Biomedical subjects

Péter Erdi

Publications and source records attributed to Péter Erdi.

12 recordsLinked to original sources

PubMed2006

Pharmacological and computational analysis of alpha-subunit preferential GABA(A) positive allosteric modulators on the rat septo-hippocampal activity.

Clinically most active anxiolytic drugs are positive allosteric modulators (PAMs) of GABA(A) receptors, represented by benzodiazepine compounds. Due to their non-selective profile, however, they potently modulate several sup-type specific GABA(A) receptors, contributing to their broad-range side effects. Based on observations in genetically altered mice, however, it has been proposed that anxiolytic action of benzodiazepines is predominantly mediated by GABA(A) alpha2/3 subunit-containing receptors. In the present study we analyzed the actions of the preferential GABA(A) alpha1 and alpha2/3 PAMs, zolpidem and L-838417, respectively on hippocampal EEG and medial septum neuronal activity in anesthetized rats. In parallel, a computational model was constructed to model pharmacological actions of these compounds on the septo-hippocampal circuitry. The present results demonstrated that zolpidem inhibited theta oscillation both in the hippocampus and septum, and profoundly inhibited firing activity of septal neurons. L-838417 also inhibited hippocampal and septal theta oscillation, however, it did not significantly alter firing rate activity of septal neurons. Our computational model showed that cessation of periodic firing of hippocampo-septal neurons, representing absence of hippocampal theta activity, disrupted oscillation of septal units, without altering their overall firing activity, similar to changes observed in our in vivo experiments following administration of L-838417. Understanding the correlation between changes in septo-hippocampal activity and actions of selective modulators of GABA(A) subtype receptor modulators would further advance design of anxiolytic drugs.

Action Potentials↗

PubMed2006

Intrinsic and synaptic mechanisms determining the timing of neuron population activity during hippocampal theta oscillation.

Hippocampal theta (3-8 Hz) is a major electrophysiological activity in rodents, which can be found in primates and humans as well. During theta activity, pyramidal cells and different classes of interneurons were shown to discharge at different phases of the extracellular theta. A recent in vitro study has shown that theta-frequency oscillation can be elicited in a hippocampal CA1 slice by the activation of metabotropic glutamate receptors with similar pharmacological and physiological profile that was found in vivo. We constructed a conductance based three-population network model of the hippocampal CA1 region to study the specific roles of neuron types in the generation of the in vitro theta oscillation and the emergent network properties. Interactions between pairs of neuron populations were studied systematically to assess synchronization and delay properties. We showed that the circuitry consisting of pyramidal cells and two types of hippocampal interneurons [basket and oriens lacunosum-moleculare (O-LM) neurons] was able to generate coherent theta-frequency population oscillation. Furthermore, we found that hyperpolarization-activated nonspecific cation current in pyramidal cells, but not in O-LM neurons, plays an important role in the timing of spike generation, and thus synchronization of pyramidal cells. The model was shown to exhibit the same phase differences between neuron population activities found in vivo, supporting the idea that these patterns of activity are determined internal to the hippocampus.

Algorithms↗

PubMed2006

From electric patterns to drugs: perspectives of computational neuroscience in drug design.

A novel way of computational modeling by integrating compartmental neural techniques and detailed kinetic description of pharmacological modulation of transmitter-receptor interaction is offered as a method to test the electro-physiological and behavioral effects of potential drugs. Even more, an inverse method is suggested as a method for controlling a neural system to realize a prescribed temporal pattern. Generation and pharamcological modulation of theta rhythm in area CA1 of the hippocampus related to anxiety is analyzed. Integrative modeling might help to find positive allosteric modulators of alpha1 subunits as potential candidates for being selective anxyolitics.

Computer-Aided Design↗

PubMed2006

Computational neuropharmacology: dynamical approaches in drug discovery.

Computational approaches that adopt dynamical models are widely accepted in basic and clinical neuroscience research as indispensable tools with which to understand normal and pathological neuronal mechanisms. Although computer-aided techniques have been used in pharmaceutical research (e.g. in structure- and ligand-based drug design), the power of dynamical models has not yet been exploited in drug discovery. We suggest that dynamical system theory and computational neuroscience--integrated with well-established, conventional molecular and electrophysiological methods--offer a broad perspective in drug discovery and in the search for novel targets and strategies for the treatment of neurological and psychiatric diseases.

Anti-Anxiety Agents↗

PubMed2005

Model-based source localization of extracellular action potentials.

A new model-based analysis method was set up for revealing information encrypted in extracellular spatial potential patterns of neocortical action potentials. Spikes were measured by extracellular linear multiple microelectrode in vivo cat's primary auditory cortex and were analyzed based on current source density (CSD) distribution models. Validity of the monopole and other point source approximations were tested on the measured potential patterns by numerical fitting. We have found, that point source models could not provide accurate description of the measured patterns. We introduced a new model of the CSD distribution on a spiking cell, called counter-current model (CCM). This new model was shown to provide better description of the spatial current distribution of the cell during the initial negative deflection of the extracellular action potential, from the onset of the spike to the negative peak. The new model was tested on simulated extracellular potentials. We proved numerically, that all the parameters of the model could be determined accurately based on measurements. Thus, fitting of the CCM allowed extraction of these parameters from the measurements. Due to model fitting, CSD could be calculated with much higher accuracy as done with the traditional method because distance dependence of the spatial potential patterns was explicitly taken into consideration in our method. Average CSD distribution of the neocortical action potentials was calculated and spatial decay constant of the dendritic trees was determined by applying our new method.

Action Potentials↗

PubMed2005

Hippocampal theta rhythms from a computational perspective: code generation, mood regulation and navigation.

In this paper three computer models are summarized discussing different functions of the cortico-hippocampal system. Mood regulation, rhythm and code generation and navigation are integrated into a coherent conceptual framework around the concepts of structural hierarchy and circular causality. First, a model of spatio-temporal code generation is reviewed in which the hippocampal population theta rhythm plays an important role. Next, generation and pharmcological modulation of this rhythm is examined using a computer model of multiple cell populations forming a feed-back loop within the hippocampus and between the septum and the hippocampus. Last, an abstract, but biologically motivated model of navigation is described which achieves a near optimal mode of navigation by composing hierarchical levels of the cortico-hippocampal system. The connections among the different hierarchical structures of the cortico-hippocampal organization and their functional roles are discussed.

Affect↗

PubMed2005

Computational theories on the function of theta oscillations.

Neural rhythms can be studied in terms of conditions for their generation, or in terms of their functional significance. The theta oscillation is a particularly prominent rhythm, reported to be present in many brain areas, and related to many important cognitive processes. The generating mechanisms of theta have extensively been studied and reviewed elsewhere; here we discuss ideas that have accumulated over the past decades on the computational roles it may subserve. Theories propose different aspects of theta oscillations as being relevant for their cognitive functions: limit cycle oscillations in neuronal firing rates, subthreshold membrane potential oscillations, periodic modulation of synaptic transmission and plasticity, and phase precession of hippocampal place cells. The relevant experimental data is briefly summarized in the light of these theories. Specific models proposing a function for theta in pattern recognition, memory, sequence learning and navigation are reviewed critically. Difficulties with testing and comparing alternative models are discussed, along with potentially important future research directions in the field.

Animals↗

PubMed2005

Theta oscillation-coupled dendritic spiking integrates inputs on a long time scale.

Persistent neural activity lasting for seconds after transient stimulation has been observed in several brain areas. This activity has been taken to be indicative of the integration of inputs on long time scales. Passive membrane properties render neural time constants to be on the order of milliseconds. Intense synaptic bombardment, characteristic of in vivo states, was previously shown to further reduce the time scale of effective integration. We explored how long-term integration in single cells could be supported by dendritic spikes coupled with the theta oscillation, a prominent brain rhythm often observed during working memory tasks. We used a two-compartmental conductance-based model of a hippocampal pyramidal cell to study the interplay of intrinsic dynamics with periodic inputs in the theta frequency band. We show that periodic dendritic spiking integrates inputs by shifting the phase relative to an external oscillation, since spiking frequency is quasi-linearly modulated by current injection. The time-constant of this integration process is practically infinite for input intensities above a threshold (the integration threshold) and can be still several hundred milliseconds long below the integration threshold. The somatic compartment received theta frequency stimulation in antiphase with the dendritic oscillation. Consequently, dendritic spikes could only elicit somatic action potentials when they were sufficiently phase-shifted and thus coincided with somatic depolarization. Somatic depolarization modulated the frequency but not the phase of firing, endowing the cell with the capability to code for two different variables at the same time. Inputs to the dendrite shifted the phase of dendritic spiking, while somatic input was modulating its firing rate. This mechanism resulted in firing patterns that closely matched experimental data from hippocampal place cells of freely behaving rats. We discuss the plausibility of our proposed mechanism and its potential to account for the firing pattern of cells outside the hippocampus during working memory tasks.

Action Potentials↗

PubMed2004

Theta-modulated feedforward network generates rate and phase coded firing in the entorhino-hippocampal system.

Principal cells of the hippocampus and of its only cortical input region, the entorhinal cortex exhibit place specific activity in the freely moving rat. While entorhinal cells have widely tuned place fields, hippocampal place fields are more localized and determine not only the rate but also the timing of place cell spikes. Several models have successfully attempted to explain this fine tuning making use of intrahippocampal attractor network dynamics provided by the recurrent collaterals of hippocampal area CA3. Recent experimental evidence shows that CA1 place cells preserve their tuning curves even in the absence of input from CA3. We propose a model in which entorhinal and hippocampal pyramidal cell populations are only connected via feedforward connections. Synaptic transmission in our sytem is gated by a class of interneurons inhibiting specifically the entorhino-hippocampal pathway. Theta rhythm modulates the activity of each component. Our results show that rhythmic shunting inhibition endows entorhinal cells with a novel type of temporal code conveyed by the phase jitter of individual spikes. This converts coarsely tuned place-specific activity in the entorhinal cortex to velocity-dependent postsynaptic excitation and, thus, provides hippocampal place cells with an input that has recently been proposed to account for their rate and phase coded firing. Hippocampal place fields are generated through this mechanism and also shown to be robust against variations in the level of tonic inhibition.

Action Potentials↗

PubMed2003

Properties of a random attachment growing network.

In this study we introduce and analyze the statistical structural properties of a model of growing networks which may be relevant to social networks. At each step a new node is added which selects k possible partners from the existing network and joins them with probability delta by undirected edges. The "activity" of the node ends here; it will get new partners only if it is selected by a newcomer. The model produces an infinite-order phase transition when a giant component appears at a specific value of delta, which depends on k. The average component size is discontinuous at the transition. In contrast, the network behaves significantly different for k=1. There is no giant component formed for any delta and thus in this sense there is no phase transition. However, the average component size diverges for delta> or =1/2.

Cluster Analysis↗

PubMed2003

Dynamically detuned oscillations account for the coupled rate and temporal code of place cell firing.

Firing of place cells in the exploring rat conveys doubly coded spatial information: both the rate of spikes and their timing relative to the phase of the ongoing field theta oscillation are correlated with the location of the animal. Specifically, the firing rate of a place cell waxes and wanes, while the timing of spikes precesses monotonically as the animal traverses the portion of the environment preferred by the cell. We propose a mechanism for the generation of this firing pattern that can be applied for place cells in all three hippocampal subfields and that encodes spatial information in the output of the cell without relying on topographical connections or topographical input. A single pyramidal cell was modeled so that the cell received rhythmic inhibition in phase with theta field potential oscillation on the soma and was excited on the dendrite with input depending on the speed of the rat. The dendrite sustained an intrinsic membrane potential oscillation, frequency modulated by its input. Firing probability of the cell was determined jointly by somatic and dendritic oscillations. Results were obtained on different levels of abstraction: a purely analytical derivation was arrived at, corroborated by numerical simulations of rate neurons, and an extension of these simulations to spiking neurons was also performed. Realistic patterns of rate and temporal coding emerged and were found to be inseparable. These results may have implications on the robustness of information coding in place cell firing and on the ways information is processed in structures downstream to the hippocampus.

Action Potentials↗

PubMed2002

Mesoscopic neurodynamics.

An overview is given on the history, theory, and applications of mesoscopic neural models. It is shown why and how we can describe the behavior of a large population of neurons by the method of statistical neurodynamics. Normal and epileptic propagation of cortical activity have been simulated.

Animals↗