Multimodal interval distributions

Summary A mathematical model is presented that is supposed to describe certain types of multimodal interval distributions of neuronal discharges. Basically it consits of the selective interaction between an excitatory and an inhibitory impulse sequence. The theoretical results are compared with nerve cell interval distributions reported in the literature, and with distributions from simulation studies. A possible relationship between the properties of this model and longtailed interval distributions is indicated. Several extensions are discussed.     

Lack of neurokinin-1 receptor expression affects tissue mast cell numbers but not their spatial relationship with nerves

A spatial association between mast cells and nerves has been described in both the gastrointestinal and genitourinary tracts. However, the factors that influence the anatomic relationship between mast cells and nerves have not been completely defined. It has been suggested that the high-affinity receptor for substance P [neurokinin-1 (NK1)] might modulate this interaction. We therefore assessed mast cell-nerve relationships in tissues isolated from wild-type and NK1 receptor knockout (NK1-/-) mice. We now report that, in the complete absence of NK1 receptor expression, there is a significant increase in the number of mast cells without a change in the anatomic relationship between mast cell and nerves in stomach and bladder tissues at the light microscopic level. We next determined whether transplanted mast cells would maintain their spatial distribution, number, and contact with nerve elements. For this purpose, mast cell-deficient Kit(W)/Kit(W-v) mice were reconstituted with wild-type or NK1-/- bone marrow. No differences in mast cell-nerve contact were observed. These results suggest that NK1 receptor expression is important in the regulation of the number of mast cells but is not important in the interaction between mast cells and nerves. Furthermore, the interaction between mast cells and nerves is not mediated through NK1 receptor expression on the mast cell. Further studies are needed to determine the molecular pathway involved in mast cell migration and interaction with nerve elements, but the model of reconstitution of Kit(W)/Kit(W-v) mice with mast cells derived from different genetically engineered mice is a useful approach to further explore these mechanisms.     

Facial Nerve Axotomy in Mice: A Model to Study Motoneuron Response to Injury

The goal of this surgical protocol is to expose the facial nerve, which innervates the facial musculature, at its exit from the stylomastoid foramen and either cut or crush it to induce peripheral nerve injury. Advantages of this surgery are its simplicity, high reproducibility, and the lack of effect on vital functions or mobility from the subsequent facial paralysis, thus resulting in a relatively mild surgical outcome compared to other nerve injury models. A major advantage of using a cranial nerve injury model is that the motoneurons reside in a relatively homogenous population in the facial motor nucleus in the pons, simplifying the study of the motoneuron cell bodies. Because of the symmetrical nature of facial nerve innervation and the lack of crosstalk between the facial motor nuclei, the operation can be performed unilaterally with the unaxotomized side serving as a paired internal control. A variety of analyses can be performed postoperatively to assess the physiologic response, details of which are beyond the scope of this article. For example, recovery of muscle function can serve as a behavioral marker for reinnervation, or the motoneurons can be quantified to measure cell survival. Additionally, the motoneurons can be accurately captured using laser microdissection for molecular analysis. Because the facial nerve axotomy is minimally invasive and well tolerated, it can be utilized on a wide variety of genetically modified mice. Also, this surgery model can be used to analyze the effectiveness of peripheral nerve injury treatments. Facial nerve injury provides a means for investigating not only motoneurons, but also the responses of the central and peripheral glial microenvironment, immune system, and target musculature. The facial nerve injury model is a widely accepted peripheral nerve injury model that serves as a powerful tool for studying nerve injury and regeneration.     

alphaVbeta8 integrin is a Schwann cell receptor for fibrin

The interaction of Schwann cells with molecules in the extracellular environment following peripheral nerve injury is a critical aspect of nerve repair. A principal component of this material is fibrin, which derives from fibrinogen infiltrating into the nerve after the injury. This study was undertaken to identify cell surface receptor(s) that mediate the interaction of Schwann cells with fibrin. We found that adhesion of Schwann cells to fibrin could be effectively inhibited by low concentrations of RGD-containing peptides. Among RGD-sensitive integrins expressed by Schwann cell, alphaVbeta8, but not alpha5beta1, was found to bind to fibrin-Sepharose. In contrast, both of these integrins bound to fibronectin-Sepharose. We also found that alphaV, but not alpha5 or beta1 integrin subunit, accumulated in focal contacts of Schwann cell plated on fibrin. Taken together, these results strongly suggest that alphaVbeta8 integrin is a Schwann cell receptor for fibrin.     

Binary specification of nerve cord and notochord cell fates in ascidian embryos

In the ascidian embryo, the nerve cord and notochord of the tail of tadpole larvae originate from the precursor blastomeres for both tissues in the 32-cell-stage embryo. Each fate is separated into two daughter blastomeres at the next cleavage. We have examined mechanisms that are responsible for nerve cord and notochord specification through experiments involving blastomere isolation, cell dissociation, and treatment with basic fibroblast growth factor (bFGF) and inhibitors for the mitogen-activated protein kinase (MAPK) cascade. It has been shown that inductive cell interaction at the 32-cell stage is required for notochord formation. Our results show that the nerve cord fate is determined autonomously without any cell interaction. Presumptive notochord blastomeres also assume a nerve cord fate when they are isolated before induction is completed. By contrast, not only presumptive notochord blastomeres but also presumptive nerve cord blastomeres forsake their default nerve cord fate and choose the notochord fate when they are treated with bFGF. When the FGF-Ras-MAPK signaling cascade is inhibited, both blastomeres choose the default nerve cord pathway, supporting the results of blastomere isolation. Thus, binary choice of alternative fates and asymmetric division are involved in this nerve cord/notochord fate determination system, mediated by FGF signaling.     

Formation of segregated regions of feature detecting cells in self-organizing nerve field

This paper investigates the formation of a segregated region for a specific set of input signals in a nerve field. The segregated region is formed by a feature detecting cell group which fires only for a specific set of input signals. This firing region is called the region of feature detecting cells for the corresponding input set. First, a basic self-organizing model is given. The model is composed of the first input layer, the second nerve cell layer with lateral inhibitory interactions (it is called a lateral-inhibition type nerve field) and an inhibitory nerve cell. An input signal is an-dimensional vector whose components assume continuous values. Next, the condition which gurantees the formation of a segregated region for a specific set of input signals is derived, and the properties of the model are discussed based on the derived condition. In addition, the behavior of the model is examined through computer-simulated experiments. The following observations are made: When a certain condition is satisfied, a segregated region is formed in the nerve field according to a specific set of input signals. By varying the parameters of learning, the region is formed depending on the similarity between input signals. The regions for similar input signals are formed near each other in the nerve field. The region is created depending on the occurence probability of the input signal and its norm.     

A new integrated method for analyzing heart mechanics using a cell-hemodynamics-autonomic nerve control coupled model of the cardiovascular system

A model of the cardiovascular system coupling cell, hemodynamics, and autonomic nerve control function is proposed for analyzing heart mechanics. We developed a comprehensive cardiovascular model with multi-physics and multi-scale characteristics that simulates the physiological events from membrane excitation of a cardiac cell to contraction of the human heart and systemic blood circulation and ultimately to autonomic nerve control. A lumped parameter model is used to compute the systemic and pulmonary circulations interacting with the cardiac cell mechanism. For autonomic control of the cardiovascular system, we used the approach suggested by Heldt et al. [2002. Computational modeling of cardiovascular response to orthostatic stress. J. Appl. Physiol. 92, 1239–1254] (Heldt model), including baroreflex and cardiopulmonary reflexes. We assumed sympathetic and parasympathetic pathways for the nerve control system. The cardiac muscle response to these reflex control systems was implemented using the activation-level changes in the L-type calcium channel and sarcoplasmic/endoplasmic reticulum calcium ATPase function based on experimental observations. Using this model, we delineated the cellular mechanism of heart contractility mediated by nerve control function. To verify the integrated method, we simulated a 10% hemorrhage, which involves cardiac cell mechanics, circulatory hemodynamics, and nerve control function. The computed and experimental results were compared. Using this methodology, the state of cardiac contractility, influenced by diverse properties such as the afterload and nerve control systems, is easily assessed in an integrated manner.     

The autonomic innervation of rat jugular vein

Summary The autonomic innervation of rat jugular vein was studied using glyoxylic acid fluorescence and acetylcholinesterase histochemical methods. The rat jugular vein is provided with both adrenergic and cholinergic nerve fibers organized in plexuses located at the adventitial-medial border. The existence of these nerve plexuses does not seem to support biochemical findings that suggest a lack of innervation in the rat jugular vein and which propose this blood vessel as a model for the analysis of drug-smooth muscle cell interaction without the interference of neuronal uptake mechanisms.     

Aβ ion channels. Prospects for treating Alzheimer's disease with Aβ channel blockers

The main pathological features in the Alzheimer’s brain are progressive depositions of amyloid protein plaques among nerve cells, and neurofibrillary tangles within the nerve cells. The major components of plaques are Aβ peptides. Numerous reports have provided evidence that Aβ peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the Aβ-membrane interaction event may be followed by the insertion of Aβ into the membrane in a structural configuration which forms an ion channel. This review summarizes experimental procedures which have been designed to test the hypothesis that the interaction of Aβ with a variety of membranes, both artificial and natural, results in the subsequent formation of Aβ ion channels We describe experiments, by ourselves and others, that support the view that Aβ is cytotoxic largely due to the action of Aβ channels in the cell membrane. The interaction of Aβ with the surface of the cell membrane may results in the activation of a chain of processes that, when large enough, become cytotoxic and induce cell death by apoptosis. Remarkably, the blockage of Aβ ion channels at the surface of the cell absolutely prevents the activation of these processes at different intracellular levels, thereby preserving the life of the cells. As a prospect for therapy for Alzheimer’s disease, our findings at cellular level may be testable on AD animal models to elucidate the potential role and the magnitude of the contribution of the Aβ channels for induction of the disease.     

A role for the neural cell adhesion molecule, NCAM, in myoblast interaction during myogenesis

The Ca2(+)-independent neural cell adhesion molecule, NCAM, is expressed by both nerve and muscle cells and has been shown to mediate both nerve-nerve and nerve-muscle cell interaction. A role for NCAM in muscle-muscle cell interaction has been proposed but not demonstrated. Here we report evidence that NCAM is expressed by embryonic chick muscle cells during in vitro development and functions together with Ca2(+)-dependent adhesion molecules in mediating myoblast interaction during the formation of multinucleate cells.     

A model of intracellular transport of particles in an axon

In this paper we develop a model of intracellular transport of cell organelles and vesicles along the axon of a nerve cell. These particles are moving alternately by processive motion along a microtubule with the aid of motor proteins, and by diffusion. The model involves a degenerate system of diffusion equations. We prove a maximum principle and establish existence and behavior of a unique solution. Numerical results show how the transportation of mass depends on the relevant parameters of the model.     

Regeneration of an adult peripheral nerve preparation in culture

The methods used to maintain the vagus nerve from the adult rat in culture and how regeneration is studied in this preparation are described. A hypothesis is presented on the triggering of the cell body reaction. It is suggested that this reaction is initiated by proteins synthesized in nonneuronal cells at the site of a nerve lesion. These proteins, referred to as regenerins, reach the nerve cell body by retrograde axonal transport, where they initiate the regeneration process.     

Capability of ganglioside GM1 in modulating interactions,structure, location and dynamics of peptides/proteins: biophysical approaches

Gangliosides, are glycosphingolipids, present in all vertebrate plasma membranes with particular abundance in nerve cell membrane. Gangliosides can act as portals for antimicrobial peptides, hormones, viruses, lectins, toxins and pathogens. They are strategically positioned on the outer membrane and hence can participate in a large number of recognition processes. Their abundance in nerve cell membrane makes them “likely” receptor candidates for neuropeptides. In this review we outline our work in the area of GM1-peptide/protein interaction. We have explored the effect of GM1 containing micelles/bicelles on structures of peptides, proteins as well as on denatured proteins. It has been observed that the peptides that are disordered or having random coil structure in aqueous solution, attained an ordered three-dimensional structure when interact with GM1. It is also observed that denatured proteins undergo refolding in presence of ganglioside. Peptides/proteins show stronger interaction with membrane lipid bilayer in presence of ganglioside than that without ganglioside. This review mainly focuses on capability of ganglioside GM1 in modulating interaction, structural, location and dynamics of peptides/proteins using a number of biophysical techniques–solution NMR, DOSY, CD, fluorescence etc.     

A model for non-linear processing in cat's retina

The model is based on the concept that non-linear lateral interaction at the inner plexiform layer accounts for most of the specialization and marked non-linearities in cat's retinal ganglion cell responses. The inputs to the lateral interaction processes are a spatio-temporal signal and its retarded, as suggested by the behaviour of simple ganglion cells. Lateral interaction in the model consists of lateral linear inhibition followed by local half wave rectification. The resulting signals are weighted and summated by the ganglion cell thereafter. A transparent and general expression is obtained for the response of the cell model which, albeit its simplicity, leads to most of known types of non-linear responses, including the rarely encountered specialized cells in cat's, retina, except colour coding units. For negligible lateral interaction, the model reduces to spatio-temporal linear models under the two paths hypothesis. A discussion of the possible role of anatomical units in these retinal processes in presented, where a general interpretation for visual processing in cat's retina evolves from.     

Network integration meets network dynamics

Molecular interaction networks provide a window on the workings of the cell. However, combining various types of networks into one coherent large-scale dynamic model remains a formidable challenge. A recent paper in BMC Systems Biology describes a promising step in this direction.     

Crystallization of kappa-bungarotoxin: preliminary X-ray data obtained from the venom-derived protein.

kappa-Bungarotoxin is a 66 residue polypeptide found in the venom of the Taiwanese banded krait, Bungarus multicinctus. It binds tightly to neuronal nicotinic acetylcholine receptors and inhibits nerve transmission mediated by these postsynaptic receptors. It is related, by similarity in amino acid sequence, to alpha-bungarotoxin and other alpha-neurotoxins, but differs sharply in physiologic action. The alpha-neurotoxins inhibit nerve transmission in nicotinic acetylcholine receptors associated with vertebrate skeletal muscle and fish electric organs. The kappa-neurotoxins inhibit nerve transmission in neuronal nicotinic acetylcholine receptors such as those found in chick ciliary ganglia. The kappa-neurotoxins display a low level of interaction with receptors that are strongly affected by alpha-neurotoxins, but alpha-neurotoxins are completely without effect on receptors that are affected by kappa-bungarotoxin. The structural basis for this physiologic differentiation is not known. Crystals of kappa-bungarotoxin have now been obtained that diffract to at least 2.3 A. These crystals are hexagonal, space group P6, and have dimensions of a = b = 80.2 A, c = 39.6 A, and angles of alpha = beta = 90 degrees and gamma = 120 degrees. Each unit cell contains 12 molecules of the 66 residue protein or two molecules per asymmetric unit. Comparison of the structure of kappa-bungarotoxin, which will result from further diffraction analysis of these crystals, with the structures of the alpha-neurotoxins that have been determined may provide information on the structural basis of physiologic action in these acetylcholine receptor antagonists.     

Mast Cell-Nerve Cell Interaction at Acupoint: Modeling Mechanotransduction Pathway Induced by Acupuncture

Mast cells are found abundant at sites of acupoints. Nerve cells share perivascular localization with mast cells. Acupuncture (mechanical stimuli) can activate mast cells to release adenosine triphosphate (ATP) which can activate nerve cells and modulates pain-processing pathways in response to acupuncture. In this paper, a mathematical model was constructed for describing intracellular Ca²⁺ signal and ATP release in a coupled mast cell and nerve cell system induced by mechanical stimuli. The results showed mechanical stimuli lead to a intracellular Ca²⁺ rise in the mast cell and ATP release, ATP diffuses in the extracellular space (ECS) and activates the nearby nerve cells, then induces electrical current in the nerve cell which spreads in the neural network. This study may facilitate our understanding of the mechanotransduction process induced by acupuncture and provide a methodology for quantitatively analyzing acupuncture treatment.     

Interaction of membrane skeletal proteins with membrane lipid domain

The object of this paper is to review briefly the studies on the interaction of red blood cell membrane skeletal proteins and their non-erythroid analogues with lipids in model systems as well as in natural membranes. An important question to be addressed is the physiological significance and possible regulatory molecular mechanisms in which these interactions are engaged.