Morphology Of Individual Neurons Research Articles

Collaborative augmented reconstruction of 3D neuron morphology in mouse and human brains

Digital reconstruction of the intricate 3D morphology of individual neurons from microscopic images is a crucial challenge in both individual laboratories and large-scale projects focusing on cell types and brain anatomy. This task often fails in both conventional manual reconstruction and state-of-the-art artificial intelligence (AI)-based automatic reconstruction algorithms. It is also challenging to organize multiple neuroanatomists to generate and cross-validate biologically relevant and mutually agreed upon reconstructions in large-scale data production. Based on collaborative group intelligence augmented by AI, we developed a collaborative augmented reconstruction (CAR) platform for neuron reconstruction at scale. This platform allows for immersive interaction and efficient collaborative editing of neuron anatomy using a variety of devices, such as desktop workstations, virtual reality headsets and mobile phones, enabling users to contribute anytime and anywhere and to take advantage of several AI-based automation tools. We tested CAR’s applicability for challenging mouse and human neurons toward scaled and faithful data production.

A Visual Interface for Exploring Hypotheses About Neural Circuits.

One of the fundamental problems in neurobiological research is to understand how neural circuits generate behaviors in response to sensory stimuli. Elucidating such neural circuits requires anatomical and functional information about the neurons that are active during the processing of the sensory information and generation of the respective response, as well as an identification of the connections between these neurons. With modern imaging techniques, both morphological properties of individual neurons as well as functional information related to sensory processing, information integration and behavior can be obtained. Given the resulting information, neurobiologists are faced with the task of identifying the anatomical structures down to individual neurons that are linked to the studied behavior and the processing of the respective sensory stimuli. Here, we present a novel interactive tool that assists neurobiologists in the aforementioned tasks by allowing them to extract hypothetical neural circuits constrained by anatomical and functional data. Our approach is based on two types of structural data: brain regions that are anatomically or functionally defined, and morphologies of individual neurons. Both types of structural data are interlinked and augmented with additional information. The presented tool allows the expert user to identify neurons using Boolean queries. The interactive formulation of these queries is supported by linked views, using, among other things, two novel 2D abstractions of neural circuits. The approach was validated in two case studies investigating the neural basis of vision-based behavioral responses in zebrafish larvae. Despite this particular application, we believe that the presented tool will be of general interest for exploring hypotheses about neural circuits in other species, genera and taxa.

Analyses of Neurite and Spine Formation by In Utero Electroporation in Mice.

Dendrite morphology and dendritic spines are key features of the neuronal networks in the brain. Abnormalities in these features have been observed in patients with psychiatric disorders and mouse models of these diseases. In utero electroporation is an easy and efficient gene transfer system for developing mouse embryos in the uterus. By combining with the Cre-loxP system, the morphology of individual neurons can be clearly and sparsely visualized. Here, we describe how this labeling system can be applied to visualize and evaluate the dendrites and dendritic spines of cortical neurons.

Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson's disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients with 22q11.2DS, was generated. The behavior of this mouse model was extensively studied and several abnormalities related to the symptoms of 22q11.2DS were found. However, the histological features of their brains have been little addressed. Here we describe the cytoarchitectures of the brains of Del(3.0Mb)/+ mice. First, we investigated the overall histology of the embryonic and adult cerebral cortices, but they were indistinguishable from the wild type. However, the morphologies of individual neurons were slightly but significantly changed from the wild type counterparts in a region-specific manner. The dendritic branches and/or dendritic spine densities of neurons in the medial prefrontal cortex, nucleus accumbens, and primary somatosensory cortex were reduced. We also observed reduced axon innervation of dopaminergic neurons into the prefrontal cortex. Given these affected neurons function together as the dopamine system to control animal behaviors, the impairment we observed may explain a part of the abnormal behaviors of Del(3.0Mb)/+ mice and the psychiatric symptoms of 22q11.2DS.

The Golgi Method.

Silver staining by the Golgi method is a classical procedure to identify the three-dimensional morphology of individual neurons. Although the method was developed in the 1870s, it is still used to study the morphological characteristics of neuron types in the central nervous system, either alone or in combination with other neuroanatomical techniques. The neuropil of insects is fully accessible to the original refractive staining procedure, and modifications of the Golgi technique have paved the path for modern structural research on the insect central nervous system. Here, we provide an introduction to this easy and low-cost method.

Morphological multivariate cluster analysis of murine retinal ganglion cells selectively expressing yellow fluorescent protein

Optic neuropathies, such as glaucoma, lead to retinal ganglion cell (RGC) death. Transgenic mouse strains that express fluorescent proteins under the control of the Thy1 promoter have permitted single RGC imaging. Specifically, in one strain of mice expressing yellow fluorescent protein (Thy1-YFP), fluorescence is expressed in only 0.2% of RGCs. This reduced expression allows visualization of the full dendritic arbour of YFP-expressing RGCs, facilitating the investigation of structural changes. As susceptibility amongst RGCs varies with morphology and subtype, labelling methods should ideally non-discriminately label RGCs to accurately determine the effects of experimental glaucoma. This study therefore sought to determine morphological subtypes of RGCs in the Thy1-YFP mouse strain. Retinas from Thy1-YFP mice were imaged ex vivo with fluorescence microscopy. With Sholl analysis, a technique for quantifying the morphology of individual neurons, the dendritic field (DF), area under the curve (AUC), normalized AUC (Nav), peak number of intersections (PNI), and skew for single RGCs were computed. The distance of the RGC from the optic nerve head (dONH) was also measured. These morphological parameters were inputted into a multivariate cluster analysis to determine the optimal number of clusters to group all RGCs analyzed, which were then grouped into “Small”, “Medium”, and “Large” sized cluster groups according to increasing DF size. A total of 178 RGCs from 10 retinas of 8 mice were analyzed from which the cluster analysis identified 13 clusters. Eighty-eight (49%), 77 (43.2%), and 13 (7.3%) RGCs were grouped into small, medium and large clusters, respectively. Clusters 1–6 had small DFs. Clusters 1 and 3 had the lowest AUC and Nav. Clusters 2, 3, and 5 had asymmetric DFs while Clusters 3, 5, and 6 were distal to the ONH. Clusters 7–11 had medium DFs; of these, Clusters 7 and 10 had the lowest AUC, Clusters 8 and 10 had the highest skew, and Clusters 7 and 11 were closest to the ONH. Clusters 12 and 13 had large DFs. Both had low skew and high AUC. High PNI and dONH distinguished Cluster 12 from Cluster 13. We present the largest study to date examining YFP expression in RGCs of transgenic Thy1-YFP mice. Among the 13 clusters, there was a wide range of morphological features with further variation within size categories. Our findings support the notion that YFP is expressed non-discriminatingly in RGCs of Thy1-YFP transgenic mice and this strain is a valuable tool for studies of experimental optic neuropathies.

Serial-section atlas of the Tritonia pedal ganglion.

The pedal ganglion of the nudibranch gastropod Tritonia diomedea has been the focus of neurophysiological studies for more than 50 yr. These investigations have examined the neural basis of behaviors as diverse as swimming, crawling, reflex withdrawals, orientation to water flow, orientation to the earth's magnetic field, and learning. Despite this sustained research focus, most studies have confined themselves to the layer of neurons that are visible on the ganglion surface, leaving many neurons, which reside in deeper layers, largely unknown and thus unstudied. To facilitate work on such neurons, the present study used serial-section light microscopy to generate a detailed pictorial atlas of the pedal ganglion. One pedal ganglion was sectioned horizontally at 2-µm intervals and another vertically at 5-µm intervals. The resulting images were examined separately or combined into stacks to generate movie tours through the ganglion. These were also used to generate 3D reconstructions of individual neurons and rotating movies of digitally desheathed whole ganglia to reveal all surface neurons. A complete neuron count of the horizontally sectioned ganglion yielded 1,885 neurons. Real and virtual sections from the image stacks were used to reveal the morphology of individual neurons, as well as the major axon bundles traveling within the ganglion to and between its several nerves and connectives. Extensive supplemental data are provided, as well as a link to the Dryad Data Repository site, where the complete sets of high-resolution serial-section images can be downloaded. NEW & NOTEWORTHY Because of the large size and relatively low numbers of their neurons, gastropod mollusks are widely used for investigations of the neural basis of behavior. Most studies, however, focus on the neurons visible on the ganglion surface, leaving the majority, located out of sight below the surface, unexamined. The present light microscopy study generates the first detailed visual atlas of all neurons of the highly studied Tritonia pedal ganglion.

All-Optical Electrophysiology for High-Throughput Functional Characterization of a Human iPSC-Derived Motor Neuron Model of ALS.

SummaryHuman induced pluripotent stem cell (iPSC)-derived neurons are an attractive substrate for modeling disease, yet the heterogeneity of these cultures presents a challenge for functional characterization by manual patch-clamp electrophysiology. Here, we describe an optimized all-optical electrophysiology, “Optopatch,” pipeline for high-throughput functional characterization of human iPSC-derived neuronal cultures. We demonstrate the method in a human iPSC-derived motor neuron (iPSC-MN) model of amyotrophic lateral sclerosis (ALS). In a comparison of iPSC-MNs with an ALS-causing mutation (SOD1 A4V) with their genome-corrected controls, the mutants showed elevated spike rates under weak or no stimulus and greater likelihood of entering depolarization block under strong optogenetic stimulus. We compared these results with numerical simulations of simple conductance-based neuronal models and with literature results in this and other iPSC-based models of ALS. Our data and simulations suggest that deficits in slowly activating potassium channels may underlie the changes in electrophysiology in the SOD1 A4V mutation.

Morphology and physiology of antennal lobe projection neurons in the hawkmoth Agrius convolvuli

The neuronal pathways involved in the processing of sex pheromone information were investigated in the hawkmoth Agrius convolvuli (Lepidoptera: Sphingidae), which uses (E,E)-11,13-hexadecadienal (E11,E13-16:Ald) as the single sex pheromone component. We first clarified the anatomical organization of the antennal lobe of A. convolvuli. Subsequently, central neurons in the antennal lobe that responded to E11,E13-16:Ald were identified. The dendritic processes of these neurons were confined within a specific glomerulus (cumulus) in the antennal lobe. The axons of these neurons projected to the inferior lateral protocerebrum and mushroom body calyx. Although the anatomical organization and morphology of individual neurons in A. convolvuli were similar to other species in the superfamily Bombycoidea, the use of cumulus as the single pathway for sex pheromone information processing was characteristic to this species.

Assessing the Migration and Morphology of Individual Neurons within Orderly Transcription Factor Domains in the Developing Zebrafish Hindbrain

Neural networks within the spinal cord and hindbrain control much of the output of the nervous system. The discovery of a transcription factor code that gives rise to the cell types in spinal cord and hindbrain has revealed simple core patterns of organization that are shared by vertebrates. In zebrafish, transcription factor domains give rise to orderly stripes of neurons that extend longitudinally in hindbrain and exhibit a topographic, age related map of recruitment and input resistance. Neurons within these stripes are actively recruited in free swimming of five‐day‐old fish, suggesting that these neurons are wired to perform behaviors prior to the formation of discrete motor nuclei. To assess whether and to what extent neurons that makeup these orderly domains migrate and shift morphologically, we examine both gross morphology in fish with fluorescently labeled transcription factor types (alx [chx10], and dbx1b) and neurotransmitter phenotypes (vglut, glyt2), as well as individually labeled cells over several time points in vivo via multi‐photon microscopy over multiple time points from 3 days post fertilization up to 27 days post fertilization. We show that both the neurotransmitter and transcription factor stripes present in the early developing hindbrain undergo significant migration within the first 2 weeks of development leaving the stripe patterns of neurotransmitter phenotypes virtually undetectable and within transcription factors still apparent, but much less defined. Furthermore, single cells expressing dbx1b tracked over time demonstrate soma migration and while there is no correlation between a cells initial dorsoventral position in a stripe (a crude age indicator) and its final location, there is a correlation between the dorsoventral position of its arbors and the dorsoventral migration of its soma, suggesting that the dendritic and axonal connections established may dictate where a neuron ultimately settles.Support or Funding InformationJ.M. was supported in part by a Ruth L. Kirschstein National Research Service Award from the National Institute for Neurological Disorders and Stroke. This work was supported by an NIH grant to J.F.

Novel bio-spectroscopic imaging reveals disturbed protein homeostasis and thiol redox with protein aggregation prior to hippocampal CA1 pyramidal neuron death induced by global brain ischemia in the rat

Global brain ischemia resulting from cardiac arrest and cardiac surgery can lead to permanent brain damage and mental impairment. A clinical hallmark of global brain ischemia is delayed neurodegeneration, particularly within the CA1 subsector of the hippocampus. Unfortunately, the biochemical mechanisms have not been fully elucidated, hindering optimization of current therapies (i.e., therapeutic hypothermia) or development of new therapies. A major limitation to elucidating the mechanisms that contribute to neurodegeneration and understanding how these are influenced by potential therapies is the inability to relate biochemical markers to alterations in the morphology of individual neurons. Although immunocytochemistry allows imaging of numerous biochemical markers at the sub-cellular level, it is not a direct chemical imaging technique and requires successful “tagging” of the desired analyte. Consequently, important biochemical parameters, particularly those that manifest from oxidative damage to biological molecules, such as aggregated protein levels, have been notoriously difficult to image at the cellular or sub-cellular level. It has been hypothesized that reactive oxygen species (ROS) generated during ischemia and reperfusion facilitate protein aggregation, impairing neuronal protein homeostasis (i.e., decreasing protein synthesis) that in turn promotes neurodegeneration. Despite indirect evidence for this theory, direct measurements of morphology and ROS induced biochemical damage, such as increased protein aggregates and decreased protein synthesis, within the same neuron is lacking, due to the unavailability of a suitable imaging method. Our experimental approach has incorporated routine histology with novel wide-field synchrotron radiation Fourier transform infrared imaging (FTIRI) of the same neurons, ex vivo within brain tissue sections. The results demonstrate for the first time that increased protein aggregation and decreased levels of total protein occur in the same CA1 pyramidal neurons 1 day after global ischemia. Further, analysis of serial tissue sections using X-ray absorption spectroscopy at the sulfur K-edge has revealed that CA1 pyramidal neurons have increased disulfide levels, a direct indicator of oxidative stress, at this time point. These changes at 1 day after ischemia precede a massive increase in aggregated protein and disulfide levels concomitant with loss of neuron integrity 2 days after ischemia. Therefore, this study has provided direct support for a correlative mechanistic link in both spatial and temporal domains between oxidative stress, protein aggregation and altered protein homeostasis prior to irreparable neuron damage following global ischemia.

Specification of Individual Adult Motor Neuron Morphologies by Combinatorial Transcription Factor Codes

How the highly stereotyped morphologies of individual neurons are genetically specified is not well understood. We identify six transcription factors (TFs) expressed in a combinatorial manner in seven post-mitotic adult leg motor neurons (MNs) that are derived from a single neuroblast in Drosophila. Unlike TFs expressed in mitotically active neuroblasts, these TFs do not regulate each other's expression. Removing the activity of a single TF resulted in specific morphological defects, including muscle targeting and dendritic arborization, and in a highly specific walking defect in adult flies. In contrast, when the expression of multiple TFs was modified, nearly complete transformations in MN morphologies were generated. These results show that the morphological characteristics of a single neuron are dictated by a combinatorial code of morphology TFs (mTFs). mTFs function at a previously unidentified regulatory tier downstream of factors acting in the NB but independently of factors that act in terminally differentiated neurons.

Interactive brain map in the Invertebrate Brain Platform (IVB-PF)

Event Abstract Back to Event Interactive brain map in the Invertebrate Brain Platform (IVB-PF) Akira Takashima1*, Tomoki Kazawa1, Shigehiro Namiki1, Daisuke Miyamoto1, Stephan Haupt1, Hidetoshi Ikeno2, Ryohei Kanzaki1 and Shiro Usui3 1 Research Center for Advanced Science and Technology, The University of Tokyo, Japan 2 School of Human Science and Environment, University of Hyogo, Japan 3 RIKEN Brain Science Institute, Japan As previously reported in INCF 2011, the Invertebrate Brain Platform (IVB-PF; http://invbrain.neuroinf.jp) project organized by the J-Node of the INCF has been initiated with the goal of integrating research results and resources from various fields, from the morphology, physiology, pharmacology, and molecular biology of single neurons to behavioral studies to promote the comprehensive understanding of the brain structure and function of invertebrates. The IVB-PF comprises databases for representative invertebrate species, such as silkmoth, honeybee, cricket, cockroach, two species of flies, ant, and crayfish, ranging from the physiology and morphology of individual neurons to the general structure of the central nervous systems. It also provides an overview over invertebrate neuroethology and a growing number of detailed descriptions dealing with sensory physiology and neuroanatomy, each of which is cross-linked to databases for more efficient usage by a variety of users. Recently, we have implemented a new database presentation methodology for individually labeled silkmoth neurons using our silkmoth standard brain atlas. The standard brain of the silkmoth was constructed from confocal image stacks of immunostained brains. Neuronal morphologies in the silkmoth brain registered in the database were mapped onto the standard brain so that neuronal locations in the brain could be elucidated in microscopic level. Selection of individual mapped neurons in the standard brain atlas provides immediate access to the associated metadata (e.g. physiology of the neuron) of the corresponding neuron in the database and vice versa, metadata are also linked to the corresponding neuronal morphology in the standard brain. This data presentation methodology implemented using the example of the silkmoth brain will be expanded to the neuronal data from other invertebrate species registered in the IVB-PF and allow users to obtain a better understanding of invertebrate brain structure and microcircuits in the future. Keywords: Infrastructural and portal services, computational neuroscience, Invertebrates, Brain Mapping, brain structure Conference: 5th INCF Congress of Neuroinformatics, Munich, Germany, 10 Sep - 12 Sep, 2012. Presentation Type: Demo Topic: Neuroinformatics Citation: Takashima A, Kazawa T, Namiki S, Miyamoto D, Haupt S, Ikeno H, Kanzaki R and Usui S (2014). Interactive brain map in the Invertebrate Brain Platform (IVB-PF). Front. Neuroinform. Conference Abstract: 5th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2014.08.00082 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Mar 2013; Published Online: 27 Feb 2014. * Correspondence: Dr. Akira Takashima, Research Center for Advanced Science and Technology, The University of Tokyo, unset, Japan, takashima@brain.imi.i.u-tokyo.ac.jp Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Akira Takashima Tomoki Kazawa Shigehiro Namiki Daisuke Miyamoto Stephan Haupt Hidetoshi Ikeno Ryohei Kanzaki Shiro Usui Google Akira Takashima Tomoki Kazawa Shigehiro Namiki Daisuke Miyamoto Stephan Haupt Hidetoshi Ikeno Ryohei Kanzaki Shiro Usui Google Scholar Akira Takashima Tomoki Kazawa Shigehiro Namiki Daisuke Miyamoto Stephan Haupt Hidetoshi Ikeno Ryohei Kanzaki Shiro Usui PubMed Akira Takashima Tomoki Kazawa Shigehiro Namiki Daisuke Miyamoto Stephan Haupt Hidetoshi Ikeno Ryohei Kanzaki Shiro Usui Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action of antidepressant drugs

Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual neurons in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.

Disorganization of neocortical lamination in focal cortical dysplasia is brain-region dependent: evidence from layer-specific marker expression

BackgroundFocal cortical dysplasias (FCD) are local disturbances of neocortical architecture and a common cause of pharmaco-resistant focal epilepsy. Little is known about the pathomechanisms leading to architectural abnormalities associated with FCD.ResultsIn the present study we compared 52 FCD cases originating from the frontal or temporal lobe with or without Ammon’s horn sclerosis (AHS) with regard to structural and molecular differences. We applied layer-specific (ER81, RORß, SMI32, TLE4) and interneuron (calbindin, parvalbumin) markers by means of immunohistochemistry, in situ hybridization (ISH), and real time RT-PCR and correlated our findings with clinical parameters. We found that: (1) Structural abnormalities were most prominent in layers III-VI including changed morphology of individual neurons or dispersion, blurring and thinning of layers. These alterations were most pronounced in isolated frontal FCD, whereas the most homogeneous group was FCD IIIa. (2) Numbers of calbindin- and parvalbumin-positive interneurons varied considerably within the different FCD groups, but were not generally reduced. A significant decrease was only found for calbindin-positive interneurons in frontal FCD, and for parvalbumin-positive interneurons in FCD IIIa. (3) Interestingly, FCD IIIa presented with significant changes in the numbers of calbindin- or TLE4-positive neurons when compared to isolated FCD or controls. (4) Correlations between clinical and cellular parameters strongly depended on FCD localisation and age of the patients.ConclusionsIn summary, our data suggest that late cortical development is disturbed in FCD, yet most likely by different causes depending on brain region, FCD type and FCD severity.

Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs

In the rTg4510 mouse model, expression of the mutant human tau variant P301L leads to development of neurofibrillary tangles (NFTs), neuronal death, and memory impairment, reminiscent of the pathology observed in human tauopathies. In the present study, we examined the effects of mutant tau expression on the electrophysiology and morphology of individual neurons using whole-cell patch-clamp recordings and biocytin filling of pyramidal cells in cortical slices prepared from rTg4510 (TG) and wild-type (WT) littermate mice. Among the TG cells, 42% contained a clear Thioflavin-S positive inclusion in the soma and were categorized as NFT positive (NFT+), while 58% had no discernable inclusion and were categorized as NFT negative (NFT−). The resting membrane potential ( V r) was significantly depolarized (+ 8 mV) in TG cells, and as a consequence, evoked repetitive action potential (AP) firing rates were also significantly increased. Further, single APs were significantly shorter in duration in TG cells and the depolarizing voltage deflection or “sag” evoked by hyperpolarization was significantly greater in amplitude. In addition to these functional electrophysiological changes, TG cells exhibited significant morphological alterations, including loss or significant atrophy of the apical tuft, reduced dendritic complexity and length, and reduced spine density. Importantly, NFT− and NFT+ TG cells were indistinguishable with regard to both morphological and electrophysiological properties. Our observations show that expression of mutated tau results in significant structural and functional changes in neurons, but that these changes occur independent of mature NFT formation.

NEST 2: A Parallel Simulator for Large Neuronal Networks

Event Abstract Back to Event NEST 2: A Parallel Simulator for Large Neuronal Networks Marc-Oliver Gewaltig1* 1 Honda Research Institute Europe GmbH, Germany NEST is a simulator for large heterogeneous networks of point neurons or neurons with few compartments. NEST supports parallel simulation on multi-core computers and computer clusters, with excellent scaling [1].NEST is best suited for models that focus on the dynamics, size, and structure of neural systems rather than on the detailed morphology of individual neurons. Examples are: Models of sensory processing in visual or auditory cortex. Models of network dynamics, e.g. in laminar cortical networks or random networks. Models of spike-synchronization in feed-forward networks such as synfire chains. Models of learning and plasticity. Here we demonstrate NEST 2 and invite visitors to try it interactively. The new Python-based user interface PyNEST makes it easier to learn and use NEST. Together with analysis packages like Scientific Python (www.scipy.org) and analysis tools from neuralensemble.org, users can now simulate networks and analyze results in one interactive Python session [2]. The new Topology module allows concise specification and efficient construction of large models with spatial structure, such as models of the visual system. A new multi-compartment model with soma, proximal and distal dendrite, provides a scaffold for users to implement their own multi-compartment models. Our new implementation of synaptic plasticity incorporates external factors such as dopamine modulation. Users can write new neuron models in NEST's simulation language SLI. The dynamic equations can be given in standard mathematical notation and NEST will compile them into efficient code.A lot of work was put into ensuring the reliability of NEST. An automated test-suite allows users to check their installation and helps us to detect errors and regressions as new features are added (see companion poster by Eppler et al.) We have also increased the numerical accuracy of many of our neuron models. NEST now supports the recently proposed MUSIC interface [3], to link NEST with different simulators and analysis modules at run-time in a parallel distributed fashion. Since 2007, pre-releases of NEST 2 have been used with great success at international computational neuroscience courses. NEST is released under an open source license for non-commercial use. For more information, please visit our web site at www.nest-initiative.org.NEST is developed by the NEST Initiative, a contract-based collaboration between academic and industrial research institutes. The author presents for the NEST Initiative and would like to thank all its members, particularly (in alphabetic order): Kittel Austvoll, Markus Diesmann, Jochen Martin Eppler, Alexander Hanuschkin, Moritz Helias, Susanne Kunkel, Rüdiger Kupper, Abigail Morrison, Hans Ekkehard Plesser, Tobias Potjans, Wiebke Potjans, and Sven Schrader. Acknowledgements: Research Council of Norway Grant 178892/V3 eNeuro, Next-Generation Supercomputer Project of MEXT, EU Grant 15879 (FACETS), BMBF Grant 01GQ0420, Helmholtz Alliance on Systems Biology

Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats

BackgroundNeurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders.ObjectiveWe tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs).Methods and ResultsThe Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [3H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity.ConclusionsDevelopmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.

Analysis of spatial relationships in three dimensions: tools for the study of nerve cell patterning

BackgroundMultiple technologies have been brought to bear on understanding the three-dimensional morphology of individual neurons and glia within the brain, but little progress has been made on understanding the rules controlling cellular patterning. We describe new matlab-based software tools, now available to the scientific community, permitting the calculation of spatial statistics associated with 3D point patterns. The analyses are largely derived from the Delaunay tessellation of the field, including the nearest neighbor and Voronoi domain analyses, and from the spatial autocorrelogram.ResultsOur tools enable the analysis of the spatial relationship between neurons within the central nervous system in 3D, and permit the modeling of these fields based on lattice-like simulations, and on simulations of minimal-distance spacing rules. Here we demonstrate the utility of our analysis methods to discriminate between two different simulated neuronal populations.ConclusionTogether, these tools can be used to reveal the presence of nerve cell patterning and to model its foundation, in turn informing on the potential developmental mechanisms that govern its establishment. Furthermore, in conjunction with analyses of dendritic morphology, they can be used to determine the degree of dendritic coverage within a volume of tissue exhibited by mature nerve cells.

Central Sensitization

Noxious skin stimuli which are sufficiently intense to produce tissue injury, characteristically generate prolonged poststimulus sensory disturbances that include continuing pain, an increased sensitivity to noxious stimuli and pain following innocuous stimuli. This could result from either a reduction in the thresholds of skin nociceptors (sensitization) or an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses. Because sensitization of peripheral receptors occurs following injury, a peripheral mechanism is widely held to be responsible for postinjury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes.