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M R Bennett

Publications and source records attributed to M R Bennett.

At least 19 recordsLinked to original sources
PubMed2005

A quantitative model of purinergic junctional transmission of calcium waves in astrocyte networks.

A principal means of transmitting intracellular calcium (Ca2+) waves at junctions between astrocytes involves the release of the chemical transmitter adenosine triphosphate (ATP). A model of this process is presented in which activation of purinergic P2Y receptors by ATP triggers the release of ATP, in an autocrine manner, as well as concomitantly increasing intracellular Ca2+. The dependence of the temporal characteristics of the Ca2+ wave are shown to critically depend on the dissociation constant (K(R)) for ATP binding to the P2Y receptor type. Incorporating this model astrocyte into networks of these cells successfully accounts for many of the properties of propagating Ca2+ waves, such as the dependence of velocity on the type of P2Y receptor and the time-lag of the Ca2+ wave behind the ATP wave. In addition, the conditions under which Ca2+ waves may jump from one set of astrocytes across an astrocyte-free lane to another set of astrocytes are quantitatively accounted for by the model. The properties of purinergic transmission at astrocyte junctions may determine many of the characteristics of Ca2+ propagation in networks of these cells.

Action Potentials↗
PubMed2005

A quantitative description of the contraction of blood vessels following the release of noradrenaline from sympathetic varicosities.

A model is presented that highlights the principal factors determining the form and extent of contraction in arteries upon stimulation of their sympathetic nerve supply. This model incorporates a previous quantitative model of the process of noradrenaline (NAd) diffusion into the vascular media and reuptake into sympathetic varicosities during nerve stimulation (J. Theor. Biol. 226 (2004) 359). It is also dependent on a model of how the subsequent activation of metabotropic receptors initiates a G-protein cascade, resulting in the production of inositol trisphosphate (IP3) and an increase in intracellular calcium concentration, [Ca2+]i, in the smooth muscle cells (J. Theor. Biol. 223 (2003) 93). In the present work we couple this rise in [Ca2+]i to the increase in phosphorylated myosin bound to actin in the cells and hence determine the force development in arteries due to nerve stimulation. The model accounts for force development as a function of [Ca2+]i and for the rate of change of force as a function of the rate of change of [Ca2+]i in single smooth muscle cells. It also accounts for the characteristic time course of the force developed by the media of the rat-tail artery upon nerve stimulation. This consists of a rapid rise to a transient peak followed by a sustained plateau of contraction during the stimulation period, after which the contraction slowly decays back to baseline at a rate dependent on the strength of the stimulation. The model indicates that the transient peak is primarily due to the partial block of the IP3 receptor by the rise in [Ca2+]i and that the main determinant of the equilibrium condition indicated by the plateau phase is the rate of pumping of calcium into the sarcoplasmic reticulum. The relatively slow decline of contraction at the end of nerve stimulation is primarily a consequence of the slow rates of removal of NAd from the media by diffusion and reuptake into the sympathetic varicosities. The model thus provides a quantitative account of vascular smooth muscle contraction upon sympathetic nerve stimulation.

Arteries↗
PubMed2005

Varicosity-Schwann cell interactions mediated by ATP in the mouse vas deferens.

Schwann cells, from a variety of sources, are known to possess P2Y purinergic metabotropic receptors. However, it is not known if Schwann cells associated with autonomic nerve terminals possess such receptors and if so whether these receptors are activated by the endogenous release of ATP from the nerve terminals. We show that such Schwann cells in the vas deferens give evoked calcium transients on nerve stimulation. These transients are mediated, at least in part, by the endogenous release of ATP, which acts on Schwann cell P2Y receptors to release calcium from within the cells. This work suggests the possibility that Schwann cells are active participants in the process of junctional transmission in the autonomic nervous system.

Adenosine Triphosphate↗
PubMed2005

Emotion and cortical-subcortical function: conceptual developments.

Biologists have studied the expression of emotions in man and other animals since at least 1806, when Charles Bell published his Anatomy and Physiology of Expression. We trace the main experimental developments since that time, including Darwin's investigations into the evolution of innate forms of expression of emotions, as well as those into cognitive versus precognitive forms of expression of emotions. In particular, contemporary studies by neuroscientists into the origins of emotional experiences are detailed, especially emotional responses to faces showing different expressions, on which much research has been carried out. We examine the various claims made by these researchers as to what their experiments show. Our conceptual analysis indicates that there is considerable confusion as to what experimental work to this time indicates about the role of cortical and subcortical structures in the expression of emotions. We attempt to clarify what can and cannot be justified as established concerning the workings of the brain and emotions.

Amygdala↗
PubMed2004

Calcium mobilization and spontaneous transient outward current characteristics upon agonist activation of P2Y2 receptors in smooth muscle cells.

A quantitative model is provided that links the process of metabotropic receptor activation and sequestration to the generation of inositol 1,4,5-trisphosphate, the subsequent release of calcium from the central sarcoplasmic reticulum, and the consequent release of calcium from subsarcolemma sarcoplasmic reticulum that acts on large-conductance potassium channels to generate spontaneous transient outward currents (STOCs). This model is applied to the case of STOC generation in vascular A7r5 smooth muscle cells that have been transfected with a chimera of the P2Y(2) metabotropic receptor and green fluorescent protein (P2Y(2)-GFP) and exposed to the P2Y(2) receptor agonist uridine 5'-triphosphate. The extent of P2Y(2)-GFP sequestration from the membrane on exposure to uridine 5'-triphosphate, the ensuing changes in cytosolic calcium concentration, as well as the interval between STOCs that are subsequently generated, are used to determine parameter values in the model. With these values, the model gives a good quantitative prediction of the dynamic changes in STOC amplitude observed upon activation of metabotropic P2Y(2) receptors in the vascular smooth muscle cell line.

Animals↗
PubMed2004

A quantitative description of the diffusion of noradrenaline in the media of blood vessels following its release from sympathetic varicosities.

A quantitative model is provided which describes how noradrenaline (NAd), released from varicosities at the adventitial surface of an artery, either diffuses into the media of the vessel to reach the intimal surface, diffuses into the volume of solution surrounding the artery, or is removed by the uptake 1 process in the varicosities. These predictions are then compared with experimental evaluations of the extent of changes in NAd to be found at the adventitial and intimal surfaces of the rat-tail artery, during and after trains of impulses, as determined using amperometry. In the model of the blood vessel there is a sequential decrease in the diffusion constant of NAd from the surrounding solution, to the adventitia, to the media, to the endothelium, to rise again in the lumen of the vessel; there is also an uptake 1 NAd pump in the varicosities described by Michaelis-Menten kinetics. This model is shown to provide a quantitative account of the spatial and temporal changes in NAd observed following trains of impulses at different frequencies of stimulation (5-40 Hz) for different periods of times (10-40 s). Changes in the spatio-temporal distribution of NAd observed following block of the uptake 1 NAd pump were also successfully predicted by the model. It is concluded that, within the context of the model, there is no need to evoke special mechanisms of buffering at the sympathetic varicosities, nor distinctions on the basis that only secreting varicosities utilize the uptake 1 mechanism, in order to describe the dynamics of NAd distribution in arteries during nerve activity.

Animals↗
PubMed2004

The facilitated probability of quantal secretion within an array of calcium channels of an active zone at the amphibian neuromuscular junction.

A Monte Carlo analysis has been made of the phenomenon of facilitation, whereby a conditioning impulse leaves nerve terminals in a state of heightened release of quanta by a subsequent test impulse, this state persisting for periods of hundreds of milliseconds. It is shown that a quantitative account of facilitation at the amphibian neuromuscular junction can be given if the exocytosis is triggered by the combined action of a low-affinity calcium-binding molecule at the site of exocytosis and a high-affinity calcium-binding molecule some distance away. The kinetic properties and spatial distribution of these molecules at the amphibian neuromuscular junction are arrived at by considering the appropriate values that the relevant parameters must take to successfully account for the experimentally observed amplitude and time course of decline of F1 and F2 facilitation after a conditioning impulse, as well as the growth of facilitation during short trains of impulses. This model of facilitation correctly predicts the effects on facilitation of exogenous buffers such as BAPTA during short trains of impulses. In addition, it accounts for the relative invariance of the kinetics of quantal release due to test-conditioning sequences of impulses as well as due to change in the extent of calcium influx during an impulse.

Amphibians↗
PubMed2003

Metabotropic receptor activation, desensitization and sequestration-I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation.

A mathematical account is given of the processes governing the time courses of calcium ions (Ca2+), inositol 1,4,5-trisphosphate (IP(3)) and phosphatidylinositol 4,5-bisphosphate (PIP(2)) in single cells following the application of external agonist to metabotropic receptors. A model is constructed that incorporates the regulation of metabotropic receptor activity, the G-protein cascade and the Ca2+ dynamics in the cytosol. It is subsequently used to reproduce observations on the extent of desensitization and sequestration of the P(2)Y(2) receptor following its activation by uridine triphosphate (UTP). The theory predicts the dependence on agonist concentration of the change in the number of receptors in the membrane as well as the time course of disappearance of receptors from the plasmalemma, upon exposure to agonist. In addition, the extent of activation and desensitization of the receptor, using the calcium transients in cells initiated by exposure to agonist, is also predicted. Model predictions show the significance of membrane PIP(2) depletion and resupply on the time course of IP(3) and Ca2+ levels. Results of the modelling also reveal the importance of receptor recycling and PIP(2) resupply for maintaining Ca2+ and IP(3) levels during sustained application of agonist.

Animals↗
PubMed2003

Metabotropic receptor activation, desensitization and sequestration-II: modelling the dynamics of the pleckstrin homology domain.

Recent observations have been made regarding the generation of inositol 1,4,5-trisphosphate (IP(3)), using chimeras of green fluorescent protein and the pleckstrin homology domain of phospholipase C-delta. In this paper a model is presented giving the quantitative relations between the green fluorescent protein-pleckstrin homology domain (GFP-PHD) construct and membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) levels as well as the concentration of IP(3), the product of hydrolysis of PIP(2). The model can correctly reproduce the dependence of cytosolic GFP-PHD fluorescence on IP(3) concentration. This model extends a previous one (Metabotropic receptor activation, desensitization and sequestration-I: modelling calcium and inositol 1,4,5-trisphosphate dynamics following receptor activation, in this issue) dealing with the processes governing the production of IP(3) and the subsequent calcium (Ca2+) changes in cells following activation of metabotropic receptors. This model is applied to the case of purinergic P(2)Y(2) receptor activation in Madin-Darby Canine Kidney (MDCK) cells with adenosine triphosphate (ATP) (Science 284 (1999) 1527). It is shown that it can correctly reproduce the dependence of GFP-PHD fluorescence on the concentration of P(2)Y(2) receptor ligand, as well as the temporal changes of GFP-PHD fluorescence following application of ligand.

Adenosine Triphosphate↗
PubMed2003

[3H]-thymidine labelling of DNA triggers apoptosis potentiated by E1A-adenoviral protein.

[(3)H]-thymidine is commonly used to analyze the accumulation of [(3)H]-labeled chromatin fragments in cells undergoing apoptosis. This study shows that [(3)H]-thymidine incorporation within DNA is sufficient per se to inhibit growth and to induce apoptosis in canine kidney epithelial cells and porcine aorta endothelial cells. Despite high-level [(3)H]-thymidine-DNA labeling, rat vascular smooth muscle cells (VSMC) showed only modest inhibition of growth and induction of apoptosis compared to other cell types. Similarly to serum deprivation, apoptosis triggered by [(3)H]-thymidine labeling was sharply potentiated by VSMC transfection with a functional analogue of c-myc, E1A-adenoviral protein (VSMC-E1A), and was suppressed by stimulation of cAMP signaling with forskolin as well as by and Na/K pump inhibition with ouabain. Both apoptosis induction and growth suppression seen in [(3)H]-thymidine-treated VSMC-E1A were reduced by the pan-caspase inhibitor z-VAD.fmk. Thus, our results show that the differential efficiency of the apoptotic machinery determines cell type-specific attenuation of growth in cells with [(3)H]-thymidine-labeled DNA. They also demonstrate that [(3)H]-thymidine-treated and serum-deprived VSMC employ common intermediates of the apoptotic machinery, including steps that are potentiated by E1A-adenoviral protein and inhibited by activation of cAMP signaling as well as by inversion of the intracellular [Na(+)](i)/[K(+)](i) ratio.

Adenovirus E1A Proteins↗
PubMed2003

Schwann cell dynamics with respect to newly formed motor-nerve terminal branches on mature (Bufo marinus) muscle fibers.

A study has been made of the formation of synaptic terminals from long processes formed at the end of motor nerve branches of endplates in mature amphibian (Bufo marinus) muscle. Injection of fluorescent dyes into individual motor axons showed the full extent of their branches at single endplates. Synaptic vesicle clusters at these branches were identified with styryl dyes. Some terminal branches consisted of well separated varicosities, each possessing a cluster of functioning synaptic vesicles whilst others formed by the same axon consisted of closely spaced clusters of vesicles in a branch of approximately uniform diameter. All the varicosities gave rise to calcium transients on stimulation of their parent axon. Both types of branches sometimes possessed short processes (<5 microm long) or very long thin processes (>10 microm long) which ended in a bulb that possessed a functional synaptic vesicle cluster. These thin processes could move and form a varicosity along their length in less than 30 min. Injection of a fluorescent dye into terminal Schwann cells (TSCs) at an endplate showed that they also possessed very long thin processes (>10 microm long) which could move over relatively short times (<30 min). Injecting fluorescent dyes into both axons and their associated TSCs showed that on some occasions long TSC processes were accompanied by a long nerve terminal process and at other times they were not. It is suggested that the mature motor-nerve terminal is a dynamic structure in which the formation of processes by TSCs guides nerve terminal sprouting.

Animals↗
PubMed2002

Potential fields in vascular smooth muscle generated by transmitter release from sympathetic varicosities.

A quantitative model is provided of how current flow occurs in the media of blood vessels upon the release of transmitter from autonomic varicosities onto ionotropic receptors located on smooth muscle cells at the adventitial surface of the vessel. In particular, the extent to which potential generated in cells at the adventitial surface (AS) conducts through to cells at the intimal surface (IS) is investigated. Experimental tests of the model have been made for the case of the rat tail artery. The model of the media is an extension of the discrete bidomain syncytium to the case where the smooth muscle syncytium is bounded on two sides by a volume conductor, as is the case with the media of blood vessels. The amplitudes and temporal characteristics of excitatory junction potentials (EJPs), recorded throughout this syncytium following the release of ATP from varicosities located on one side of the syncytium, are predicted by the theory. Current injection into a single cell at the AS will not give rise to a detectable membrane potential at the IS; however, simultaneous injection of current into all the cells at the AS can give rise to a membrane potential at the IS that has an amplitude of about 50% of that at the AS, in agreement with experimental findings. In addition, the effects of perturbing the electrical couplings between cells in the syncytium on the EJPs recorded at different sites in the syncytium are also predicted. This work shows that the discrete bidomain model of the syncytium gives a quantitative description of the current and potential fields that occur throughout the smooth muscle of the media of blood vessels following the release of transmitter from varicosities at the adventitial surface of the vessels. The theory can be applied to the media of blood vessels of any size to determine the relative effectiveness of sympathetic nerves in controlling the excitability of smooth muscle cells through the media.

Action Potentials↗
PubMed2002

Quantal current fields around individual boutons in sympathetic ganglia.

The release of a quantum of neurotransmitter from an active zone of a bouton is accompanied by the flow of extracellular current that creates a potential field about the site of transmitter action beneath the bouton. It is shown theoretically that the density of the field at the peak of the quantal current gives rise to an extracellular potential that declines to values of less than 5 microV at 1.3 microm distance in the circumferential direction around the neuron and equally rapidly in the radial direction away from the neuron. A loose-patch electrode placed over a bouton distorts the quantal field about the bouton and calculations show that under current-clamp conditions, potentials of over 40 microV can be recorded with an electrode of tip diameter 2 microm, provided the separation between the tip and the neuron's surface is about 0.1 microm. Quantal release recorded from visualized boutons on rat monopolar pelvic ganglion cells with loose-patch electrodes is in agreement with the properties of the quantal potential field given in the theoretical analysis.

Animals↗
PubMed2002

The motor system in neuroscience: a history and analysis of conceptual developments.

Neuroscientific reflection on the integrative action of the nervous system was dominated by consideration of the motor system from the time of Aristotle in the 4th century B.C. to that of Sherrington, his contemporaries and proteges in the first-half of the 20th century. We describe the significant discoveries concerning the action of the spinal cord and cortex in motor phenomena during this period. This provides a vivid account of how great neuroscientists, over a period of more than 2000 years, have endeavoured to clarify notions concerning the integrative action of the nervous system in the context of the prevailing philosophical traditions of their times. We examine these traditions as well as the conceptual schemes offered by neuroscientists, especially in relation to the workings of the cortex. It is shown that neuroscientists cleave to this day to a tradition that goes back to Descartes, and that this is the case even for those who explicitly claim to reject such a tradition. The review concludes with what we take to be an appropriate basis for rejecting the Cartesian paradigm that we hope will assist neuroscientists in understanding the integrative action of the nervous system.

Animals↗
PubMed2001

Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling.

Apoptosis of vascular smooth muscle cells (VSMCs) is increased in atherosclerosis compared with normal vessels, where it may contribute to plaque rupture. We have previously found that human plaque-derived VSMCs (pVSMCs) are intrinsically sensitive to apoptosis and not responsive to the protective effects of insulin-like growth factor-1 (IGF-1). We therefore examined the mechanism underlying this defect. Human pVSMCs showed <25% (125)I-IGF-1 surface binding, <20% IGF-1 receptor (IGF-1R) expression than that of normal medial VSMCs, and <40% Akt kinase activity in response to IGF-1. pVSMCs expressed and secreted high levels of IGF-1 binding proteins (IGFBPs), and the IGF-1 analogues, long R3 and Des 1,3 IGF-1, which do not bind to IGFBPs, were able to increase pVSMC survival to normal medial VSMC levels. The long R3 survival effect was phosphatidylinositol 3-kinase-mediated, but it was not dependent on Akt activity alone. Intimal pVSMCs in vivo showed reduced IGF-1R expression compared with medial VSMCs, in particular at the shoulder regions of plaques. We conclude that human pVSMCs show an intrinsic sensitivity to apoptosis caused in part by defective expression of IGF-1R, impaired IGF-1-mediated survival signaling and increased IGFBP secretion. This impaired IGF-1 protection against apoptosis may promote VSMC loss and plaque instability in atherosclerosis.

Androstadienes↗