Steerable-filter based quantification of axonal populations at the developing optic chiasm reveal significant defects in Slit2(-/-) as well as Slit1(-/-)Slit2(-/-) embryos

<p>Abstract</p> <p>Background</p> <p>Previous studies have suggested that the axon guidance proteins Slit1 and Slit2 co-operate to establish the optic chiasm in its correct position at the ventral diencephalic midline. This is based on the observation that, although both Slit1 and Slit2 are expressed around the ventral midline, mice defective in either gene alone exhibit few or no axon guidance defects at the optic chiasm whereas embryos lacking both Slit1 and Slit2 develop a large additional chiasm anterior to the chiasm’s normal position. Here we used steerable-filters to quantify key properties of the population of axons at the chiasm in wild-type, <it>Slit1</it>^{<it>−/−</it>}, <it>Slit2</it>^{<it>−/−</it>} and <it>Slit1</it>^{<it>−/−</it>}<it>Slit2</it>^{<it>−/−</it>} embryos.</p> <p>Results</p> <p>We applied the steerable-filter algorithm successfully to images of embryonic retinal axons labelled from a single eye shortly after they have crossed the midline. We combined data from multiple embryos of the same genotype and made statistical comparisons of axonal distributions, orientations and curvatures between genotype groups. We compared data from the analysis of axons with data on the expression of <it>Slit1</it> and <it>Slit2.</it> The results showed a misorientation and a corresponding anterior shift in the position of many axons at the chiasm of both <it>Slit2</it>^{<it>−/−</it>} and <it>Slit1</it>^{<it>−/−</it>}<it>Slit2</it>^{<it>−/−</it>} mutants. There were very few axon defects at the chiasm of <it>Slit1</it>^{<it>−/−</it>} mutants.</p> <p>Conclusions</p> <p>We found defects of the chiasms of <it>Slit1</it>^{<it>−/−</it>}<it>Slit2</it>^{<it>−/−</it>} and <it>Slit1</it>^{<it>−/−</it>} mutants similar to those reported previously. In addition, we discovered previously unreported defects resulting from loss of Slit2 alone. This indicates the value of a quantitative approach to complex pathway analysis and shows that Slit2 can act alone to control aspects of retinal axon routing across the ventral diencephalic midline.</p

Elastic net model of ocular dominance - overall stripe pattern and monocular deprivation

The elastic net (Durbin and Willshaw 1987) can account for the development of both topography and ocular dominance in the mapping from the lateral geniculate nucleus to primary visual cortex (Goodhill and Willshaw 1990). Here it is further shown for this model that (1) the overall pattern of stripes produced is strongly influenced by the shape of the cortex: in particular, stripes with a global order similar to that seen biologically can be produced under appropriate conditions, and (2) the observed changes in stripe width associated with monocular deprivation are reproduced in the model

On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

Standard Anatomical and Visual Space for the Mouse Retina: Computational Reconstruction and Transformation of Flattened Retinae with the Retistruct Package

The concept of topographic mapping is central to the understanding of the visual system at many levels, from the developmental to the computational. It is important to be able to relate different coordinate systems, e.g. maps of the visual field and maps of the retina. Retinal maps are frequently based on flat-mount preparations. These use dissection and relaxing cuts to render the quasi-spherical retina into a 2D preparation. The variable nature of relaxing cuts and associated tears limits quantitative cross-animal comparisons. We present an algorithm, "Retistruct," that reconstructs retinal flat-mounts by mapping them into a standard, spherical retinal space. This is achieved by: stitching the marked-up cuts of the flat-mount outline; dividing the stitched outline into a mesh whose vertices then are mapped onto a curtailed sphere; and finally moving the vertices so as to minimise a physically-inspired deformation energy function. Our validation studies indicate that the algorithm can estimate the position of a point on the intact adult retina to within 8° of arc (3.6% of nasotemporal axis). The coordinates in reconstructed retinae can be transformed to visuotopic coordinates. Retistruct is used to investigate the organisation of the adult mouse visual system. We orient the retina relative to the nictitating membrane and compare this to eye muscle insertions. To align the retinotopic and visuotopic coordinate systems in the mouse, we utilised the geometry of binocular vision. In standard retinal space, the composite decussation line for the uncrossed retinal projection is located 64° away from the retinal pole. Projecting anatomically defined uncrossed retinal projections into visual space gives binocular congruence if the optical axis of the mouse eye is oriented at 64° azimuth and 22° elevation, in concordance with previous results. Moreover, using these coordinates, the dorsoventral boundary for S-opsin expressing cones closely matches the horizontal meridian

Collagen-Like Proteins in Pathogenic E. coli Strains

The genome sequences of enterohaemorrhagic E. coli O157:H7 strains show multiple open-reading frames with collagen-like sequences that are absent from the common laboratory strain K-12. These putative collagens are included in prophages embedded in O157:H7 genomes. These prophages carry numerous genes related to strain virulence and have been shown to be inducible and capable of disseminating virulence factors by horizontal gene transfer. We have cloned two collagen-like proteins from E. coli O157:H7 into a laboratory strain and analysed the structure and conformation of the recombinant proteins and several of their constituting domains by a variety of spectroscopic, biophysical, and electron microscopy techniques. We show that these molecules exhibit many of the characteristics of vertebrate collagens, including trimer formation and the presence of a collagen triple helical domain. They also contain a C-terminal trimerization domain, and a trimeric α-helical coiled-coil domain with an unusual amino acid sequence almost completely lacking leucine, valine or isoleucine residues. Intriguingly, these molecules show high thermal stability, with the collagen domain being more stable than those of vertebrate fibrillar collagens, which are much longer and post-translationally modified. Under the electron microscope, collagen-like proteins from E. coli O157:H7 show a dumbbell shape, with two globular domains joined by a hinged stalk. This morphology is consistent with their likely role as trimeric phage side-tail proteins that participate in the attachment of phage particles to E. coli target cells, either directly or through assembly with other phage tail proteins. Thus, collagen-like proteins in enterohaemorrhagic E. coli genomes may have a direct role in the dissemination of virulence-related genes through infection of harmless strains by induced bacteriophages

Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition

Toward standard practices for sharing computer code and programs in neuroscience

Computational techniques are central in many areas of neuroscience and are relatively easy to share. This paper describes why computer programs underlying scientific publications should be shared and lists simple steps for sharing. Together with ongoing efforts in data sharing, this should aid reproducibility of research.This article is based on discussions from a workshop to encourage sharing in neuroscience, held in Cambridge, UK, December 2014. It was financially supported and organized by the International Neuroinformatics Coordinating Facility (http://www.incf.org), with additional support from the Software Sustainability institute (http://www.software.ac.uk). M.H. was supported by funds from the German federal state of Saxony-Anhalt and the European Regional Development Fund (ERDF), Project: Center for Behavioral Brain Sciences

Synaptic rewiring in neuromorphic VLSI for topographic map formation

A generalised model of biological topographic map development is presented which combines both weight plasticity and the formation and elimination of synapses (synaptic rewiring) as well as both activity-dependent and -independent processes. The question of whether an activity-dependent process can refine a mapping created by an activity-independent process is investigated using a statistical approach to analysingmapping quality. The model is then implemented in custom mixed-signal VLSI. Novel aspects of this implementation include: (1) a distributed and locally reprogrammable address-event receiver, with which large axonal fan-out does not reduce channel capacity; (2) an analogue current-mode circuit for Euclidean distance calculation which is suitable for operation across multiple chips; (3) slow probabilistic synaptic rewiring driven by (pseudo-)random noise; (4) the application of a very-low-current design technique to improving the stability of weights stored on capacitors; (5) exploiting transistor non-ideality to implement partially weightdependent spike-timing-dependent plasticity; (6) the use of the non-linear capacitance of MOSCAP devices to compensate for other non-linearities. The performance of the chip is characterised and it is shown that the fabricated chips are capable of implementing the model, resulting in biologically relevant behaviours such as activity-dependent reduction of the spatial variance of receptive fields. Complementing a fast synaptic weight change mechanism with a slow synapse rewiring mechanism is suggested as a method of increasing the stability of learned patterns.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Synaptic Rewiring for Topographic Map Formation

Abstract. A model of topographic map development is presented which combines both weight plasticity and the formation and elimination of synapses as well as both activity-dependent and -independent processes. We statistically address the question of whether an activity-dependent process can refine a mapping created by an activity-independent process. A new method of evaluating the quality of topographic projections is presented which allows independent consideration of the development of a projection&apos;s preferred locations and variance. Synapse formation and elimination embed in the network topology changes in the weight distributions of synapses due to the activity-dependent learning rule used (spike-timing-dependent plasticity). In this model, variance of a projection can be reduced by an activity dependent mechanism with or without spatially correlated inputs, but the accuracy of preferred locations will not necessarily improve when synapses are formed based on distributions with on-average perfect topography