Neurotoxicology: principles and considerations of in vitro assessment

Neurotoxicology is an exciting area of science, not only because of the importance of toxic injury to the nervous system in human disease, but also because specific toxicants have served as invaluable tools for the advancement of our knowledge of "normal" neurobiological processes. In fact, much of our understanding of the organisation and function of the nervous system is based on observations derived from the actions of neurotoxicants. This paper addresses various physiological aspects behind the exquisite sensitivity of the nervous system to toxic agents, including the privileged status of the nervous system vis-a-vis blood-brain barrier function, the extensions of the nervous system over space and the requirements of cells with such a complex geometry, and the transmission of information across extracellular space. In addition, in vitro models and their utility in the assessment of neurotoxicological outcome are discussed, with reference to both their advantages and disadvantages.     

Face to phase: pitfalls in time delay estimation from coherency phase

Coherency phase is often interpreted as a time delay reflecting a transmission delay between spatially separated neural populations. However, time delays estimated from corticomuscular coherency are conflicting and often shorter than expected physiologically. Recent work suggests that corticomuscular coherence is influenced by afferent sensory feedback and bidirectional interactions. We investigated how bidirectional interaction affects time delay estimated from coherency, using a feedback model of the corticomuscular system. We also evaluated the effect of bidirectional interaction on two popular directed connectivity measures: directed transfer function (DTF) and partial directed coherence (PDC). The model is able to reproduce the range of time delays found experimentally from coherency phase by varying the strengths of the efferent and afferent pathways and the recording of sensory feedback in the cortical signal. Both coherency phase and DTF phase were affected by sensory feedback, resulting in an underestimation of the transmission delay. Coherency phase was altered by the recording of sensory feedback in the cortical signals and both measures were affected by the presence of a closed loop feedback system. Only PDC phase led to the correct estimation of efferent transmission delay in all simulated model configurations. Coherency and DTF phase should not be used to estimate transmission delays in neural networks as the estimated time delays are meaningless in the presence of sensory feedback and closed feedback loops.     

The z-model — A proposal for spatial and temporal modeling of visual threshold perception

By considering only the modulation transfer functions of stationary, uniformly moved, and time modulated sinusoidal gratings it is possible to derive a simple model, the z-model, for the spatio-temporal frequency behaviour of one-dimensional patterns. The transmission function of this model is a band pass function of a single coordinate z, which is a quadratic form of the spatial and temporal frequencies (rotational symmetry with respect to space and time). The model is determined by only three constants. Optionally a time phase which accounts for delay and phase distortion can be added. This model can also be derived from reaction time measurements for switched on sinusoidal gratings. With this model the response of a wide variety of spatio-temporal patterns have been calculated and compared with measured threshold data. For two-dimensional patterns orientational filtering has to be added to the model leading to a further parameter. This model predicts satisfactorily the threshold modulation for a great variety of arbitrary spatio-temporal patterns. However the absolute threshold value for aperiodic transient patterns differs slightly in direction of smaller sensitivity as compared with periodic stationary patterns. This suggests that the peak detection scheme usually used in threshold detection modeling should be replaced by an integrative mechanism.     

Information Transmission in a Neuron-Astrocyte Coupled Model

A coupled model containing two neurons and one astrocyte is constructed by integrating Hodgkin-Huxley neuronal model and Li-Rinzel calcium model. Based on this hybrid model, information transmission between neurons is studied numerically. Our results show that when the successive spikes are produced in neuron 1 (N1), the bursting-like spikes (BLSs) occur in two neurons simultaneously during the spikes being transferred to neuron 2 (N2). The existence of the astrocyte and a higher expression level of mGluRs facilitate the occurrence of BLSs, but the rate of occurrence is not sensitive to the parameters. Furthermore, time delay τ occurs during the information transmission, and τ is almost independent of the effect of the astrocyte. Additionally, we found that low coupling strength may result in the distortion of the information, and this distortion is also proven to be almost independent of the astrocyte.     

Aspects on the integrative actions of the brain from neural networks to "brain-body medicine"

"Integration" is a key term in describing how nervous system can perform high level functions. A first condition to have "integration" is obviously the presence of efficient "communication processes" among the parts that have to be combined into the harmonious whole. In this respect, two types of communication processes, called wiring transmission (WT) and volume transmission (VT), respectively, were found to play a major role in the nervous system, allowing the exchange of signals not only between neurons, but rather among all cell types present in the central nervous system (CNS). A second fundamental aspect of a communication process is obviously the recognition/decoding process at target level. As far as this point is concerned, increasing evidence emphasizes the importance of supramolecular complexes of receptors (the so called receptor mosaics) generated by direct receptor-receptor interactions. Their assemblage would allow a first integration of the incoming information already at the plasma membrane level. Recently, evidence of two new subtypes of WT and VT has been obtained, namely the tunnelling nanotubes mediated WT and the microvesicle (in particular exosomes) mediated VT allowing the horizontal transfer of bioactive molecules, including receptors, RNAs and micro-RNAs. The physiological and pathological implications of these types of communication have opened up a new field that is largely still unexplored. In fact, likely unsuspected integrative actions of the nervous system could occur. In this context, a holistic approach to the brain-body complex as an indissoluble system has been proposed. Thus, the hypothesis has been introduced on the existence of a brain-body integrative structure formed by the "area postrema/nucleus tractus solitarius" (AP/NTS) and the "anteroventral third ventricle region/basal hypothalamus with the median eminence" (AV3V-BH). These highly interconnected regions operate as specialized interfaces between the brain and the body integrating brain-borne and body-borne neural and humoral signals.     

Transmission delays and frequency detuning can regulate information flow between brain regions

Brain networks exhibit very variable and dynamical functional connectivity and flexible configurations of information exchange despite their overall fixed structure. Brain oscillations are hypothesized to underlie time-dependent functional connectivity by periodically changing the excitability of neural populations. In this paper, we investigate the role of the connection delay and the detuning between the natural frequencies of neural populations in the transmission of signals. Based on numerical simulations and analytical arguments, we show that the amount of information transfer between two oscillating neural populations could be determined by their connection delay and the mismatch in their oscillation frequencies. Our results highlight the role of the collective phase response curve of the oscillating neural populations for the efficacy of signal transmission and the quality of the information transfer in brain networks.     

Tests of two models for the transmission of the Mu mutator in maize

Summary The mutator system Mu does not follow a typical Mendelian mode of transmission. In outcrosses in which 50 per cent mutator plants are expected, about 90 per cent are observed. Two possible models of transmission are tested. One assumes that Mu has segregation distortion activity such as has been described for the SD locus in Drosophila. The second model assumes an extra-chromosomal factor that is transmitted through the cytoplasm. No evidence of SD activity was found. Mutation frequencies in lines in which Mu was transmitted through the female were not greater than the frequencies observed when Mu was transmitted through the male; as might be expected on some models of cytoplasmic transmission. Thus, cytoplasmic transmission was not established. Other possible models of extrachromosomal inheritance that might not be detected by reciprocal crosses are discussed.     

Analysis of thought dissociation in schizophrenia on the basis of Wedensky-Pavlov phasic states

Clinical analysis shows that a fundamental element of thought dissociation in schizophrenia is semantic and sound "derailments" of the associative processes. On a pathophysiological level these derailments could be explained through the parabiotic phasic states of Wedensky-Pavlov. In particular these derailments could be explained through the distortion of reciprocal relations between verbal structures by means of Pavlov's ultraparadoxical phase, wherein the positive stimuli become negative and vice versa. The author assumes that in appropriate (adequate) circumstances one of the mechanisms by which the leading idea directs the associative process is the reciprocal inhibiting-facilitating relations between the verbal (and nonverbal) structures. In schizophrenia (which Pavlov considered as a chronic hypnotic phasic state) these inhibiting-facilitating relations are disorganized and the associative process reveals phasic disintegrative deviations. Therefore thought dissociation in schizophrenia, by the magnifying glass of the pathology, indicates that a reciprocal inhibiting-facilitating relation is a basic principle of functional organization not only on the lower levels of the nervous system, but also on its highest levels.     

Phase-Coherence Transitions and Communication in the Gamma Range between Delay-Coupled Neuronal Populations

Synchronization between neuronal populations plays an important role in information transmission between brain areas. In particular, collective oscillations emerging from the synchronized activity of thousands of neurons can increase the functional connectivity between neural assemblies by coherently coordinating their phases. This synchrony of neuronal activity can take place within a cortical patch or between different cortical regions. While short-range interactions between neurons involve just a few milliseconds, communication through long-range projections between different regions could take up to tens of milliseconds. How these heterogeneous transmission delays affect communication between neuronal populations is not well known. To address this question, we have studied the dynamics of two bidirectionally delayed-coupled neuronal populations using conductance-based spiking models, examining how different synaptic delays give rise to in-phase/anti-phase transitions at particular frequencies within the gamma range, and how this behavior is related to the phase coherence between the two populations at different frequencies. We have used spectral analysis and information theory to quantify the information exchanged between the two networks. For different transmission delays between the two coupled populations, we analyze how the local field potential and multi-unit activity calculated from one population convey information in response to a set of external inputs applied to the other population. The results confirm that zero-lag synchronization maximizes information transmission, although out-of-phase synchronization allows for efficient communication provided the coupling delay, the phase lag between the populations, and the frequency of the oscillations are properly matched.     

Information-theoretic model of evolution over protein communication channel

In this paper, we propose a communication model of evolution and investigate its information-theoretic bounds. The process of evolution is modeled as the retransmission of information over a protein communication channel, where the transmitted message is the organism's proteome encoded in the DNA. We compute the capacity and the rate distortion functions of the protein communication system for the three domains of life: Archaea, Bacteria, and Eukaryotes. The tradeoff between the transmission rate and the distortion in noisy protein communication channels is analyzed. As expected, comparison between the optimal transmission rate and the channel capacity indicates that the biological fidelity does not reach the Shannon optimal distortion. However, the relationship between the channel capacity and rate distortion achieved for different biological domains provides tremendous insight into the dynamics of the evolutionary processes of the three domains of life. We rely on these results to provide a model of genome sequence evolution based on the two major evolutionary driving forces: mutations and unequal crossovers.     

Characteristics and plasticity of electrical synaptic transmission

Electrical synapses are an omnipresent feature of nervous systems, from the simple nerve nets of cnidarians to complex brains of mammals. Formed by gap junction channels between neurons, electrical synapses allow direct transmission of voltage signals between coupled cells. The relative simplicity of this arrangement belies the sophistication of these synapses. Coupling via electrical synapses can be regulated by a variety of mechanisms on times scales ranging from milliseconds to days, and active properties of the coupled neurons can impart emergent properties such as signal amplification, phase shifts and frequency-selective transmission. This article reviews the biophysical characteristics of electrical synapses and some of the core mechanisms that control their plasticity in the vertebrate central nervous system.     

Towards a unified model of pavlovian conditioning: short review of trace conditioning models

There are three basic paradigms of classical conditioning: delay, trace and context conditioning where presentation of a conditioned stimulus (CS) or a context typically predicts an unconditioned stimulus (US). In delay conditioning CS and US normally coterminate, whereas in trace conditioning an interval of time exists between CS termination and US onset. The modeling of trace conditioning is a rather difficult computational problem and is a challenge to the behavior and connectionist approaches mainly due to a time gap between CS and US. To account for trace conditioning, Pavlov (Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex, Oxford University Press, London, 1927) postulated the existence of a stimulus “trace” in the nervous system. Meanwhile, there exist many other options for solving this association problem. There are several excellent reviews of computational models of classical conditioning but none has thus far been devoted to trace conditioning. Eight representative models of trace conditioning aimed at building a prospective model are being reviewed below in a brief form. As a result, one of them, comprising the most important features of its predecessors, can be suggested as a real candidate for a unified model of trace conditioning.     

Molecular complexity at the synapse: new proteins and multiple isoforms detected in Drosophila.

Synaptic transmission and its context-dependent modification are pivotal for all forms of information processing in the nervous system including learning and memory. The molecular components of the presynaptic nerve terminal are therefore under intensive study. Using a reverse genetic approach in Drosophila we have cloned the first invertebrate homologue to vertebrate synapsins and identified two new protein families, the "synapse-associated protein of 47 kD" (SAP47) and the cysteine string proteins (CSPs), which are conserved throughout higher eukaryotic evolution. Information on the molecular, cellular and systemic functions of these proteins and their isoforms is summarized in this review.     

油松毛虫幼虫,蛹种群聚集动态的分析

本文用灰色聚类分析、模糊聚类分析方法研究油松毛虫(Dendrolimustabulaeformis)幼虫、蛹种群的聚集动态。两种聚类分析方法综合分析结果表明:油松毛虫从越冬幼虫至蛹的种群聚集动态过程可分为:高度聚集,中等聚集程度和低聚集度三个阶段,它们各自相应的生物学阶段是:“刚刚上树期”,“上树后重新分布,扩散期(死亡率较高期)”,“取食盛期”以及蛹期,其中前二个阶段为“高聚集度”阶段。     

Selection, Generalized Transmission and the Evolution of Modifier Genes. I. the Reduction Principle

Modifier gene models are used to explore the evolution of features of organisms, such as the genetic system, that are not directly involved in the determination of fitness. Recent work has shown that a general "reduction principle" holds in models of selectively neutral modifiers of recombination, mutation, and migration. Here we present a framework for models of modifier genes that shows these reduction results to be part of a more general theory, for which recombination and mutation are special cases. The deterministic forces that affect the genetic composition of a population can be partitioned into two categories: selection and transmission. Selection includes differential viabilities, fertilities, and mating success. Imperfect transmission occurs as a result of such phenomena as recombination, mutation and migration, meiosis, gene conversion, and meiotic drive. Selectively neutral modifier genes affect transmission, and a neutral modifier gene can evolve only by generating association with selected genes whose transmission it affects. We show that, in randomly mating populations at equilibrium, imperfect transmission of selected genes allows a variance in their marginal fitnesses to be maintained. This variance in the marginal fitnesses of selected genes is what drives the evolution of neutral modifier genes. Populations with a variance in marginal fitnesses at equilibrium are always subject to invasion by modifier genes that bring about perfect transmission of the selected genes. It is also found, within certain constraints, that for modifier genes producing what we call "linear variation" in the transmission processes, a new modifier allele can invade a population at equilibrium if it reduces the level of imperfect transmission acting on the selected genes, and will be expelled if it increases the level of imperfect transmission. Moreover, the strength of the induced selection on the modifier gene is shown to range up to the order of the departure of the genetic system from perfect transmission.     

Infection of organotypic slice cultures from rat central nervous tissue with Neospora caninum: an alternative approach to study host-parasite interactions

Neospora caninum is an apicomplexan parasite which has emerged as an important cause of bovine abortion worldwide. Abortion is usually triggered by reactivation of dormant bradyzoites during pregnancy and subsequent congenital infection of the foetus, where the central nervous system appears to be most frequently affected. We here report on an organotypic tissue culture model for Neospora infection which can be used to study certain aspects of the cerebral phase of neosporosis within the context of a three-dimensionally organised neuronal network. Organotypic slice cultures of rat cortical tissue were infected with N. caninum tachyzoites, and the kinetics of parasite proliferation, as well as the proliferation-inhibitory effect of interferon-gamma (IFN-gamma), were monitored by either immunofluorescence, transmission electron microscopy, and a quantitative PCR-assay using the LightCycler instrument, respectively. In addition, the neuronal cytoskeletal elements, namely glial acidic protein filaments as well as actin microfilament bundles were shown to be largely colocalising with the pseudocyst periphery. This organotypic culture model for cerebral neosporosis provides a system, which is useful to study the proliferation, ultrastructural characteristics, development, and the interactions of N. caninum within the context of neuronal tissue, which at the same time can be modulated and influenced under controlled conditions, and will be useful in the future to gain more information on the cerebral phase of neosporosis.     

Transmission characteristics of axial waves in blood vessels

The elastic behavior of blood vessels can be quantitatively examined by measuring the propagation characteristics of waves transmitted by them. In addition, specific information regarding the viscoelastic properties of the vessel wall can be deduced by comparing the observed wave transmission data with theoretical predictions. The relevance of these deductions is directly dependent on the validity of the mathematical model for the mechanical behavior of blood vessels used in the theoretical analysis. Previous experimental investigations of waves in blood vessels have been restricted to pressure waves even though theoretical studies predict three types of waves with distinctly different transmission characteristics. These waves can be distinguished by the dominant displacement component of the vessel wall and are accordingly referred to as radial, axial and circumferential waves. The radial waves are also referred to as pressure waves since they exhibit pronounced pressure fluctuations. For a thorough evaluation of the mathematical models used in the analysis it is necessary to measure also the dispersion and attenuation of the axial and circumferential (torsion) waves.

To this end a method has been developed to determine the phase velocities and damping of sinusoidal axial waves in the carotid artery of anesthetized dogs with the aid of an electro-optical tracking system. For frequencies between 25 and 150 Hz the speed of the axial waves was between 20 and 40 m/sec and generally increased with frequency, while the natural pressure wave travelled at a speed of about 10 m/sec. On the basis of an isotropic wall model the axial wave speed should however be approximately 5 times higher than the pressure wave speed. This discrepancy can be interpreted as an indication for an anisotropic behavior of the carotid wall. The carotid artery appears to be more elastic in the axial than in the circumferential direction.     

Effect of sensory-motor latencies and active muscular stiffness on stability for an ankle-hip model of balance on a balance board

To achieve human upright posture (UP) and avoid falls, the central nervous system processes visual, vestibular, and proprioceptive information to activate the appropriate muscles to accelerate or decelerate the body’s center of mass. In this process, sensory-motor (SM) latencies and muscular deficits, even in healthy older adults, may cause falls. This condition is worse for people with chronic neuromuscular deficits (stroke survivors, patients with multiple sclerosis or Parkinson’s disease). One therapeutic approach is to recover or improve quiet UP by utilizing a balance board (BB) (a rotating surface with a tunable stiffness and time delay), where a patient attempts to maintain UP while task difficulty is manipulated. While BBs are commonly used, it is unclear how UP is maintained or how changes in system parameters such as SM latencies and BB time delay affect UP stability. To understand these questions, it is important that mathematical models be developed with enough degrees-of-freedom to capture the many responses evoked during the maintenance of UP on a BB. This paper presents an ankle-hip model of balance on a BB, which is used to study the combined effect of SM latencies and active muscular stiffness of the ankle and hip joints, and the BB stiffness and time delay on UP stability. The analysis predicts that people with proprioceptive, visual, vestibular loss, or increased SM latencies may show either leaning postures or larger body-sway. The results show that the BB time delay and the visual and vestibular feedback have the largest impact on UP stability.     

Integration of diffraction phase microscopy and Raman imaging for label‐free morpho‐molecular assessment of live cells

Label‐free quantitative imaging is highly desirable for studying live cells by extracting pathophysiological information without perturbing cell functions. Here, we demonstrate a novel label‐free multimodal optical imaging system with the capability of providing comprehensive morphological and molecular attributes of live cells. Our morpho‐molecular microscopy (3M) system draws on the combined strength of quantitative phase microscopy (QPM) and Raman microscopy to probe the morphological features and molecular fingerprinting characteristics of each cell under observation. While the commonr‐path geometry of our QPM system allows for highly sensitive phase measurement, the Raman microscopy is equipped with dual excitation wavelengths and utilizes the same detection and dispersion system, making it a distinctive multi‐wavelength system with a small footprint. We demonstrate the applicability of the 3M system by investigating nucleated and nonnucleated cells. This integrated label‐free platform has a promising potential in preclinical research, as well as in clinical diagnosis in the near future.