Biomedical subjects

G B Ermentrout

Publications and source records attributed to G B Ermentrout.

At least 19 recordsLinked to original sources

PubMed2005

Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores.

We propose a mathematical model for mitochondria-dependent apoptosis, in which kinetic cooperativity in formation of the apoptosome is a key element ensuring bistability. We examine the role of Bax and Bcl-2 synthesis and degradation rates, as well as the number of mitochondrial permeability transition pores (MPTPs), on the cell response to apoptotic stimuli. Our analysis suggests that cooperative apoptosome formation is a mechanism for inducing bistability, much more robust than that induced by other mechanisms, such as inhibition of caspase-3 by the inhibitor of apoptosis (IAP). Simulations predict a pathological state in which cells will exhibit a monostable cell survival if Bax degradation rate is above a threshold value, or if Bax expression rate is below a threshold value. Otherwise, cell death or survival occur depending on initial caspase-3 levels. We show that high expression rates of Bcl-2 can counteract the effects of Bax. Our simulations also demonstrate a monostable (pathological) apoptotic response if the number of MPTPs exceeds a threshold value. This study supports our contention, based on mathematical modeling, that cooperativity in apoptosome formation is critically important for determining the healthy responses to apoptotic stimuli, and helps define the roles of Bax, Bcl-2, and MPTP vis-à-vis apoptosome formation.

Animals↗

PubMed2001

Bistability in pulse propagation in networks of excitatory and inhibitory populations.

We study the propagation of traveling solitary pulses in one-dimensional networks of excitatory and inhibitory integrate-and-fire neurons. Slow pulses, during which inhibitory cells fire well before neighboring excitatory cells, can propagate along the network at intermediate inhibition levels. At higher levels, they destabilize via a Hopf bifurcation. There is a bistable parameter regime in which both fast and slow pulses can propagate. Lurching pulses with spatiotemporal periodicity can propagate in regimes for which continuous pulses do not exist.

Membrane Potentials↗

PubMed2001

A model for actin-filament length distribution in a lamellipod.

A mathematical model is derived to describe the distributions of lengths of cytoskeletal actin filaments, along a 1 D transect of the lamellipod (or along the axis of a filopod) in an animal cell. We use the facts that actin filament barbed ends are aligned towards the cell membrane and that these ends grow rapidly in the presence of actin monomer as long as they are uncapped. Once a barbed end is capped, its filament tends to be degraded by fragmentation or depolymerization. Both the growth (by polymerization) and the fragmentation by actin-cutting agents are depicted in the model, which takes into account the dependence of cutting probability on the position along a filament. It is assumed that barbed ends are capped rapidly away from the cell membrane. The model consists of a system of discrete-integro-PDE's that describe the densities of barbed filament ends as a function of spatial position and length of their actin filament "tails". The population of capped barbed ends and their trailing filaments is similarly represented. This formulation allows us to investigate hypotheses about the fragmentation and polymerization of filaments in a caricature of the lamellipod and compare theoretical and observed actin density profiles.

Actins↗

PubMed2001

Traveling electrical waves in cortex: insights from phase dynamics and speculation on a computational role.

The theory of coupled phase oscillators provides a framework to understand the emergent properties of networks of neuronal oscillators. When the architecture of the network is dominated by short-range connections, the pattern of electrical output is predicted to correspond to traveling plane and rotating waves, in addition to synchronized output. We argue that this theory provides the foundation for understanding the traveling electrical waves that are observed across olfactory, visual, and visuomotor areas of cortex in a variety of species. The waves are typically present during periods outside of stimulation, while synchronous activity typically dominates in the presence of a strong stimulus. We suggest that the continuum of phase shifts during epochs with traveling waves provides a means to scan the incoming sensory stream for novel features. Experiments to test our theoretical approach are presented.

Animals↗

PubMed2000

Gamma rhythms and beta rhythms have different synchronization properties.

Experimental and modeling efforts suggest that rhythms in the CA1 region of the hippocampus that are in the beta range (12-29 Hz) have a different dynamical structure than that of gamma (30-70 Hz). We use a simplified model to show that the different rhythms employ different dynamical mechanisms to synchronize, based on different ionic currents. The beta frequency is able to synchronize over long conduction delays (corresponding to signals traveling a significant distance in the brain) that apparently cannot be tolerated by gamma rhythms. The synchronization properties are consistent with data suggesting that gamma rhythms are used for relatively local computations whereas beta rhythms are used for higher level interactions involving more distant structures.

Animals↗

PubMed2000

Models for spatial polymerization dynamics of rod-like polymers.

We investigate the polymerization kinetics of rod-like polymer filaments interacting with a distribution of monomer in one spatial dimension (e.g. along a narrow tube). We consider a variety of possible cases, including competition by the filament tips for the available monomer, and behaviour analogous to "treadmilling" in which the polymer adds subunits to one end and loses them at the other end so as to maintain a constant length. Applications to biological polymers such as actin filaments and microtubules are discussed.

Actins↗

PubMed1999

Continuous and lurching traveling pulses in neuronal networks with delay and spatially decaying connectivity.

Propagation of discharges in cortical and thalamic systems, which is used as a probe for examining network circuitry, is studied by constructing a one-dimensional model of integrate-and-fire neurons that are coupled by excitatory synapses with delay. Each neuron fires only one spike. The velocity and stability of propagating continuous pulses are calculated analytically. Above a certain critical value of the constant delay, these pulses lose stability. Instead, lurching pulses propagate with discontinuous and periodic spatio-temporal characteristics. The parameter regime for which lurching occurs is strongly affected by the footprint (connectivity) shape; bistability may occur with a square footprint shape but not with an exponential footprint shape. For strong synaptic coupling, the velocity of both continuous and lurching pulses increases logarithmically with the synaptic coupling strength g(syn) for an exponential footprint shape, and it is bounded for a step footprint shape. We conclude that the differences in velocity and shape between the front of thalamic spindle waves in vitro and cortical paroxysmal discharges stem from their different effective delay; in thalamic networks, large effective delay between inhibitory neurons arises from their effective interaction via the excitatory cells which display postinhibitory rebound.

Axons↗

PubMed1998

Dynamics of membrane excitability determine interspike interval variability: a link between spike generation mechanisms and cortical spike train statistics.

We propose a biophysical mechanism for the high interspike interval variability observed in cortical spike trains. The key lies in the nonlinear dynamics of cortical spike generation, which are consistent with type I membranes where saddle-node dynamics underlie excitability (Rinzel & Ermentrout, 1989). We present a canonical model for type I membranes, the theta-neuron. The theta-neuron is a phase model whose dynamics reflect salient features of type I membranes. This model generates spike trains with coefficient of variation (CV) above 0.6 when brought to firing by noisy inputs. This happens because the timing of spikes for a type I excitable cell is exquisitely sensitive to the amplitude of the suprathreshold stimulus pulses. A noisy input current, giving random amplitude "kicks" to the cell, evokes highly irregular firing across a wide range of firing rates; an intrinsically oscillating cell gives regular spike trains. We corroborate the results with simulations of the Morris-Lecar (M-L) neural model with random synaptic inputs: type I M-L yields high CVs. When this model is modified to have type II dynamics (periodicity arises via a Hopf bifurcation), however, it gives regular spike trains (CV below 0.3). Our results suggest that the high CV values such as those observed in cortical spike trains are an intrinsic characteristic of type I membranes driven to firing by "random" inputs. In contrast, neural oscillators or neurons exhibiting type II excitability should produce regular spike trains.

Algorithms↗

PubMed1998

Spike frequency adaptation affects the synchronization properties of networks of cortical oscillations.

Oscillations in many regions of the cortex have common temporal characteristics with dominant frequencies centered around the 40 Hz (gamma) frequency range and the 5-10 Hz (theta) frequency range. Experimental results also reveal spatially synchronous oscillations, which are stimulus dependent (Gray & Singer, 1987; Gray, Konig, Engel, & Singer, 1989; Engel, Konig, Kreiter, Schillern, & Singer, 1992). This rhythmic activity suggests that the coherence of neural populations is a crucial feature of cortical dynamics (Gray, 1994). Using both simulations and a theoretical coupled oscillator approach, we demonstrate that the spike frequency adaptation seen in many pyramidal cells plays a subtle but important role in the dynamics of cortical networks. Without adaptation, excitatory connections among model pyramidal cells are desynchronizing. However, the slow processes associated with adaptation encourage stable synchronous behavior.

Action Potentials↗

PubMed1998

Fine structure of neural spiking and synchronization in the presence of conduction delays.

Hippocampal networks of excitatory and inhibitory neurons that produce gamma-frequency rhythms display behavior in which the inhibitory cells produce spike doublets when there is strong stimulation at separated sites. It has been suggested that the doublets play a key role in the ability to synchronize over a distance. Here we analyze the mechanisms by which timing in the spike doublet can affect the synchronization process. The analysis describes two independent effects: one comes from the timing of excitation from separated local circuits to an inhibitory cell, and the other comes from the timing of inhibition from separated local circuits to an excitatory cell. We show that a network with both of these effects has different synchronization properties than a network with either excitatory or inhibitory type of coupling alone, and we give a rationale for the shorter space scales associated with inhibitory interactions.

Brain Mapping↗

PubMed1998

Models for the length distributions of actin filaments: I. Simple polymerization and fragmentation.

We studied mathematical models for the length distributions of actin filaments under the effects of polymerization/depolymerization, and fragmentation. In this paper, we emphasize the effects of these two processes acting alone. In this case, simple discrete and continuous models can be derived and solved explicitly (in several special cases), making the problem interesting from a modeling and pedagogical point of view. In a companion paper (Ermentrout and Edelstein-Keshet, 1998, Bull. Math. Biol. 60, 477-503) we investigate what happens when the processes act together, with particular attention to fragmentation by gelsolin, and with a greater level of biological detail.

Actins↗

PubMed1998

Models for the length distributions of actin filaments: II. Polymerization and fragmentation by gelsolin acting together.

In a previous paper, we studied elementary models for polymerization, depolymerization, and fragmentation of actin filaments (Edelstein-Keshet and Ermentrout, 1988, Bull. Math. Biol. 60, 449-475). When these processes act together, more complicated dynamics occur. We concentrate on a particular case study, using the actin-fragmenting protein gelsolin. A set of biological parameter values (drawn from the experimental literature) is used in computer simulations of the kinetics of gelsolin-mediated actin filament fragmentation.

Actins↗

PubMed1998

Dendritic and synaptic effects in systems of coupled cortical oscillators.

We explore the influence of synaptic location and form on the behavior of networks of coupled cortical oscillators. First, we develop a model of two coupled somatic oscillators that includes passive dendritic cables. Using a phase model approach, we show that the synchronous solution can change from a stable solution to an unstable one as the cable lengthens and the synaptic position moves further from the soma. We confirm this prediction using a system of coupled compartmental models. We also demonstrate that when the synchronous solution becomes unstable, a bifurcation occurs and a pair of asynchronous stable solutions appear, causing a phase lag between the cells in the system. Then using a variety of coupling functions and different synaptic positions, we show that distal connections and broad synaptic time courses encourage phase lags that can be reduced, eliminated, or enhanced by the presence of active currents in the dendrite. This mechanism may appear in neural systems where proximal connections could be used to encourage synchrony, and distal connections and broad synaptic time courses could be used to produce phase lags that can be modulated by active currents.

Dendrites↗

PubMed1997

A model of ocular dominance column development by competition for trophic factor.

Recent experimental evidence has shown that application of certain neurotrophic factors (NTs) to the developing primary visual cortex prevents the development of ocular dominance (OD) columns. One interpretation of this result is that afferents from the lateral geniculate nucleus compete for postsynaptic trophic factor in an activity-dependent manner. Application of excess trophic factor eliminates this competition, thereby preventing OD column formation. We present a model of OD column development, incorporating Hebbian synaptic modification and activity-driven competition for NT, which accounts for both normal OD column development as well as the prevention of that development when competition is removed. In the "control" situation, when available NT is below a critical amount, OD columns form normally. These columns form without weight normalization procedures and in the presence of positive inter-eye correlations. In the "experimental" case, OD column development is prevented in a local neighborhood in which excess NT has been added. Our model proposes a biologically plausible mechanism for competition between neural populations that is motivated by several pieces of experimental data, thereby accounting for both normal and experimentally perturbed conditions.

Animals↗

PubMed1997

The role of axonal delay in the synchronization of networks of coupled cortical oscillators.

Coupled oscillator models use a single phase variable to approximate the voltage oscillation of each neuron during repetitive firing where the behavior of the model depends on the connectivity and the interaction function chosen to describe the coupling. We introduce a network model consisting of a continuum of these oscillators that includes the effects of spatially decaying coupling and axonal delay. We derive equations for determining the stability of solutions and analyze the network behavior for two different interaction functions. The first is a sine function, and the second is derived from a compartmental model of a pyramidal cell. In both cases, the system of coupled neural oscillators can undergo a bifurcation from synchronous oscillations to waves. The change in qualitative behavior is due to the axonal delay, which causes distant connections to encourage a phase shift between cells. We suggest that this mechanism could contribute to the behavior observed in several neurobiological systems.

Axons↗

PubMed1996

A quantitative population model of whisker barrels: re-examining the Wilson-Cowan equations.

Beginning from a biologically based integrate and fire model of a rat whisker barrel, we employ semirigorous techniques to reduce the system to a simple set of equations, similar to the Wilson-Cowan equations, while retaining the ability for both qualitative and quantitative comparisons with the biological system. This is made possible through the clarification of three distinct measures of population activity: voltage, firing rate, and a new term called synaptic drive. The model is activated by prerecorded neural activity obtained from thalamic "barreloid" neurons in response to whisker stimuli. Output is produced in the form of population PSTHs, one each corresponding to activity of spiny (excitatory) and smooth (inhibitory) barrel neurons, which is quantitatively comparable to PSTHs from electrophysiologically studied regular-spike and fast-spike neurons. Through further analysis, the model yields novel physiological predictions not readily apparent from the full model or from experimental studies.

Animals↗

PubMed1996

Selecting a common direction. II. Peak-like solutions representing total alignment of cell clusters.

The problem of alignment of cells (or other objects) that interact in an angle-dependent way was described in Mogilner and Edelstein-Keshet (1995). In this sequel we consider in detail a special limiting case of nearly complete alignment. This occurs when the rotational diffusion of individual objects becomes very slow. In this case, the motion of the objects is essentially deterministic, and the individuals or objects tend to gather in clusters at various orientations. (Numerical solutions show that the angular distribution develops sharp peaks at various discrete orientations.) To understand the behaviour of the deterministic models with analytic tools, we represent the distribution as a number of delta-like peaks. This approximation of a true solution by a set of (infinitely sharp) peaks will be referred to as the peak ansatz. For weak but nonzero angular diffusion, the peaks are smoothed out. The analysis of this case leads to a singular perturbation problem which we investigate. We briefly discuss other applications of similar techniques.

Animals↗

PubMed1994

When inhibition not excitation synchronizes neural firing.

Excitatory and inhibitory synaptic coupling can have counter-intuitive effects on the synchronization of neuronal firing. While it might appear that excitatory coupling would lead to synchronization, we show that frequently inhibition rather than excitation synchronizes firing. We study two identical neurons described by integrate-and-fire models, general phase-coupled models or the Hodgkin-Huxley model with mutual, non-instantaneous excitatory or inhibitory synapses between them. We find that if the rise time of the synapse is longer than the duration of an action potential, inhibition not excitation leads to synchronized firing.

Action Potentials↗