Anatomical circuitry of lateral inhibition in the eye of the horseshoe crab, Limulus polyphemus

Lengthy uninterrupted series of sections of the neural plexus in the compound eye of the horseshoe crab, Limulus polyphemus, have been used to reconstruct all the arborizations and their synaptic interconnections in a neuropil knot. This one microglomerulus contains the axons of 19 retinular cells, which pass by without contacts; 13 efferent fibres with 44 synapses to and from eccentric cell collaterals; and arborizations from 54 eccentric cells with 577 synapses. Eccentric cell axons are devoid of synaptic input. Their collaterals ramify in synaptic knots and subserve both pre- and postsynaptic functions simultaneously. Arborizations near the axon of origin have a highly branched pattern (up to 20 bifurcations), a high synaptic input: output ratio (up to about 9:1), and high synaptic density (a maximum of 12 per micrometre of neurite length). The opposite extreme is represented by sparsely branched eccentric cell collaterals distant from their axons of origin with very little synaptic input and sparse output. Spatially graded lateral inhibition is the apparent outcome of a radially decreasing distribution of inhibitory synapses on the arborizations of eccentric cell collaterals combined with possible decremental signal transmission in the plexus. The synaptic analysis has a bearing on most physiological aspects of lateral inhibition that have been studied in the Limulus eye. Implied in the results is the suggestion that synapse formation is an intrinsic property of the presynaptic element, but that the connectivity is governed by the electrical activity of target neurons.     

The effect of photoreceptor coupling and synapse nonlinearity on signal:noise ratio in early visual processing

Electrical coupling of vertebrate photoreceptors is well known to improve the signal: noise ratio in the photoreceptor layer for large-area stimuli. For example, if N photoreceptors are perfectly coupled to each other, the signal: noise ratio is improved for stimuli illuminating more than a number M = square root of N of the receptors but is made worse for small-area stimuli illuminating less than M of the N receptors. Using the model of Lamb & Simon (J. Physiol., Lond. 263, 257 (1976], which treats the photoreceptor layer as a square array of cells, each coupled through a resistive gap junction to the four cells around it, we show that the signal:noise ratio for small-area stimuli is much greater than would be expected from a model in which receptors are assumed to be perfectly coupled. Contrary to predictions made assuming perfect coupling, receptor coupling should not prevent rods from detecting single photons, but whether the single photon signal can be detected at the bipolar cell level depends on how signals are read out of the receptor layer. The signal:noise ratio in bipolar cells postsynaptic to the photo-receptor layer is determined partly by synaptic convergence and nonlinearity in synaptic transmission from receptors. If the synaptic gain decreases with light-induced receptor hyperpolarization, as is found experimentally, then receptor coupling can improve the postsynaptic signal:noise ratio for stimuli illuminating only one receptor, even though coupling decreases the presynaptic signal:noise ratio for such stimuli. Moreover, increasing the number of coupled receptors projecting to a bipolar cell can improve the signal:noise ratio for localized stimuli if the synapse is sufficiently nonlinear (although, for the degree of nonlinearity seen in lower vertebrates, synaptic convergence makes the ratio worse for the single photon event). The fact that receptor coupling and synaptic convergence can, under some circumstances, improve the signal:noise ratio in bipolar cells suggests a principle of retinal design that may compete with the requirements of high spatial resolution.     

Systems biology of bacterial chemotaxis

Motile bacteria regulate chemotaxis through a highly conserved chemosensory signal-transduction system. System-wide analyses and mathematical modeling are facilitated by extensive experimental observations regarding bacterial chemotaxis proteins, including biochemical parameters, protein structures and protein-protein interaction maps. Thousands of signaling and regulatory chemotaxis proteins within a bacteria cell form a highly interconnected network through distinct protein-protein interactions. A bacterial cell is able to respond to multiple stimuli through a collection of chemoreceptors with different sensory modalities, which interact to affect the cooperativity and sensitivity of the chemotaxis response. The robustness or insensitivity of the chemotaxis system to perturbations in biochemical parameters is a product of the system's hierarchical network architecture.     

Interspecific interactions drive cultural co-evolution and acoustic convergence in syntopic species

1.?Antagonistic interactions have been favourite subjects of studies on species co-evolution, because coexistence among competing species often results in quantifiable character displacement. A common output for competitive interactions is trait divergence, although the opposite phenomenon, convergence, has been proposed to evolve in some instances, for example in the communication behaviour of species that maintain mutually exclusive territories. 2.?I use here experimental and observational evidence to study how species interactions drive heterospecific signal convergence and analyse how convergence feeds back to the interaction itself, in the form of aggressive behaviour. I recorded the learned territorial signals of two non-hybridizing larks, Galerida cristata and G.?theklae, and used allopatric populations as controls for evaluating acoustic convergence in syntopy. Acoustic variation was analysed with respect to social conditions controlling for other potential agents of natural selection, habitat and climate. 3.?Interspecific convergence of Galerida calls peaked in syntopy. Although call acoustic structure was affected by climate and habitat, it matched gradients of density and proximity to congeners even at small local scales. The process of cultural transmission, in which individuals may acquire components of behaviour by copying neighbours, enhances the correlation between call acoustics and the local social milieu. 4.?Territories were defended against both species, but playback stimuli of convergent congener calls elicited a stronger aggressive reaction than congener calls from allopatric locations. 5.?This study shows that learned behaviours may co-evolve as a consequence of antagonistic interactions, determining reciprocal cultural evolution or cultural co-evolution. As for (biological) co-evolution, the distribution of competing species influences whether a particular area becomes a syntopic environment in which convergence is occurring, or an allopatric environment lacking interactions and reciprocal change. Because of their plastic nature, cultural coadaptations may rapidly shift in response to fluctuating social selection, thus propelling dynamic interactions and fine adjustments to the local environment.     

Sources and targets of nitric oxide signalling in insect nervous systems

Nitric oxide (NO) is a membrane permeant signalling molecule which activates soluble guanylyl cyclase and leads to the formation of cyclic GMP (cGMP) in target cells. In the nervous system, NO/cGMP signalling is thought to play essential roles in synaptic plasticity during development and also in the mature animal. This review summarizes neurochemical, cell biological, and physiological investigations of NO/cGMP signalling in the nervous system of insects. The anatomical localization of donor and target cells suggests functions in olfaction, vision, and mechanosensation. Behavioural assays have uncovered contributions of NO signalling in oxygen sensing, habituation to chemosensory stimuli, and associative memory formation. During development, NO regulates cell proliferation, axonal outgrowth, and synaptic maturation. The cellular distribution of NO-responsive cells suggests that NO can serve as a retrograde synaptic messenger, as an intracellular messenger, and as a lateral diffusible messenger irrespective of conventional synaptic connectivity.     

Ultrastructure within the Lateral Plexus of the Limulus Eye

The ultrastructure of the lateral plexus in the compound eye of Limulus is investigated by serial section technique. "Cores" of tissue containing the axons, lateral plexus, and neuropile associated with one sensory ommatidium show the following features: (a) collateral branches from retinular cells do not contribute to the lateral plexus proper, but do form retinular neuropile by contacting collaterals of a self-contained cluster of retinular axons; (b) collateral branches from eccentric cell axons always branch repeatedly upon leaving the parent axon, and compose the bulk of the lateral plexus; (c) the most distal collateral branches from an eccentric cell axon appear to form neuropile and synaptic contacts with each other, whereas more proximal branches form synaptic contacts with collaterals from eccentric cell axons of neighboring ommatidia. We conclude that the ribbon synapses and associated transmitter substance in eccentric cell collaterals must be inhibitory, and that two pathways for self-inhibition may exist. We suggest, as a working hypothesis for the structure of the lateral plexus, a branching pattern with depth that mirrors the horizontal spread of lateral inhibition measured physiologically.     

Interplay between Short- and Long-Term Plasticity in Cell-Assembly Formation

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.     

Optimal information storage and the distribution of synaptic weights: perceptron versus Purkinje cell

It is widely believed that synaptic modifications underlie learning and memory. However, few studies have examined what can be deduced about the learning process from the distribution of synaptic weights. We analyze the perceptron, a prototypical feedforward neural network, and obtain the optimal synaptic weight distribution for a perceptron with excitatory synapses. It contains more than 50% silent synapses, and this fraction increases with storage reliability: silent synapses are therefore a necessary byproduct of optimizing learning and reliability. Exploiting the classical analogy between the perceptron and the cerebellar Purkinje cell, we fitted the optimal weight distribution to that measured for granule cell-Purkinje cell synapses. The two distributions agreed well, suggesting that the Purkinje cell can learn up to 5 kilobytes of information, in the form of 40,000 input-output associations.     

Bifurcation-based approach reveals synergism and optimal combinatorial perturbation

Cells accomplish the process of fate decisions and form terminal lineages through a series of binary choices in which cells switch stable states from one branch to another as the interacting strengths of regulatory factors continuously vary. Various combinatorial effects may occur because almost all regulatory processes are managed in a combinatorial fashion. Combinatorial regulation is crucial for cell fate decisions because it may effectively integrate many different signaling pathways to meet the higher regulation demand during cell development. However, whether the contribution of combinatorial regulation to the state transition is better than that of a single one and if so, what the optimal combination strategy is, seem to be significant issue from the point of view of both biology and mathematics. Using the approaches of combinatorial perturbations and bifurcation analysis, we provide a general framework for the quantitative analysis of synergism in molecular networks. Different from the known methods, the bifurcation-based approach depends only on stable state responses to stimuli because the state transition induced by combinatorial perturbations occurs between stable states. More importantly, an optimal combinatorial perturbation strategy can be determined by investigating the relationship between the bifurcation curve of a synergistic perturbation pair and the level set of a specific objective function. The approach is applied to two models, i.e., a theoretical multistable decision model and a biologically realistic CREB model, to show its validity, although the approach holds for a general class of biological systems.     

Initial processing of visual information within the retina and the LGN

The initial stage of information processing by the visual system reduces the information contained in the continuous image on the retina into a discrete set of responses which are carried from the lateral geniculate nucleus (LGN) to the visual cortex.-1. The optimal sampling of the light intensity distribution in the visual environment is achieved only if each channel in the visual pathways carries undistorted information corresponding to an image element. The visual system approaches as closely as possible the scheme of optimal spatial sampling, retaining the full information on the low spatial frequency content of the object light intensity. The ideal receptive field of a sustained LGN cell is then of the form J ₁ (Kr)/Kr.-2. The experimentally determined receptive fields of sustained LGN cells (and to some extent retinal ganglion cells as well) in cat closely resemble the functional form J ₁ (Kr)/Kr. The centre-surround organization of the receptive fields is therefore understood as a scheme which leads to a maximal information flow through the visual pathways.-3. The optimal sampling scheme cannot be realized by the retina alone, because of restrictions on the size of neural networks. It is therefore constructed in two stages, ending at the LGN level. A recombination of ganglion cell signals into optimal receptive fields is a major role of the LGN.     

Target neuron specification of short-term synaptic facilitation and depression in the cricket CNS

We investigated the role of retrograde signals in the regulation of short-term synaptic depression and facilitation by characterizing the form of plasticity expressed at novel synapses on four giant interneurons in the cricket cercal sensory system. We induced the formation of novel synapses by transplanting a mesothoracic leg and its associated sensory neurons to the cricket terminal abdominal segment. Axons of ectopic leg sensory neurons regenerated and innervated the host terminal abdominal ganglion forming monosynaptic connections with the medial giant interneuron (MGI), lateral giant interneuron (LGI), and interneurons 7-1a and 9-2a. The plasticity expressed by these synapses was characterized by stimulating a sensory neuron with pairs of stimuli at various frequencies or with trains of 10 stimuli delivered at 100 Hz and measuring the change in excitatory postsynaptic potential amplitude recorded in the postsynaptic neuron. Novel synapses of a leg tactile hair on 7-1a depressed, as did control synapses of cercal sensory neurons on this interneuron. Novel synapses of leg campaniform sensilla (CS) sensory neurons on MGI, like MGI's control synapses, always facilitated. The form of plasticity expressed by novel synapses is thus consistent with that observed at control synapses. Leg CS synapses with 9-2a also facilitated; however, the plasticity expressed by these sensory neurons is dependent on the identity of the postsynaptic cell since the synapses these same sensory neurons formed with LGI always depressed. We conclude that the form of plasticity expressed at these synaptic connections is determined retrogradely by the postsynaptic cell. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 700–714, 1998     

Feedforward Inhibition and Synaptic Scaling – Two Sides of the Same Coin?

Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing.     

Appearance and distribution of fetal brain macrophages in mice

Summary A study on the localization of fetal and neonatal brain macrophages of mice from embryonic day 10 (E10) to postnatal day 21 (P21) was carried out immunohistochemically using a monoclonal antibody against a macrophage differentiation antigen (Mac-1) and the labeled avidin-biotin technique. In the central nervous system, the macrophages recognized first were mainly located in the choroid plexuses of the fourth and lateral ventricles at E14. Their number increased at E17–P3 and gradually decreased thereafter. In the cerebral parenchyma, a few macrophages appeared at E14 in the matrix cell layer. They were also detected in the migrating zone at E15, E17 and in the cortical plate at E19. Mapping of positive cells at the stage of neuroblast formation (E15, E17, E19) disclosed the precise distribution of cerebral macrophages. The macrophages that appeared first in the choroid plexuses at E15 may be derived from the subarachnoid vessels, which extend into the stroma of the choroid plexuses when the matrix cell layer invaginates into the lateral ventricle to form the choroid plexuses. Almost all of the macrophages recognized in the cerebral parenchyma disappeared at P9 when the cytoarchitecture seemed to be completed. In the cerebellum, which develops later than the cerebrum, macrophages appeared after birth and were located mainly in the internal granular layer. The brain macrophages always appeared in the regions where cell proliferation and brain remodeling are most active at each stage. These findings suggest that fetal and neonatal brain macrophages may play an important role in scavenging degenerated cells and cell debris during histogenesis of the central nervous system.     

Transmembrane mechanisms in the assembly of the postsynaptic apparatus at the neuromuscular junction

The vertebrate neuromuscular junction (NMJ) is marked by molecular specializations that include postsynaptic clusters of acetylcholine receptor (AChR) and acetylcholinesterase (AChE). Whereas AChRs are aggregated in the postsynaptic muscle membrane to a density of 10,000/mum(2), AChE is concentrated, also to a high density, in the synaptic basement membrane (BM). In recent years considerable progress has been made in understanding the cellular and molecular mechanisms of AChR clustering. It is known that during the early stages of motoneuron-muscle interaction, the nerve-secreted proteoglycan agrin activates the muscle-specific kinase MuSK, which leads to the formation of a postsynaptic cytoskeletal scaffold that immobilizes and concentrates AChRs through a process generally accepted to involve diffusion-mediated trapping of the receptors. We have recently tested this diffusion-trap model at the single molecule level for the first time by using quantum-dot labeling to track individual AChRs during NMJ development. Our results showed that single AChRs exhibit Brownian-type movement, with diffusion coefficients of 10(-11) to 10(-9)cm(2)/s, until they become immobilized at "traps" assembled in response to synaptogenic stimuli. Thus, free diffusion of AChRs is an integral part of their clustering mechanism. What is the mechanism for AChE clustering? We previously showed that the A(12) asymmetric form of AChE binds to perlecan, a heparan-sulfate proteoglycan which in turn interacts with the transmembrane dystroglycan complex. Through this linkage AChE becomes bound to the muscle membrane and, like AChRs, may exhibit lateral mobility along the membrane. Consistent with this idea, pre-existent AChE at the cell surface becomes clustered together with AChRs following synaptogenic stimulation. Future studies testing diffusion-mediated trapping of AChE should provide insights into the synaptic localization of BM-bound molecules at the NMJ.     

Plastic and nonplastic pyramidal cells perform unique roles in a network capable of adaptive redundancy reduction

Pyramidal cells show marked variation in their morphology, including dendritic structure, which is correlated with physiological diversity; however, it is not known how this variation is related to a cell's role within neural networks. In this report, we describe correlations among electrosensory lateral line lobe (ELL) pyramidal cells' highly variable dendritic morphology and their ability to adaptively cancel redundant inputs via an anti-Hebbian form of synaptic plasticity. A subset of cells, those with the largest apical dendrites, are plastic, but those with the smallest dendrites are not. A model of the network's connectivity predicts that efficient redundancy reduction requires that nonplastic cells provide feedback input to those that are plastic. Anatomical results confirm the model's prediction of optimal network architecture. These results provide a demonstration of different roles for morphological/physiological variants of a single cell type within a neural network performing a well-defined function.     

Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice

Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans. We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness. In two unrelated families, a heterozygous missense mutation, c.632C→T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls. Linkage-disequilibrium analysis suggested that the families have a distant common ancestor. The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role. In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Ca²⁺-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse.     

A growth chamber for idealized studies of seedling root growth dynamics and structure

A root growth chamber is described which allows seedling root growth dynamics and structure to be monitored continuously under a variety of conditions for several weeks. The chamber consists of two cells with inner dimensions 18×20×0.12 cm. To simulate the soil matrix, each cell was filled with spherical glass beads of 0.1 cm diameter. Given the 0.12 cm width of each cell, the glass bead matrix was approximately one bead layer thick. Roots were therefore grown in a quasi -two-dimensional and transparent environment. This enabled root images of high spatial and temporal resolution to be collected and analysed quantitatively using standard image analysis techniques. The chamber was constructed such that the root environment could be manipulated with regard to nutrient distribution, `soil' matrix structure and other perturbations to the system. Preliminary experiments of the growth dynamics of lentil roots (Lens culinaris L. cv. Verte du Puy) in the chamber were conducted. The majority of the primary and lateral roots followed a similar growth pattern with high growth rates between days 5 and 9 and days 14 and 18 separated by a period of low growth rate between days 10 and 12 after seeding in the chamber. Thus, primary and lateral root growth was to a certain extent synchronized. Lateral roots developed after 3 to 8 days on the outer curve (convex side) of the primary root. The roots shared many of the characteristics of roots developed in three-dimensional systems indicating that the chamber did not induce artificial root behaviour. Thus, the idealized and quantitative studies that can be conducted in the chamber may enable many aspects of the complex interactions between the root system and environment to be studied.     

Formation and remodeling of epithelial polarity

Polarity is a fundamental property of all eukaryotic cells that underlies many developmental processes. A recent EMBO workshop (March 27-31) organized by Thomas Lecuit, Norbert Perrimon, and Keith Mostov brought cell and developmental biologists together on the Mediterranean coast near Marseille, France, to share views on how epithelium polarity is established and remodeled during development and disease. Participants witnessed and celebrated the emerging convergence of intellectual and experimental approaches to address how individual cells acquire polarity and form polarized tissues in the context of developing embryos.     

Vesicle-binding properties of wild-type and cysteine mutant forms of alpha(1) domain of apolipoprotein B

Previous studies demonstrated that structural perturbation of the alpha(1) domain of apolipoprotein B (apoB) blocked the initiation of lipoprotein assembly. We explored the hypothesis that this domain may interact with the inner leaflet of the endoplasmic reticulum membrane in a manner that may nucleate microsomal triglyceride transfer protein-dependent lipid sequestration. ApoB-17 (amino-terminal 17% of apoB), which contains most of the alpha(1) domain, was expressed stably in rat hepatoma cells and recovered from medium in lipid-poor form. On incubation with phospholipid vesicles composed of 1-myristol-2-myristoyl-sn-glycero-3-phosphocholine or 1-palmitoyl-2-oleoyl-sn-gylycero-3-phosphocholine, apoB-17 underwent vesicle binding and was recovered in the d < 1.25 g/ml gradient fraction. To determine whether vesicle binding is disrupted by the same structural perturbations that block lipoprotein assembly in vivo, apoB-17 was subjected to partial and complete chemical reduction. Although normally a soluble peptide, mild reduction of apoB-17 caused its precipitation, suggesting that hydrophobic, solvent-inaccessible domains within the alpha(1) domain of apoB are stabilized by intramolecular disulfide bonds. In contrast to apoB-17 chemically reduced in vitro, forms of apoB-17 bearing pairwise cysteine-to-serine substitutions were recovered in soluble form from transiently transfected COS-1 cell extracts. Although individual disruption of disulfide bond 2 or 4 in apoB-28 and apoB-50 was previously shown to block lipoprotein assembly in vivo, these alterations had no impact on the ability of apoB-17 to bind to phospholipid vesicles in vitro or on its capacity to form recombinant lipoprotein particles. These results suggest that while the vesicle/lipid-binding property of the alpha(1) domain may reflect an essential role required for the initiation of lipoprotein formation, some other aspect of alpha(1) domain function is perturbed by disruption of native disulfide bonds. -- DeLozier, J. A., J. S. Parks, and G. S. Shelness. Vesicle-binding properties of wild-type and cysteine mutant forms of alpha(1) domain of apolipoprotein B. J. Lipid Res. 2001. 42: 399--406.