Eytan and Marom [1] recently showed that the spontaneous burst activity of rat neuron cultures in... more Eytan and Marom [1] recently showed that the spontaneous burst activity of rat neuron cultures includes 'first to fire' cells that consistently fire earlier than others. Here we analyze the behavior of these neurons in long term recordings of spontaneous activity of rat hippocampal and rat cortical neuron cultures from three different laboratories. We identify precursor events that may either subside ('small events') or can lead to a full-blown burst ('pre-bursts'). We find that the activation in the pre-burst typically has a first neuron ('leader'), followed by a localized response in its neighborhood. Locality is diminished in the bursts themselves. The long term dynamics of the leaders is relatively robust, evolving with a halflife of 23-34 hours. Stimulation of the culture can temporarily alter the leader distribution, but it returns to the previous distribution within about 1 hour. We show that the leaders carry information about the identity of the burst, as measured by the signature of the number of spikes per neuron in a burst. The number of spikes from leaders in the first few spikes of a precursor event is furthermore shown to be predictive with regard to the transition into a burst (pre-burst versus small event). We conclude that the leaders play a rôle in the development of the bursts, and conjecture that they are part of an underlying sub-network that is excited first and then act as nucleation centers for the burst.
Eve Marder and Shimon Marom argue that, while we celebrate the remarkable new technologies and th... more Eve Marder and Shimon Marom argue that, while we celebrate the remarkable new technologies and their ability to generate new knowledge, we mourn a concurrent loss of knowledge and expertise.
Emergence and maintenance of excitability is often phrased in terms of arriving at and remaining ... more Emergence and maintenance of excitability is often phrased in terms of arriving at and remaining about a manifold of 'solutions' embedded in a high dimensional parameter space. Alongside studies that extend traditional focus on control-based regulation of structural parameters (channel densities), there is a budding interest in self-organization of kinetic parameters. In this picture, ionic channels are continually forced by activity in-and-out of a large pool of states not available for the mechanism of excitability. The process, acting on expressed structure, provides a bed for generation of a spectrum of excitability modes. Driven by microscopic fluctuations over a broad range of temporal scales, self-organization of kinetic parameters extends the metaphors and tools used in the study of development of excitability. Highlights
Cortical networks, in-vitro as well as in-vivo, can spontaneously generate a variety of collectiv... more Cortical networks, in-vitro as well as in-vivo, can spontaneously generate a variety of collective dynamical events such as network spikes, UP and DOWN states, global oscillations, and avalanches. Though each of them have been variously recognized in previous works as expressions of the excitability of the cortical tissue and the associated nonlinear dynamics, a unified picture of their determinant factors (dynamical and architectural) is desirable and not yet available. Progress has also been partially hindered by the use of a variety of statistical measures to define the network events of interest. We propose here a common probabilistic definition of network events that, applied to the firing activity of cultured neural networks, highlights the co-occurrence of network spikes, power-law distributed avalanches, and exponentially distributed 'quasi-orbits', which offer a third type of collective behavior. A rate model, including synaptic excitation and inhibition with no imposed 1
1. Introduction 631.1 Outline 631.2 Universals versus realizations in the study of learning and m... more 1. Introduction 631.1 Outline 631.2 Universals versus realizations in the study of learning and memory 642. Large random cortical networks developing ex vivo 652.1 Preparation 652.2 Measuring electrical activity 673. Spontaneous development 693.1 Activity 693.2 Connectivity 704. Consequences of spontaneous activity: pharmacological manipulations 724.1 Structural consequences 724.2 Functional consequences 735. Effects of stimulation 745.1 Response to focal stimulation 745.2 Stimulation-induced changes in connectivity 746. Embedding functionality in real neural networks 776.1 Facing the physiological definition of ‘reward’: two classes of theories 786.2 Closing the loop 797. Concluding remarks 848. Acknowledgments 859. References 85The phenomena of learning and memory are inherent to neural systems that differ from each other markedly. The differences, at the molecular, cellular and anatomical levels, reflect the wealth of possible instantiations of two neural learning and memory univ...
We present experimental and theoretical arguments, at the single neuron level, suggesting that ne... more We present experimental and theoretical arguments, at the single neuron level, suggesting that neuronal response fluctuations reflect a process that positions the neuron near a transition point that separates excitable and unexcitable phases. This view is supported by the dynamical properties of the system as observed in experiments on isolated cultured cortical neurons, as well as by a theoretical mapping between the constructs of self organized criticality and membrane excitability biophysics.
Neural network models include at least one synaptic interaction between a pair of neurons so that... more Neural network models include at least one synaptic interaction between a pair of neurons so that plasticity can be conferred on the system. The single neuron is usually treated unrealistically in these models, functioning as a simple machine that transforms weighted ...
We present the elements of a mathematical computational model that reflects the experimental find... more We present the elements of a mathematical computational model that reflects the experimental finding that the timescale of a neuron is not fixed; but rather varies with the history of its stimulus. Unlike most physiological models, there are no predetermined rates associated with transitions between states of the system nor are there predetermined constants associated with adaptation rates; instead, the model is a kind of ''modulating automata'' where the rates emerge from the history of the system itself. We focus in this paper on the temporal dynamics of a neuron and show how a simple internal structure will give rise to complex temporal behavior. The internal structure modeled here is an abstraction of a reasonably well-understood physiological structure. We also suggest that this behavior can be used to transform a ''rate'' code into a ''temporal one''.
In this perspective we provide an example for the limits of reverse engineering in neuroscience. ... more In this perspective we provide an example for the limits of reverse engineering in neuroscience. We demonstrate that application of reverse engineering to the study of the design principle of a functional neuro-system with a known mechanism, may result in a perfectly valid but wrong induction of the system's design principle. If in the very simple setup we bring here (static environment, primitive task and practically unlimited access to every piece of relevant information), it is diffi cult to induce a design principle, what are our chances of exposing biological design principles when more realistic conditions are examined? Implications to the way we do Biology are discussed.
Memory is a property of diverse biological systems, including brain and heart. Studies in cortica... more Memory is a property of diverse biological systems, including brain and heart. Studies in cortical neuronal networks have identified an increased sensitivity to infrequent (rare) stimulation patterns that can result in their achieving dominance over network firing. This adaptive behavior is applied to the heart in an attempt to explain the ability of pulmonary venous and other ectopic foci to achieve dominance over cardiac rhythm. Developmental changes in determinants of cardiac rhythm are explored as possible determinants of the range of rhythms expressed by the heart. By understanding the mechanisms for these behavior patterns, we may obtain new means for manipulating memory to return dysrhythmic hearts to normal sinus rhythm.
In this report trial-to-trial variations in the synchronized responses of neural networks are off... more In this report trial-to-trial variations in the synchronized responses of neural networks are offered as evidence for excitation-inhibition ratio being a dynamic variable over time scales of minutes. Synchronized network responses to stimuli were studied in ex-vivo large scale cortical networks. We show that sub-second measures of the individual synchronous response, namely-its latency and decay duration, are related to minutes-scale network response dynamics. Network responsiveness is reflected as residency in, or shifting amongst, areas of the latency-decay plane. The different sensitivities of latency and decay durations to synaptic blockers imply that these two measures reflect the effective impacts of inhibitory and excitatory neuronal populations on response dynamics. Taken together, the data suggest that network response variations under repeated stimuli result from excitation-inhibition ratio being a dynamic variable rather than a parameter.
American Journal of Physiology-Renal Physiology, 1989
This is a description and kinetic characterization of cation channels from rat kidney brush-borde... more This is a description and kinetic characterization of cation channels from rat kidney brush-border membrane vesicles and from apical membranes of proximal tubule cells in culture. Channel activity was demonstrated and characterized in both artificial phospholipid bilayers and in tissue culture. Intermediate conductance, approximately 50 pS, cation-selective channels were observed by both methods. Channels were characterized by a Na permeability (PNa)/K permeability (PK) of 1-5:1. Open-channel current-voltage curves were linear in symmetric 300 mM NaCl. In tissue culture the gating kinetics are described by two open-time constants and two closed-time constants. Channel activity was neither voltage nor Ca2+ dependent and the probability of being in the open state ranged from 0.6 to 0.95. In tissue culture experiments the channel demonstrated nonstationary gating activity. A second, 15-pS cation channel, seen in planar bilayers, demonstrated a higher selectivity for Na+ with a (PNa/PK ...
A key property of neural systems is their ability to adapt selectively to stimuli with different ... more A key property of neural systems is their ability to adapt selectively to stimuli with different features. Using multisite electrical recordings from networks of cortical neurons developingex vivo, we show that neurons adapt selectively to different stimuli invading the network. We focus on selective adaptation to frequent and rare stimuli; networks were stimulated at two sites with two different stimulus frequencies. When both stimuli were presented within the same period, neurons in the network attenuated their responsiveness to the more frequent input, whereas their responsiveness to the rarely delivered stimuli showed a marked average increase. The amplification of the response to rare stimuli required the presence of the other, more frequent stimulation source. By contrast, the decreased response to the frequent stimuli occurred regardless of the presence of the rare stimuli. Analysis of the response of single units suggests that both of these effects are caused by changes in s...
Studies in history and philosophy of biological and biomedical sciences, Jan 19, 2015
The phenomenon of biology provides a prime example for a naturally occurring complex system. The ... more The phenomenon of biology provides a prime example for a naturally occurring complex system. The approach to this complexity reflects the tension between a reductionist, reverse-engineering stance, and more abstract, systemic ones. Both of us are reductionists, but our observations challenge reductionism, at least the naive version of it. Here we describe the challenge, focusing on two universal characteristics of biological complexity: two-way microscopic-macroscopic degeneracy, and lack of time scale separation within and between levels of organization. These two features and their consequences for the praxis of experimental biology, reflect inherent difficulties in separating the dynamics of any given level of organization from the coupled dynamics of all other levels, including the environment within which the system is embedded. Where these difficulties are not deeply acknowledged, the impacts of fallacies that are inherent to naive reductionism are significant. In an era where...
In this report trial-to-trial variations in the synchronized responses of neural networks are exp... more In this report trial-to-trial variations in the synchronized responses of neural networks are explored over time scales of minutes, in ex-vivo large scale cortical networks. We show that sub-second measures of the individual synchronous response, namely-its latency and decay duration, are related to minutes-scale network response dynamics. Network responsiveness is reflected as residency in, or shifting amongst, areas of the latency-decay plane. The different sensitivities of latency and decay durations to synaptic blockers imply that these two measures reflect aspects of inhibitory and excitatory activities. Taken together, the data suggest that trial-to-trial variations in the synchronized responses of neural networks might be related to effective excitation-inhibition ratio being a dynamic variable over time scales of minutes.
This contribution describes the use of multi-site interaction with large cortical networks in the... more This contribution describes the use of multi-site interaction with large cortical networks in the study of learning. The general physiological properties of the network are described, and the concept of learning is mapped to the experimental network preparation. Learning is then analyzed in terms of exploration (defined as changes in the configuration of associations within the biological network) and recognition (the stabilization of "worthy" associations).
Advances in Experimental Medicine and Biology, 1995
ABSTRACT The study aims at exploring effects of microscopic channel fluctuations on macroscopic d... more ABSTRACT The study aims at exploring effects of microscopic channel fluctuations on macroscopic dynamics of excitable systems. Molecular biology techniques are used in order to construct a minimal excitable system that is built of cloned channels embedded in a ...
Eytan and Marom [1] recently showed that the spontaneous burst activity of rat neuron cultures in... more Eytan and Marom [1] recently showed that the spontaneous burst activity of rat neuron cultures includes 'first to fire' cells that consistently fire earlier than others. Here we analyze the behavior of these neurons in long term recordings of spontaneous activity of rat hippocampal and rat cortical neuron cultures from three different laboratories. We identify precursor events that may either subside ('small events') or can lead to a full-blown burst ('pre-bursts'). We find that the activation in the pre-burst typically has a first neuron ('leader'), followed by a localized response in its neighborhood. Locality is diminished in the bursts themselves. The long term dynamics of the leaders is relatively robust, evolving with a halflife of 23-34 hours. Stimulation of the culture can temporarily alter the leader distribution, but it returns to the previous distribution within about 1 hour. We show that the leaders carry information about the identity of the burst, as measured by the signature of the number of spikes per neuron in a burst. The number of spikes from leaders in the first few spikes of a precursor event is furthermore shown to be predictive with regard to the transition into a burst (pre-burst versus small event). We conclude that the leaders play a rôle in the development of the bursts, and conjecture that they are part of an underlying sub-network that is excited first and then act as nucleation centers for the burst.
Eve Marder and Shimon Marom argue that, while we celebrate the remarkable new technologies and th... more Eve Marder and Shimon Marom argue that, while we celebrate the remarkable new technologies and their ability to generate new knowledge, we mourn a concurrent loss of knowledge and expertise.
Emergence and maintenance of excitability is often phrased in terms of arriving at and remaining ... more Emergence and maintenance of excitability is often phrased in terms of arriving at and remaining about a manifold of 'solutions' embedded in a high dimensional parameter space. Alongside studies that extend traditional focus on control-based regulation of structural parameters (channel densities), there is a budding interest in self-organization of kinetic parameters. In this picture, ionic channels are continually forced by activity in-and-out of a large pool of states not available for the mechanism of excitability. The process, acting on expressed structure, provides a bed for generation of a spectrum of excitability modes. Driven by microscopic fluctuations over a broad range of temporal scales, self-organization of kinetic parameters extends the metaphors and tools used in the study of development of excitability. Highlights
Cortical networks, in-vitro as well as in-vivo, can spontaneously generate a variety of collectiv... more Cortical networks, in-vitro as well as in-vivo, can spontaneously generate a variety of collective dynamical events such as network spikes, UP and DOWN states, global oscillations, and avalanches. Though each of them have been variously recognized in previous works as expressions of the excitability of the cortical tissue and the associated nonlinear dynamics, a unified picture of their determinant factors (dynamical and architectural) is desirable and not yet available. Progress has also been partially hindered by the use of a variety of statistical measures to define the network events of interest. We propose here a common probabilistic definition of network events that, applied to the firing activity of cultured neural networks, highlights the co-occurrence of network spikes, power-law distributed avalanches, and exponentially distributed 'quasi-orbits', which offer a third type of collective behavior. A rate model, including synaptic excitation and inhibition with no imposed 1
1. Introduction 631.1 Outline 631.2 Universals versus realizations in the study of learning and m... more 1. Introduction 631.1 Outline 631.2 Universals versus realizations in the study of learning and memory 642. Large random cortical networks developing ex vivo 652.1 Preparation 652.2 Measuring electrical activity 673. Spontaneous development 693.1 Activity 693.2 Connectivity 704. Consequences of spontaneous activity: pharmacological manipulations 724.1 Structural consequences 724.2 Functional consequences 735. Effects of stimulation 745.1 Response to focal stimulation 745.2 Stimulation-induced changes in connectivity 746. Embedding functionality in real neural networks 776.1 Facing the physiological definition of ‘reward’: two classes of theories 786.2 Closing the loop 797. Concluding remarks 848. Acknowledgments 859. References 85The phenomena of learning and memory are inherent to neural systems that differ from each other markedly. The differences, at the molecular, cellular and anatomical levels, reflect the wealth of possible instantiations of two neural learning and memory univ...
We present experimental and theoretical arguments, at the single neuron level, suggesting that ne... more We present experimental and theoretical arguments, at the single neuron level, suggesting that neuronal response fluctuations reflect a process that positions the neuron near a transition point that separates excitable and unexcitable phases. This view is supported by the dynamical properties of the system as observed in experiments on isolated cultured cortical neurons, as well as by a theoretical mapping between the constructs of self organized criticality and membrane excitability biophysics.
Neural network models include at least one synaptic interaction between a pair of neurons so that... more Neural network models include at least one synaptic interaction between a pair of neurons so that plasticity can be conferred on the system. The single neuron is usually treated unrealistically in these models, functioning as a simple machine that transforms weighted ...
We present the elements of a mathematical computational model that reflects the experimental find... more We present the elements of a mathematical computational model that reflects the experimental finding that the timescale of a neuron is not fixed; but rather varies with the history of its stimulus. Unlike most physiological models, there are no predetermined rates associated with transitions between states of the system nor are there predetermined constants associated with adaptation rates; instead, the model is a kind of ''modulating automata'' where the rates emerge from the history of the system itself. We focus in this paper on the temporal dynamics of a neuron and show how a simple internal structure will give rise to complex temporal behavior. The internal structure modeled here is an abstraction of a reasonably well-understood physiological structure. We also suggest that this behavior can be used to transform a ''rate'' code into a ''temporal one''.
In this perspective we provide an example for the limits of reverse engineering in neuroscience. ... more In this perspective we provide an example for the limits of reverse engineering in neuroscience. We demonstrate that application of reverse engineering to the study of the design principle of a functional neuro-system with a known mechanism, may result in a perfectly valid but wrong induction of the system's design principle. If in the very simple setup we bring here (static environment, primitive task and practically unlimited access to every piece of relevant information), it is diffi cult to induce a design principle, what are our chances of exposing biological design principles when more realistic conditions are examined? Implications to the way we do Biology are discussed.
Memory is a property of diverse biological systems, including brain and heart. Studies in cortica... more Memory is a property of diverse biological systems, including brain and heart. Studies in cortical neuronal networks have identified an increased sensitivity to infrequent (rare) stimulation patterns that can result in their achieving dominance over network firing. This adaptive behavior is applied to the heart in an attempt to explain the ability of pulmonary venous and other ectopic foci to achieve dominance over cardiac rhythm. Developmental changes in determinants of cardiac rhythm are explored as possible determinants of the range of rhythms expressed by the heart. By understanding the mechanisms for these behavior patterns, we may obtain new means for manipulating memory to return dysrhythmic hearts to normal sinus rhythm.
In this report trial-to-trial variations in the synchronized responses of neural networks are off... more In this report trial-to-trial variations in the synchronized responses of neural networks are offered as evidence for excitation-inhibition ratio being a dynamic variable over time scales of minutes. Synchronized network responses to stimuli were studied in ex-vivo large scale cortical networks. We show that sub-second measures of the individual synchronous response, namely-its latency and decay duration, are related to minutes-scale network response dynamics. Network responsiveness is reflected as residency in, or shifting amongst, areas of the latency-decay plane. The different sensitivities of latency and decay durations to synaptic blockers imply that these two measures reflect the effective impacts of inhibitory and excitatory neuronal populations on response dynamics. Taken together, the data suggest that network response variations under repeated stimuli result from excitation-inhibition ratio being a dynamic variable rather than a parameter.
American Journal of Physiology-Renal Physiology, 1989
This is a description and kinetic characterization of cation channels from rat kidney brush-borde... more This is a description and kinetic characterization of cation channels from rat kidney brush-border membrane vesicles and from apical membranes of proximal tubule cells in culture. Channel activity was demonstrated and characterized in both artificial phospholipid bilayers and in tissue culture. Intermediate conductance, approximately 50 pS, cation-selective channels were observed by both methods. Channels were characterized by a Na permeability (PNa)/K permeability (PK) of 1-5:1. Open-channel current-voltage curves were linear in symmetric 300 mM NaCl. In tissue culture the gating kinetics are described by two open-time constants and two closed-time constants. Channel activity was neither voltage nor Ca2+ dependent and the probability of being in the open state ranged from 0.6 to 0.95. In tissue culture experiments the channel demonstrated nonstationary gating activity. A second, 15-pS cation channel, seen in planar bilayers, demonstrated a higher selectivity for Na+ with a (PNa/PK ...
A key property of neural systems is their ability to adapt selectively to stimuli with different ... more A key property of neural systems is their ability to adapt selectively to stimuli with different features. Using multisite electrical recordings from networks of cortical neurons developingex vivo, we show that neurons adapt selectively to different stimuli invading the network. We focus on selective adaptation to frequent and rare stimuli; networks were stimulated at two sites with two different stimulus frequencies. When both stimuli were presented within the same period, neurons in the network attenuated their responsiveness to the more frequent input, whereas their responsiveness to the rarely delivered stimuli showed a marked average increase. The amplification of the response to rare stimuli required the presence of the other, more frequent stimulation source. By contrast, the decreased response to the frequent stimuli occurred regardless of the presence of the rare stimuli. Analysis of the response of single units suggests that both of these effects are caused by changes in s...
Studies in history and philosophy of biological and biomedical sciences, Jan 19, 2015
The phenomenon of biology provides a prime example for a naturally occurring complex system. The ... more The phenomenon of biology provides a prime example for a naturally occurring complex system. The approach to this complexity reflects the tension between a reductionist, reverse-engineering stance, and more abstract, systemic ones. Both of us are reductionists, but our observations challenge reductionism, at least the naive version of it. Here we describe the challenge, focusing on two universal characteristics of biological complexity: two-way microscopic-macroscopic degeneracy, and lack of time scale separation within and between levels of organization. These two features and their consequences for the praxis of experimental biology, reflect inherent difficulties in separating the dynamics of any given level of organization from the coupled dynamics of all other levels, including the environment within which the system is embedded. Where these difficulties are not deeply acknowledged, the impacts of fallacies that are inherent to naive reductionism are significant. In an era where...
In this report trial-to-trial variations in the synchronized responses of neural networks are exp... more In this report trial-to-trial variations in the synchronized responses of neural networks are explored over time scales of minutes, in ex-vivo large scale cortical networks. We show that sub-second measures of the individual synchronous response, namely-its latency and decay duration, are related to minutes-scale network response dynamics. Network responsiveness is reflected as residency in, or shifting amongst, areas of the latency-decay plane. The different sensitivities of latency and decay durations to synaptic blockers imply that these two measures reflect aspects of inhibitory and excitatory activities. Taken together, the data suggest that trial-to-trial variations in the synchronized responses of neural networks might be related to effective excitation-inhibition ratio being a dynamic variable over time scales of minutes.
This contribution describes the use of multi-site interaction with large cortical networks in the... more This contribution describes the use of multi-site interaction with large cortical networks in the study of learning. The general physiological properties of the network are described, and the concept of learning is mapped to the experimental network preparation. Learning is then analyzed in terms of exploration (defined as changes in the configuration of associations within the biological network) and recognition (the stabilization of "worthy" associations).
Advances in Experimental Medicine and Biology, 1995
ABSTRACT The study aims at exploring effects of microscopic channel fluctuations on macroscopic d... more ABSTRACT The study aims at exploring effects of microscopic channel fluctuations on macroscopic dynamics of excitable systems. Molecular biology techniques are used in order to construct a minimal excitable system that is built of cloned channels embedded in a ...
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