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Hippocampal CA1 interneurons: an in vivo intracellular labeling study.

Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats. The full extent of their dendrites and axonal arborizations as well as their calcium binding protein content were examined. Based on the spatial extent of axon collaterals, local circuit cells (basket and O-LM neurons) and long-range cells (bistratified, trilaminar, and backprojection neurons) could be distinguished. Basket cells were immunoreactive for parvalbumin and their axon collaterals were confined to the pyramidal layer. A single basket cell contacted more than 1500 pyramidal neurons and 60 other parvalbumin-positive interneurons. Commissural stimulation directly discharged basket cells, followed by an early and late IPSPs, indicating interneuronal inhibition of basket cells. The dendrites of another local circuit neuron (O-LM) were confined to stratum oriens and it had a small but high-density axonal terminal field in stratum lacunosum-moleculare. The fastest firing cell of all interneurons was a calbindin-immunoreactive bistratified neuron with axonal targets in stratum oriens and radiatum. Two neurons with their cell bodies in the alveus innervated the CA3 region (backprojection cells), in addition to rich axon collaterals in the CA1 region. The trilaminar interneuron had axon collaterals in strata radiatum, oriens and pyramidale with its dendrites confined to stratum oriens. Commissural stimulation evoked an early EPSP-IPSP-late depolarizing potential sequence in this cell. All interneurons formed symmetric synapses with their targets at the electron microscopic level. These findings indicate that interneurons with distinct axonal targets have differential functions in shaping the physiological patterns of the CA1 network.

Animals↗

A developmental model for the evolution of artificial neural networks.

We present a model of decentralized growth and development for artificial neural networks (ANNs), inspired by developmental biology and the physiology of nervous systems. In this model, each individual artificial neuron is an autonomous unit whose behavior is determined only by the genetic information it harbors and local concentrations of substrates. The chemicals and substrates, in turn, are modeled by a simple artificial chemistry. While the system is designed to allow for the evolution of complex networks, we demonstrate the power of the artificial chemistry by analyzing engineered (handwritten) genomes that lead to the growth of simple networks with behaviors known from physiology. To evolve more complex structures, a Java-based, platform-independent, asynchronous, distributed genetic algorithm (GA) has been implemented that allows users to participate in evolutionary experiments via the World Wide Web.

Algorithms↗

Adaptive evolution of bacterial metabolic networks by horizontal gene transfer.

Numerous studies have considered the emergence of metabolic pathways, but the modes of recent evolution of metabolic networks are poorly understood. Here, we integrate comparative genomics with flux balance analysis to examine (i) the contribution of different genetic mechanisms to network growth in bacteria, (ii) the selective forces driving network evolution and (iii) the integration of new nodes into the network. Most changes to the metabolic network of Escherichia coli in the past 100 million years are due to horizontal gene transfer, with little contribution from gene duplicates. Networks grow by acquiring genes involved in the transport and catalysis of external nutrients, driven by adaptations to changing environments. Accordingly, horizontally transferred genes are integrated at the periphery of the network, whereas central parts remain evolutionarily stable. Genes encoding physiologically coupled reactions are often transferred together, frequently in operons. Thus, bacterial metabolic networks evolve by direct uptake of peripheral reactions in response to changed environments.

Adaptation, Physiological↗

On the complexity of directed biological networks.

Recently there was an increased interest towards network approach to biology and environmental sciences. Networks are believed to be the key to the understanding of the work of biological machine in cells, organs, organisms, and ecosystems. While complexity of undirected networks has been recently analyzed, the assessment of complexity in directed networks has specificity that has not been explored so far. The present paper aims to address the existing gap by discussing the applicability of the available complexity descriptors. New specific measures (vertex accessibility, accessible connectedness, and adjusted average distance) are introduced based on assessment of the reduced accessibility of nodes in directed networks.

Animals↗

Evolutionary Reorganization of Transcriptomic Architecture Across a UVB Tolerance Gradient in Fish.

Environmental stressors such as ultraviolet radiation impose strong selective pressures on organisms, yet how adaptation to such stressors shapes transcriptomic responses at the network level remains poorly understood. Although stratospheric ozone is recovering globally, substantial regional variation in UV exposure persists, particularly in high-altitude environments where extreme UV levels can occur. Here, we compared three fish models representing distinct biological responses to UVB exposure: wild-type zebrafish (Danio rerio), a melanin-deficient zebrafish mutant (nacre) lacking a major protective mechanism against UVB damage, and the high-altitude Andean killifish Orestias ascotanensis, a species naturally exposed to extreme UVB radiation. Together, these models define a gradient spanning physiological protection, impaired protection, and evolutionary adaptation to UVB stress. Using RNA-seq and protein-protein interaction networks, we show that transcriptomic responses differ markedly across this gradient. Wild-type and nacre zebrafish exhibited relatively limited transcriptomic changes (∼2%-2.4% of genes changing), whereas O. ascotanensis displayed a large-scale and highly coordinated response (∼21.6% of genes changing) characterized by functionally specialized networks enriched in DNA repair pathways. These differences involved not only transcriptomic magnitude but also marked reorganization of transcriptomic architecture. Integration with positive selection analyses revealed that positively selected genes were concentrated within highly interconnected regions of transcriptomic networks, consistent with adaptation involving network reorganization. Furthermore, ortholog-based analyses suggest that adaptive responses involve differential reorganization of a conserved functional background. Together, our results support a model in which adaptation to environmental stress is associated with the reorganization of conserved transcriptomic networks across physiological and evolutionary contexts, providing a systems-level perspective on the molecular basis of adaptation.

UVB radiation↗

Hierarchical microimaging for multiscale analysis of large vascular networks.

There is a wide range of diseases and normal physiological processes that are associated with alterations of the vascular system in organs. Ex vivo imaging of large vascular networks became feasible with recent developments in microcomputed tomography (microCT). Current methods permit to visualize only limited numbers of physically excised regions of interests (ROIs) from larger samples. We developed a method based on modified vascular corrosion casting (VCC), scanning electron microscopy (SEM), and desktop and synchrotron radiation microCT (SRmicroCT) technologies to image vasculature at increasing levels of resolution, also referred to as hierarchical imaging. This novel approach allows nondestructive 3D visualization and quantification of large microvascular networks, while retaining a precise anatomical context for ROIs scanned at very high resolution. Scans of entire mouse brain VCCs were performed at 16-microm resolution with a desktop microCT system. Custom-made navigation software with a ROI selection tool enabled the identification of anatomical brain structures and precise placement of multiple ROIs. These were then scanned at 1.4-microm voxel size using SRmicroCT and a local tomography setup. A framework was developed for fast sample positioning, precise selection of ROIs, and sequential high-throughput scanning of a large numbers of brain VCCs. Despite the use of local tomography, exceptional image quality was achieved with SRmicroCT. This method enables qualitative and quantitative assessment of vasculature at unprecedented resolution and volume with relatively high throughput, opening new possibilities to study vessel architecture and vascular alterations in models of disease.

Animals↗

Modeling the normal and neoplastic cell cycle with "realistic Boolean genetic networks": their application for understanding carcinogenesis and assessing therapeutic strategies.

In this paper we show how Boolean genetic networks could be used to address complex problems in cancer biology. First, we describe a general strategy to generate Boolean genetic networks that incorporate all relevant biochemical and physiological parameters and cover all of their regulatory interactions in a deterministic manner. Second, we introduce "realistic Boolean genetic networks" that produce time series measurements very similar to those detected in actual biological systems. Third, we outline a series of essential questions related to cancer biology and cancer therapy that could be addressed by the use of "realistic Boolean genetic network" modeling.

Cell Cycle↗

Spike independency in feed-forward networks.

A cortical neuron puts thousands of synaptic contacts on other neurons. The effect of the spike event spreads over a large number of neurons. So it is possible for spike timings to be correlated to each other. But there have not been so many reports of spike timing correlations, while there have been many reports of somewhat longer time range correlations through mean spike rates. Can independent firings be preserved in spite of a number of connections? The present study attempts to determine whether independent firings can be propagated through a simple feed-forward neural network. It is assumed that each unit obeys a threshold mechanism at each discrete time and that connections are statistically uniform with the excitation balanced to the inhibition and delay distributed. It is found that the independent firings can be stably propagated through the feed-forward network at a network parameter region, which contains the physiologically reasonable range. Another interesting result is that the independency-stable spike probability has a lower limit 0.0323.

Action Potentials↗

Neural network approaches to visual motion perception.

This paper concerns certain difficult problems in image processing and perception: neurocomputation of visual motion information. The first part of this paper deals with the spatial physiological integration by the figure-ground discrimination neural network in the visual system of the fly. We have outlined the fundamental organization and algorithms of this neural network, and mainly concentrated on the results of computer simulations of spatial physiological integration. It has been shown that the gain control mechanism, the nonlinearity of synaptic transmission characteristic, the interaction between the two eyes, and the directional selectivity of the pool cells play decisive roles in the spatial physiological integration. In the second part, we have presented a self-organizing neural network for the perception of visual motion by using a retinotopic array of Reichardt's motion detectors and Kohonen's self-organizing maps. It has been demonstrated by computer simulations that the network is able to learn to solve the ambiguities given by local motion detection mechanism. The resultant self-organized configuration in the output layer is resembling direction selective columns which first appear in area MT of the primate visual system. It has been explored that the spatio-temporal coherences, mapping, cooperation, competition, and Hebb rule are the basic neural principles for visual motion perception.

Animals↗

A fibrillar elastic apparatus around human lymph capillaries.

A fibrillar elastic apparatus around the wall of human lymph capillaries is demonstrated by means of histochemical and ultrastructural techniques. This apparatus consists of three interlinked components listed here in order of increasing distance from the capillary wall: 1) oxytalan fibres connected to the abluminal surface of the endothelial cells, known also as "anchoring filaments" and consisting of bundles of microfibrils; 2) elaunin fibres consisting of microfibrils and a small amount of elastin; and 3) typical elastic fibres consisting of microfibrils and abundant elastin. The microfibrillar constituent has similar ultrastructural features in the three components of the elastic apparatus. Microfibrils have a diameter of 12-14 nm, an electron-transparent core and a wall with 3-5 electron-dense subunits and oblique cross striations with a period of 15-17 nm. Microfibrils are the common element of the three components of the elastic apparatus and they link them to one another and to the elastic network of the perivascular connective tissue. An elastic apparatus was not found around blood capillaries and it can thus provide a histological marker to identify lymph capillaries. The possible role of the lymphatic elastic apparatus in the physiological activity of the lymphatic absorbing network is discussed and it is proposed that its disconnection from the elastic network of the tissue may promote pathological conditions such as lymphoedema or diseases related to impaired immune responses.

Actin Cytoskeleton↗

[Modeling of elastic deformation and vascular resistance of arterial and venous vasa vasorum].

As in most living tissues, a network of nutritional vessels, the so-called vasa vasorum, irrigates the vessel wall under physiological conditions. An alteration or obstruction of this network can induce severe lesions. Most normal arteries and veins are irrigated by a vasa vasorum network located mainly in the adventice. They essentially supply oxygen to the outer layers of the vascular wall, the inner layer being mainly oxygenated by direct diffusion from bloodstream. Vasa vasorum responds to vasomotor stimuli and can even regress, e.g., after vascularization of arterial grafts. Their pathophysiological importance for arteries is now established. Indeed, it is known that an infusion disorder or vasa vasorum alteration may induce or promote early atherosclerotic lesions, fibrodysplasia or even media necrosis. From a mechanical point of view, and considering the three layers as a unique material, the vessel shows non-isotropic linear elastic and incompressible (v = 0.5) behaviour in the case of minimal or moderate deformation. But in the case of major deformation, the vessel displays a non-linear behaviour. The interaction between vasa vasorum supply and the mechanical properties of the arterial vascular wall can promote the occurrence of aneurysms as soon as vasa vasorum irrigation decreases. Some authors have hypothesized that these microvessels could fulfil the same function in the venous wall. It appears also that microcirculation flow rates are lower in varicose veins than in healthy ones and that partial oxygen pressure, already low in a healthy vein media, is even lower in a varicose vein. All these facts underline the importance of supply by the vasa vasorum network and its determining role in maintaining vascular wall integrity. In addition, the influence of vessel non-linear properties and their pathological changes on microcirculation would partially explain media necrosis in arteries and veins. Studying vascular wall deformation under the influence of intraluminal pressure revealed that an initially circular vasa vasorum rapidly takes on an elliptical shape which results more from crosswise circumferential stretching of the wall than from radial crushing. This induces increased hydraulic resistance. Thus permanent overpressure reduces vascular wall irrigation. Once the wall has been devascularized, it will loose its elasticity, harden and retain its maximal deformation. A vicious circle is then created. This phenomenon, noticeable in arteries, could be more serious in veins because their walls are thinner and elasticity modulus is lower. For example, for an intraluminal overpressure of 100 mmHg in an artery and 10 mmHg in a vein the ellipticity of the vasa vasorum becomes 1.2 and 3 respectively. Based on the hypothesis of a linear elastic behaviour and a periodical intraluminal overpressure, the ratio of the two axis of an arterial vasa vasorum B/A varies from 1.13 to 1.28 for Pa = 100 + 30 sin (2 pi t) mmHg, and from 1.24 to 1.44 for Pa = 160 + 40 sin (2 pi t) mmHg. In this case, the ratio of hydraulic resistances R(ellipse)/R(circle) changes little (less than 1, the ratio of the axis varies from 1.1 to 2.6 for Pa = 5 + 5 sin (2 pi t) mmHg) and from 1.8 to 5.8 for Pa = 10 + 5 sin (2 pi t) mmHg). Thus the ratio of hydraulic resistance varies from 1 to 1.5 and from 1.2 to 2.8 respectively. In practice Young's modulus increases in parallel with luminal pressure by limiting vascular wall and vasa vasorum deformation. If we consider the non-linear behaviour of the vessel wall and suppose the same conditions of intraluminal pressure, the ratio of the axis of the venous vasa vasorum in a hypertensive patient varies from 1.6 to 2.6 (instead of 1.8 to 5.8 in the case of linear model). This ratio is higher than that of the healthy subject which is less than 1.7. So the vascular structure in physiological conditions itself reacts to the pressure increases which may jeopardize vasa vasorum irrigation by delaying mural transfor

Animals↗

Quo vadis basic and clinical chronobiology: promise for health maintenance.

Chronobiology is the eminently interdisciplinary science of interactions in time among metabolic, hormonal, and neuronal networks. It involves anatomy, biochemistry, microbiology, physiology, and pharmacology, at the molecular, intracellular, intercellular, and still higher levels of organization. The compounds coordinating a time structure--proteins, steroids, and amino-acid derivatives--provide for the scheduling of interactions among membrane, cytoplasmic, and nuclear events in a network involving rhythmic enzyme reactions and other intracellular mechanisms. The integrated temporal features of the processes of induction, repression, transcription, and translation of gene expression remain to be mapped in relation to the available framework, consisting of the sequences of phospholipid and RNA labeling, DNA formation, and mitosis, to delineate a circadian cell cycle upon which further hormonal and neural coordination acts (Halberg et al., 1959a,b, 1979a). There is a need for communication over temporal as well as spatial distances among different specialized structures devoted, in individuals, to metabolism, growth, reproduction, and the ability to adjust, and, in species, to the capacity to adapt. For a better understanding at all levels of behavior in its broader sense of organization in time, chronobiology requires familiarity with temporal aspects of metabolism, hormones, and neurons. In other words, broadly trained, full-time "general practitioners" of a chronobiology in its own right are needed.

Adrenal Cortex↗

GeneNet: a gene network database and its automated visualization.

MOTIVATION: Gene networks that provide the regulation of physiological processes are the basic feature of organisms. Information regarding the regulation of gene expression and signal transduction pathways is increasing rapidly. However, the information is hard to formalize and systematize. Ways and means for automated visualization of the gene networks based on their formalized description are needed. RESULTS: The object-oriented database GeneNet and the software for its automated visualization have been developed. The main principles of a formalized description of the gene network have been worked out. Antiviral response and erythropoiesis are provided as examples to show how this is achieved. The GeneNet graphical user interface written in Java provides automated generation of the gene network diagrams and allows visualization and exploration of the GeneNet database through the Internet. A system of filters allows the selection of particular components of the network for visualization. AVAILABILITY: The GeneNet database and its graphical user interface are available at http://wwwmgs.bionet.nsc.ru/systems/MGL/GeneN et/ CONTACT: fedor@bionet.nsc.ru

Computational Biology↗

The T-tubular network and its triads in the sole plate sarcoplasm of the motor end-plate of mammals.

The transition between the subsynaptic folds and the T-tubules demonstrated in a former paper was further investigated in the sole plate area by using the extracellular marker Lanthanum. A tubular network of the T-system of the sole plate area which is connected to the subsynaptic folds and to the t-tubular elements between the myofibrils is described for the first time. T-tubules of this network criss-cross through the sarcoplasm of the sole plate and lie in close proximity to sole plate nuclei and mitochondria. Cisterns of sarcoplasmic reticulum of the sole plate area make contact with these t-tubules forming triads. The possible physiological role of this sole plate network and its triads will be discussed with regard to a transport of substances in tubules with the dimension of nanotubes and Ca2+ activated processes in the sole plate area.

Animals↗

Transient rhythmic network activity in the somatosensory cortex evoked by distributed input in vitro.

The initiation and maintenance of physiological and pathophysiological oscillatory activity depends on the synaptic interactions within neuronal networks. We studied the mechanisms underlying evoked transient network oscillation in acute slices of the adolescent rat somatosensory cortex and modeled its underpinning mechanisms. Oscillations were evoked by brief spatially distributed noisy extracellular stimulation, delivered via bipolar electrodes. Evoked transient network oscillation was detected with multi-neuron patch-clamp recordings under different pharmacological conditions. The observed oscillations are in the frequency range of 2-5 Hz and consist of 4-12 mV large, 40-150 ms wide compound synaptic events with rare overlying action potentials. This evoked transient network oscillation is only weakly expressed in the somatosensory cortex and requires increased [K+]o of 6.25 mM and decreased [Ca2+]o of 1.5 mM and [Mg2+]o of 0.5 mM. A peak in the cross-correlation among membrane potential in layers II/III, IV and V neurons reflects the underlying network-driven basis of the evoked transient network oscillation. The initiation of the evoked transient network oscillation is accompanied by an increased [K+]o and can be prevented by the K+ channel blocker quinidine. In addition, a shift of the chloride reversal potential takes place during stimulation, resulting in a depolarizing type A GABA (GABAA) receptor response. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA), N-methyl-D-aspartate (NMDA), or GABA(A) receptors as well as gap junctions prevents evoked transient network oscillation while a reduction of AMPA or GABA(A) receptor desensitization increases its duration and amplitude. The apparent reversal potential of -27 mV of the evoked transient network oscillation, its pharmacological profile, as well as the modeling results suggest a mixed contribution of glutamatergic, excitatory GABAergic, and gap junctional conductances in initiation and maintenance of this oscillatory activity. With these properties, evoked transient network oscillation resembles epileptic afterdischarges more than any other form of physiological or pathophysiological neocortical oscillatory activity.

Animals↗

Visual-vestibular interactions during vestibular compensation: role of the pretectal not in horizontal VOR recovery after hemilabyrinthectomy in rhesus monkey.

Damage to the vestibular labyrinth leads to profound nystagmus and vertigo. Over time, the vestibular-ocular system recovers in a process called vestibular compensation leading to reduced nystagmus and vertigo provided visual signals are available. Our study was directed at identifying sources of visual information that could play a role in vestibular compensation. Specifically, we investigated the role of the pretectal nucleus of the optic tract (NOT) in vestibular compensation after hemilabyrinthectomy (HL) in rhesus monkeys. We chose the NOT because this structure provides critical visual motion information for adaptive modification of the vestibular ocular reflex (VOR). We produced bilateral NOT lesions by injecting the excitotoxin ibotenic acid. We compared vestibular compensation after HL in NOT-lesioned and control animals with intact NOTs. We measured eye movements with an electromagnetic method employing scleral search coils. Measurements included slow-phase eye velocity during spontaneous nystagmus, per- and postrotatory nystagmus and the horizontal VOR (hVOR) gain (eye-velocity/head velocity) associated with per- and postrotatory and sinusoidal (0.2-2.0 Hz; 30-90 degrees/s) whole body oscillation around the earth-vertical axis. VOR gain was low (<0.5) for rotation toward the HL side. Our control animal evinced significant vestibular compensation with VOR gains approaching unity by 100 days post HL. In contrast, monkeys with bilateral lesions of the NOT never obtained this significant recovery with hVOR gains well below unity at 100 days and beyond. Therefore our studies demonstrate that the NOT is an essential source of visual signals for the process of vestibular compensation after HL.

Adaptation, Physiological↗

The insect frontal ganglion and stomatogastric pattern generator networks.

Insect neural networks have been widely and successfully employed as model systems in the study of the neural basis of behavior. The insect frontal ganglion is a principal part of the stomatogastric nervous system and is found in most insect orders. The frontal ganglion constitutes a major source of innervation to foregut muscles and plays a key role in the control of foregut movements. Following a brief description of the anatomy and development of the system in different insect groups, this review presents the current knowledge of the way neural networks in the insect frontal ganglion generate and control behavior. The frontal ganglion is instrumental in two distinct and fundamental insect behaviors: feeding and molting. Central pattern-generating circuit(s) within the frontal ganglion generates foregut rhythmic motor patterns. The frontal ganglion networks can be modulated in-vitro by several neuromodulators to generate a variety of motor outputs. Chemical modulation as well as sensory input from the gut and input from other neural centers enable the frontal ganglion to induce foregut rhythmic patterns under different physiological conditions. Frontal ganglion neurons themselves are also an important source of neurosecretion. The neurosecretory material from the frontal ganglion can control and modulate motor patterns of muscles of the alimentary canal. The current and potential future importance of the insect stomatogastric nervous system and frontal ganglion in the study of the neural mechanisms of behavior are discussed.

Animals↗