application that tries to fill this need. OntoSlug has been developed for use in classroom settings and scientific laboratory environment.

Estrogen regulation of proteins in the rat ventromedial nucleus of the hypothalamus.

The effects of estradiol (E2) on the expression of proteins in the pars lateralis of the ventromedial nucleus of the hypothalamus (VMNpl) in ovariectomized rats was studied using 2-dimensional gel electrophoresis followed by RPLC-nanoESI-MS/MS. E2 treatment resulted in the up-regulation of 29 identified proteins. Many of these proteins are implicated in the promotion of neuronal plasticity and signaling.

Proteomic analysis of the ventromedial nucleus of the hypothalamus (pars lateralis) in the female rat.

The use of proteomics to study changes in the expression of CNS proteins, which may underlie the regulation of physiological and/or behavioral responses, represents an emerging application of this technology. In the current study, the Palkovits' microdissection method was evaluated as a means of obtaining proteomic data from discrete brain nuclei. The pars lateralis of the ventromedial nucleus of the hypothalamus (VMN) was chosen for the initial studies because of its established role in the expression of gonadal hormone dependent female sexual behavior. The VMN from ovariectomized rats was microdissected from 300 microm frozen brain sections using a 500 microm punch. Total proteins were separated using 2-DE. A group consensus of 432 protein spots, visualized by SYPRO Ruby stain, was obtained from gels from four independent VMN samples. A low mean CV and high gel-to-gel correlation coefficients indicate that reproducible 2-DE gels can be generated from microdissected tissue samples. Proteins from the mediobasal hypothalamus (MBH) were also separated on 2-DE gels. Evaluation of the 2-DE maps from the VMN and the MBH revealed different protein profiles, and indicates that microdissection improves the detection of low-abundance proteins, and reduces the relative occurrence of abundant proteins on 2-DE maps.

Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of medial ganglionic eminence-derived neurons.

Correct positioning of cortical neurons during development depends on the radial migration of the projection neurons and on the coordinated tangential and radial migrations of the subcortically generated interneurons. As previously shown, a transient and moderate maternal deficiency in thyroxin during early corticogenesis alters the radial migration of projection neurons. To determine if a similar effect might also affect tangential migration of medial ganglionic eminence (MGE)-derived neurons at the origin of cortical interneurons, explants of MGE from green fluorescent protein (GFP)-transgenic embryos were implanted into flat cortical mounts from wild-type embryos. The distances covered and the preferential migration (medially) of GFP-MGE neurons from embryos of hypothyroxinemic dams are not affected in their tangential migration into wild-type control cortices. In contrast, when GFP-MGE neurons from embryos of control or hypothyroxinemic dams migrate within cortices from embryos of hypothyroxinemic dams, the GFP-MGE-derived neurons lose their preferential direction of migration, although they still migrate for long distances throughout the cortex. Our results show that maternal hypothyroxinemia alters the tangential migration of GFP-MGE-derived neurons in the neocortex of the progeny and suggest that this alteration is not derived from the migratory neurons themselves but through undefined short- and long-range cues responsible for the guidance of their migration.