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PubMed2001

Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible.

Xenopus oocyte maturation is an example of an all-or-none, irreversible cell fate induction process. In response to a submaximal concentration of the steroid hormone progesterone, a given oocyte may either mature or not mature, but it can exist in intermediate states only transiently. Moreover, once an oocyte has matured, it will remain arrested in the mature state even after the progesterone is removed. It has been hypothesized that the all-or-none character of oocyte maturation, and some aspects of the irreversibility of maturation, arise out of the bistability of the signal transduction system that triggers maturation. The bistability, in turn, is hypothesized to arise from the way the signal transducers are organized into a signaling circuit that includes positive feedback (which makes it so that the system cannot rest in intermediate states) and ultrasensitivity (which filters small stimuli out of the feedback loop, allowing the system to have a stable off-state). Here we review two simple graphical methods that are commonly used to analyze bistable systems, discuss the experimental evidence for bistability in oocyte maturation, and suggest that bistability may be a common means of producing all-or-none responses and a type of biochemical memory. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed2006

Understanding bistability in complex enzyme-driven reaction networks.

Much attention has been paid recently to bistability and switch-like behavior that might be resident in important biochemical reaction networks. There is, in fact, a great deal of subtlety in the relationship between the structure of a reaction network and its capacity to engender bistability. In common physicochemical settings, large classes of extremely complex networks, taken with mass action kinetics, cannot give rise to bistability no matter what values the rate constants take. On the other hand, bistable behavior can be induced in those same settings by certain very simple and classical mass action mechanisms for enzyme catalysis of a single overall reaction. We present a theorem that distinguishes between those mass action networks that might support bistable behavior and those that cannot. Moreover, we indicate how switch-like behavior results from a well-studied mechanism for the action of human dihydrofolate reductase, an important anti-cancer target.

Enzyme Stability↗
PubMed2006

Bistability from double phosphorylation in signal transduction. Kinetic and structural requirements.

Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.

Animals↗
PubMed1989

Bistable firing properties of soleus motor units in unrestrained rats.

EMG recordings from single motor units in the soleus muscle were performed in alert unrestrained rats. A cuff electrode around the tibial nerve and subcutaneously placed electrodes in the foot permitted stimulation of afferent fibres. The movements of the rat and the simultaneous EMG activity were displayed together on a video monitor. Most motor units were tonically active for extended periods during quiet standing. During tonic discharge, maintained shifts between stable low (8-12 Hz; quartiles) and high (16-22.8 Hz) frequency ranges were initiated by short-lasting synaptic excitation of the motoneuron pool by stimulation of Ia afferents, or inhibition by stimulation of skin afferents. The shifts were not related to gross limb movements. This phenomenon is referred to as a bistable firing pattern. Bistable firing also occurred spontaneously during quiet standing. Typically the firing frequency shifted between a low (9-12.5 Hz) and a high (20-24.5 Hz) mode. During recordings of simultaneous activity in two units, spontaneous and stimulus-induced frequency jumps causing maintained changes in firing frequency were regularly seen to occur in one unit, while the frequency in the second unit was unchanged or only phasically influenced. These results demonstrate for the first time a bistable firing pattern during postural activity in the intact animal. The firing pattern closely resembles the bistable behaviour described in spinal motoneurons in reduced preparations, where it is due to the presence of a plateau potential. This suggests that the bistable firing is unexplained by plateau potentials also in the intact animal.

Action Potentials↗
PubMed2002

Effects of chloride transport on bistable behaviour of the membrane potential in mouse skeletal muscle.

The lumbrical skeletal muscle fibres of mice exhibited electrically bistable behaviour due to the nonlinear properties of the inwardly rectifying potassium conductance. When the membrane potential (V(m)) was measured continuously using intracellular microelectrodes, either a depolarization or a hyperpolarization was observed following reduction of the extracellular potassium concentration (K+o) from 5.7 mM to values in the range 0.76-3.8 mM, and V(m) showed hysteresis when K+o was slowly decreased and then increased within this range. Hypertonicity caused membrane depolarization by enhancing chloride import through the Na+-K+-2Cl- cotransporter and altered the bistable behaviour of the muscle fibres. Addition of bumetanide, a potent inhibitor of the Na+-K+-2Cl- cotransporter, and of anthracene-9-carboxylic acid, a blocker of chloride channels, caused membrane hyperpolarization particularly under hypertonic conditions, and also altered the bistable behaviour of the cells. Hysteresis loops shifted with hypertonicity to higher K+o values and with bumetanide to lower values. The addition of 80 microM BaCl2 or temperature reduction from 35 to 27 degrees C induced a depolarization of cells that were originally hyperpolarized. In the K+o range of 5.7-22.8 mM, cells in isotonic media (289 mmol x kg(-1)) responded nearly Nernstianly to K+o reduction, i.e. 50 mV per decade; in hypertonic media this dependence was reduced to 36 mV per decade (319 mmol x kg(-1)) or to 31 mV per decade (340 mmol x kg(-1)). Our data can explain apparent discrepancies in DeltaV(m) found in the literature. We conclude that chloride import through the Na+-K+-2Cl- cotransporter and export through Cl- channels influenced the V(m) and the bistable behaviour of mammalian skeletal muscle cells. The possible implication of this bistable behaviour in hypokalaemic periodic paralysis is discussed.

Animals↗
PubMed2005

Bistable behavior originating in the axon of a crustacean motor neuron.

Both vertebrate and invertebrate motor neurons can display bistable behavior in which self-sustained tonic firing results from a brief excitatory stimulus. Induction of the bistability is usually dependent on activation of intrinsic conductances located in the somatodendritic area and is commonly sensitive to action of neuromodulators. We have observed bistable behavior in a neuromuscular preparation from the foregut of the crab Cancer borealis that consists of the gastric mill 4 (gm4) muscle and the nerve that innervates it, the dorsal gastric nerve (dgn). Nerve-evoked contractions of enhanced amplitude and long duration (>30 s) were induced by extracellular stimulation when the stimulus voltage was above a certain threshold. Intracellular and extracellular recordings showed that the large contractions were accompanied by persistent firing of the dorsal gastric (DG) motor neuron that innervates gm4. The persistent firing could be induced only by stimulating a specific region of the axon and could not be triggered by depolarizing the soma, even at current amplitudes that induced high-frequency firing of the neuron. The bistable behavior was abolished in low-Ca2+ saline or when nicardipine or flufenamic acid, blockers of L-type Ca2+ and Ca2+-activated nonselective cation currents, respectively, was applied to the axonal stimulation region of the dgn. Negative immunostaining for synapsin and synaptotagmin argued against the presence of synaptic/modulatory neuropil in the dgn. Collectively, our results suggest that bistable behavior in a motor neuron can originate in the axon and may not require the action of a locally released neuromodulator.

Action Potentials↗
PubMed1998

Ionic basis for serotonin-induced bistable membrane properties in guinea pig trigeminal motoneurons.

Intracellular recordings and pharmacological manipulations were employed to investigate the ionic basis for serotonin-induced bistable membrane behaviors in guinea pig trigeminal motoneurons (TMNs). In voltage clamp, 10 microM serotonin (5-HT) induced a region of negative slope resistance (NSR) in the steady-state current-voltage (I-V) relationship at potentials less negative than -58 mV, creating the necessary conditions for membrane bistability. The contributions of sustained Na+ and Ca2+ currents to the generation of the NSR were investigated using specific ion channel antagonists and agonists. The NSR was eliminated by the L-type Ca2+ channel antagonist nifedipine (5-10 microM), indicating the contribution of L channels. In nifedipine, inward rectification was present in the I-V relationship in a similar voltage range (greater than -58 mV). This region was subsequently linearized by tetrodotoxin (TTX), indicating the presence of a persistent Na+ current. When the 5-HT-induced NSR was eliminated by perfusion in low Ca2+ solution (0.4 mM), it was restored by the Na+ channel agonist veratridine (10 microM). Commensurate with bistability, in current clamp during bath application of 5-HT, plateau potentials were elicited by transient depolarizing or hyperpolarizing stimuli. Plateau potentials evoked by depolarization were observed under control and TTX conditions, but were blocked by nifedipine, suggesting the participation of an L-type Ca2+ current. Plateau potentials initiated after release from hyperpolarization (anode break) were blocked by 300 microM Ni2+, suggesting the responses relied on deinactivation of a T-type Ca2+ current. Conditional bursting was also observed in 5-HT. Nifedipine or low Ca2+ solutions blocked bursting, and the L-channel agonist Bay K 8644 (10 microM) extended the duration of individual bursts, demonstrating the role of L-type Ca2+ currents. Interestingly, when bursting was blocked by nifedipine or low Ca2+, it could be restored by veratridine application via enhancement of the persistent Na+ current. We conclude that bistable membrane behaviors in TMNs are mediated by L-type Ca2+ and persistent Na+ currents. 5-HT is associated with enhancement of TMN activity during oral-motor activity; the induction of bistable membrane properties by 5-HT represents a cellular mechanism for this enhancement.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

Do variables that affect similar bistable apparent-movement displays result in similar changes in perception?

Two bistable apparent-movement displays (i.e. ones that generate two qualitatively different kinds of movement percepts under different conditions) were compared. They were designed to be as similar as possible spatially, and were studied with identical stimulus manipulations to see whether changes in balance between their bistable percepts would be similar. Results show that the two displays had different response characteristics to the same stimulus manipulations. Two models of motion perception that have previously predicted at least one kind of bistable apparent motion were considered in terms of how well they address the current data. As yet, neither model has been shown to predict the motion states and bistable behavior of the two displays studied here. It is concluded that results of the type described here (specifically, differences in the psychophysical functions yielded by two structurally similar but qualitatively different bistable displays) present a challenge for theories of motion perception.

Adolescent↗
PubMed2004

Bistability and hysteresis of the 'Secteur' differentiation are controlled by a two-gene locus in Nectria haematococca.

BACKGROUND: Bistability and hysteresis are increasingly recognized as major properties of regulatory networks governing numerous biological phenomena, such as differentiation and cell cycle progression. The full scope of the underlying molecular mechanisms leading to bistability and hysteresis remains elusive. Nectria haemaotcocca, a saprophytic or pathogenic fungus with sexual reproduction, exhibits a bistable morphological modification characterized by a reduced growth rate and an intense pigmentation. Bistability is triggered by the presence or absence of sigma, a cytoplasmic determinant. This determinant spreads in an infectious manner in the hyphae of the growing margin, insuring hysteresis of the differentiation. RESULTS: Seven mutants specifically affected in the generation of sigma were selected through two different screening strategies. The s1 and s2 mutations completely abolish the generation of sigma and of its morphological expression, the Secteur. The remaining five mutations promote its constitutive generation, which determines an intense pigmentation but not growth alteration. The seven mutations map at the same locus, Ses (for 'Secteur-specific'). The s2 mutant was obtained by an insertional mutagenesis strategy, which permitted the cloning of the Ses locus. Sequence and transcription analysis reveals that Ses is composed of two closely linked genes, SesA, mutated in the s1 and s2 mutant strains, and SesB, mutated in the s* mutant strains. SesB shares sequence similarity with animal and fungal putative proteins, with potential esterase/lipase/thioesterase activity, whereas SesA is similar to proteins of unknown function present only in the filamentous fungi Fusarium graminearum and Podospora anserina. CONCLUSIONS: The cloning of Ses provides evidence that a system encoded by two linked genes directs a bistable and hysteretic switch in a eukaryote. Atypical regulatory relations between the two proteins may account for the hysteresis of Secteur differentiation.

Cloning, Molecular↗
PubMed1995

A minimal, compartmental model for a dendritic origin of bistability of motoneuron firing patterns.

Various nonlinear regenerative responses, including plateau potentials and bistable repetitive firing modes, have been observed in motoneurons under certain conditions. Our simulation results support the hypothesis that these responses are due to plateau-generating currents in the dendrites, consistent with a major role for a noninactivating calcium L-type current as suggested by experiments. Bistability as observed in the soma of low- and higher-frequency spiking or, under TTX, of near resting and depolarized plateau potentials, occurs because the dendrites can be in a near resting or depolarized stable steady state. We formulate and study a two-compartment minimal model of a motoneuron that segregates currents for fast spiking into a soma-like compartment and currents responsible for plateau potentials into a dendrite-like compartment. Current flows between compartments through a coupling conductance, mimicking electrotonic spread. We use bifurcation techniques to illuminate how the coupling strength affects somatic behavior. We look closely at the case of weak coupling strength to gain insight into the development of bistable patterns. Robust somatic bistability depends on the electrical separation since it occurs only for weak to moderate coupling conductance. We also illustrate that hysteresis of the two spiking states is a natural consequence of the plateau behavior in the dendrite compartment.

Animals↗
PubMed1986

The role of visual pattern persistence in bistable stroboscopic motion.

Two alternating frames, each consisting of three square elements, were used to study bistable stroboscopic motion percepts. Bistable percepts were obtained which depend on the interstimulus interval (ISI) between the alternating frames. At short ISIs only end-to-end element motion was observed; and at higher ISIs only group motion was perceived. It was found that the progressive ISI-dependent transitions from element to group motion depended on element size and frame duration. These dependencies are predictable from the systematic influence which these variables are known also to exert on visual pattern persistence, indicating that such persistence contributes to determining which precept dominates during bistable stroboscopic motion sequences. These findings bear relevantly on recent attempts to conceptually relate bistable motion percepts to short-range stroboscopic motion processes.

Form Perception↗
PubMed1996

Bistable characteristics of motoneurone activity during DOPA induced fictive locomotion in spinal cats.

Bistable motoneuronal firing characteristics were investigated in anaemically decapitated paralysed high spinal cats during DOPA induced fictive locomotion. The activity of alpha-motoneurons was recorded intracellularly and/or from identified ventral root filaments or peripheral nerves. During stable fictive locomotor rhythmic activity the long lasting motoneuronal activity during the active phase of a motoneurone pool revealed indications for the development of bistable properties: (1) motoneuronal membrane potentials switched between two levels. Depolarization during active phases was characterised by stable fixed levels and could partly anticipatedly be initiated by excitatory inputs and terminated by inhibitor inputs. (2) Discharge patterns of motoneurones resembled patterns occurring during bistable firing behaviour. (3) Occasionally motoneuronal activity was switched 'on' during a certain phase of a step cycle but was not switched 'off' at the end of that phase but at the end of a corresponding phase several step cycles later. It is assumed, that the bistable firing pattern of the motoneurones during DOPA induced fictive locomotion is generated by plateau potentials. This mechanism would reduce the need for synaptic drive to motoneurones during locomotion. Motoneurones would not require sustained excitatory input from the rhythm generator during their active phase but a short-lasting initial excitation and a terminating inhibition.

Action Potentials↗
PubMed2006

Temporal dynamics of auditory and visual bistability reveal common principles of perceptual organization.

When dealing with natural scenes, sensory systems have to process an often messy and ambiguous flow of information. A stable perceptual organization nevertheless has to be achieved in order to guide behavior. The neural mechanisms involved can be highlighted by intrinsically ambiguous situations. In such cases, bistable perception occurs: distinct interpretations of the unchanging stimulus alternate spontaneously in the mind of the observer. Bistable stimuli have been used extensively for more than two centuries to study visual perception. Here we demonstrate that bistable perception also occurs in the auditory modality. We compared the temporal dynamics of percept alternations observed during auditory streaming with those observed for visual plaids and the susceptibilities of both modalities to volitional control. Strong similarities indicate that auditory and visual alternations share common principles of perceptual bistability. The absence of correlation across modalities for subject-specific biases, however, suggests that these common principles are implemented at least partly independently across sensory modalities. We propose that visual and auditory perceptual organization could rely on distributed but functionally similar neural competition mechanisms aimed at resolving sensory ambiguities.

Acoustic Stimulation↗
PubMed2005

Beyond bistability: biophysics and temporal dynamics of working memory.

Working memory has often been modeled and conceptualized as a kind of binary (bistable) memory switch, where stimuli turn on plateau-like persistent activity in subsets of cells, in line with many in vivo electrophysiological reports. A potentially related form of bistability, termed up- and down-states, has been studied with regard to its synaptic and ionic basis in vivo and in reduced cortical preparations. Also single cell mechanisms for producing bistability have been proposed and investigated in brain slices and computationally. Recently, however, it has been emphasized that clear plateau-like bistable activity is rather rare during working memory tasks, and that neurons exhibit a multitude of different temporally unfolding activity profiles and temporal structure within their spiking dynamics. Hence, working memory seems to be a highly dynamical neural process with yet unknown mappings from dynamical to computational properties. Empirical findings on ramping activity profiles and temporal structure will be reviewed, as well as neural models that attempt to account for it and its computational significance. Furthermore, recent in vivo, neural culture, and in vitro preparations will be discussed that offer new possibilities for studying the biophysical mechanisms underlying computational processes during working memory. These preparations have revealed additional evidence for temporal structure and spatio-temporally organized attractor states in cortical networks, as well as for specific computational properties that may characterize synaptic processing during high-activity states as during working memory. Together such findings may lay the foundations for highly dynamical theories of working memory based on biophysical principles.

Action Potentials↗
PubMed2002

Spatial reconfiguration of charge transfer effectiveness in active bistable dendritic arborizations.

The aim of this work was to explore the electrical spatial profile of the dendritic arborization during membrane potential oscillations of a bistable motoneuron. Computational simulations provided the spatial counterparts of the temporal dynamics of bistability and allowed simultaneous depiction the electrical states of any sites in the arborization. We assumed that the dendritic membrane had homogeneously distributed specific electrical properties and was equipped with a cocktail of passive extrasynaptic and NMDA synaptic conductances. The electrical conditions for evoking bistability in a single isopotential compartment and in a whole dendritic arborization were computed and showed differences, revealing a crucial effect of dendritic geometry. Snapshots of the whole arborization during bistability revealed the spatial distribution of the density of the transmembrane current generated at the synapses and the effectiveness of the current transfer from any dendritic site to the soma. These functional maps changed dynamically according to the phase of the oscillatory cycle. In the low depolarization state, the current density was low in the proximal dendrites and higher in the distal parts of the arborization while the transfer effectiveness varied in a narrow range with small differences between proximal and distal dendritic segments. When the neuron switched to high depolarization state, the current density was high in the proximal dendrites and low in the distal branches while a large domain of the dendritic field became electrically disconnected beyond 200 micro m from the soma with a null transfer efficiency. These spatial reconfigurations affected dynamically the size and shape of the functional dendritic field and were strongly geometry-dependent.

Abducens Nerve↗
PubMed2001

Robustness of the bistable behavior of a biological signaling feedback loop.

Biological signaling networks comprised of cellular components including signaling proteins and small molecule messengers control the many cell function in responses to various extracellular and intracellular signals including hormone and neurotransmitter inputs, and genetic events. Many signaling pathways have motifs familiar to electronics and control theory design. Feedback loops are among the most common of these. Using experimentally derived parameters, we modeled a positive feedback loop in signaling pathways used by growth factors to trigger cell proliferation. This feedback loop is bistable under physiological conditions, although the system can move to a monostable state as well. We find that bistability persists under a wide range of regulatory conditions, even when core enzymes in the feedback loop deviate from physiological values. We did not observe any other phenomena in the core feedback loop, but the addition of a delayed inhibitory feedback was able to generate oscillations under rather extreme parameter conditions. Such oscillations may not be of physiological relevance. We propose that the kinetic properties of this feedback loop have evolved to support bistability and flexibility in going between bistable and monostable modes, while simultaneously being very refractory to oscillatory states. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed2000

Existence of bistability and correlation with arrhythmogenesis in paced sheep atria.

INTRODUCTION: Studies of the electrical dynamics of cardiac tissue are important for understanding the mechanisms of arrhythmias. This study uses high-frequency pacing to investigate the dynamics of sheep atria. METHODS AND RESULTS: A 504-electrode mapping plaque was affixed to the right atrium in six sheep. Cathodal pacing stimuli were delivered to the center of the plaque. Pacing period (Tp) was decreased from 275 +/- 25 msec to 75 +/- 25 msec and then increased to 230 +/- 70 msec in steps of either 5 or 10 msec. In all 21 trials in six sheep, the atrium responded 1:1 at longer Tps and 2:1 at shorter Tps. As Tp was decreased, the response switched to 2:1 at a particular Tp. Conversely, as Tp was increased, the response switched back to 1:1 at a particular Tp. Over 21 trials, the 1:1-to-2:1 and 2:1-to-1:1 transitions occurred at 119.5 +/- 18.8 msec and 130.0 +/- 19.1 msec, respectively. This hysteretic behavior yielded bistability windows, 10.5 +/- 7.2 msec wide, wherein 1:1 and 2:1 responses existed at the same Tp. In 15 trials and in all animals, idiopathic wavefronts emanating from outside the mapped region passed through the mapped region. In 13 of those trials, the idiopathic wavefronts occurred at Tps within the bistability window or within 35 msec of its upper or lower limit. CONCLUSION: Bistability windows and idiopathic wavefronts were observed and found to be correlated with each other, suggesting a connection between bistability and arrhythmogenesis.

Animals↗
PubMed1996

Influence of voltage-sensitive dendritic conductances on bistable firing and effective synaptic current in cat spinal motoneurons in vivo.

1. After application of the noradrenergic alpha 1 agonist methoxamine, muscle spindle Ia input evoked bistable firing patterns (i.e., persistent discharges after Ia input ceased) in adult spinal motoneurons in the decerebrate cat preparation. These bistable discharge patterns were compared with the Ia currents generated in voltage-clamp conditions. 2. During voltage clamp at depolarized holding potentials, the Ia effective synaptic current underwent strong amplification. In those cells with strong bistable firing, a prolonged tail current followed the Ia input. Because the voltage clamp held the behavior of somatic conductances constant, these data indicate that voltage-sensitive conductances in the motoneuron dendrites made an important contribution to bistable firing.

Action Potentials↗