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W W Lytton

Publications and source records attributed to W W Lytton.

At least 19 recordsLinked to original sources
PubMed1999

Potentiation of Ca2+ influx through NMDA channels by action potentials: a computer model.

In pyramidal cells, somatic action potentials can propagate actively back into the apical dendrites and potentiate calcium influx at simultaneously activated glutamatergic synapses, presumably by relieving the voltage-dependent block of NMDA channels. We have used computer simulations to investigate the conditions under which this potentiation will be optimal. We find that a spike with a long duration and limited amplitude (peak of approximately -10 mV) will be most effective. A back-propagating action potential will achieve this form if the dendritic membrane has a low K+ channel density and a modest Na+ channel density (30-70 pS/microm2, similar to experimentally observed densities). The relative increase in calcium due to the backpropagating spike will be small, however, unless the accumulated calcium is rapidly removed.

Action Potentials↗
PubMed1999

Can the hippocampus tell time? The temporo-septal engram shift model.

An essential feature of episodic memory, the type of memory dependent on hippocampus, is that individual memories belong to particular moments in time. Recent PET studies suggest that memory encoding and recall occur at different locations in human hippocampus. Coupled with other attributes of hippocampus, this suggested to us that the septo-temporal hippocampal axis may play an important role in time perception. We propose a temporo-septal engram shift model of hippocampal memory. The model posits that memories gradually move along the hippocampus from a temporal encoding site to ever more septal sites from which they are recalled. We propose that the sense of time is encoded by the location of the engram along the temporo-septal axis.

Hippocampus↗
PubMed1999

Burst firing in identified rat geniculate interneurons.

We used whole-cell patch recording to study 102 local interneurons in the rat dorsal lateral geniculate nucleus in vitro. Input impedance with this technique (607.0+/-222.4 MOhm) was far larger than that measured with sharp electrode techniques, suggesting that interneurons may be more electrotonically compact than previously believed. Consistent and robust burst firing was observed in all interneurons when a slight depolarizing boost was given from a potential at, or slightly hyperpolarized from, resting membrane potential. These bursts had some similarities to the low-threshold spike described previously in other thalamic neuron types. The bursting responses were blocked by Ni+, suggesting that the low-threshold calcium current I(T), responsible for the low-threshold spike, was also involved in interneuron burst firing. Compared to the low-threshold spike of thalamocortical cells, however, the interneuron bursts were of relatively long duration and low intraburst frequency. The requirement for a depolarizing boost to elicit the burst is consistent with previous reports of a depolarizing shift of the I(T) activation curve of interneurons relative to thalamocortical cells, a finding we confirmed using voltage-clamp. Voltage-clamp study also revealed an additional long-lasting current that could be tentatively identified as the calcium activated non-selective cation current, I(CAN), based on reversal potential and on pharmacological characteristics. Computer simulation of the interneuron burst demonstrated that its particular morphology is likely due to the interaction of I(T) and I(CAN). In the slice, bursts could also be elicited by stimulation of the optic tract, suggesting that they may occur in response to natural stimulation. Synaptically triggered bursts were only partially blocked by Ni+, but could then be completely blocked by further addition of (+/-)-2-amino-5-phosphonopentanoic acid. The existence of robust bursts in this cell type suggests an additional role for interneurons in sculpting sensory responses by feedforward inhibition of thalamocortical cells. The low-threshold spike is a mechanism whereby activity in a neuron is dependent on a prior lack of activity in that same neuron. Understanding of the low-threshold spike in the other major neuron types of the thalamus has brought many new insights into how thalamic oscillations might be involved in sleep and epilepsy. Our description of this phenomenon in the interneurons of the thalamus suggests that these network oscillations might be even more complicated than previously believed.

Animals↗
PubMed1999

Properties of a hyperpolarization-activated cation current in interneurons in the rat lateral geniculate nucleus.

A hyperpolarization-activated cation conductance contributes to the membrane properties of a variety of cell types. In the thalamus, a prominent hyperpolarization-activated cation conductance exists in thalamocortical cells, and this current is implicated in the neuromodulation of complex firing behaviors. In contrast, the GABAergic cells in the reticular nucleus in the thalamus appear to lack this conductance. The presence and role of this cation conductance in the other type of thalamic GABAergic cells, local interneurons, is still unclear. To resolve this issue, we studied 54 physiologically and morphologically identified local interneurons in the rat dorsal lateral geniculate nucleus using an in vitro whole-cell patch recording technique. We found that hyperpolarizing current injections induced depolarizing voltage sags in these geniculate interneurons. The I-V relationship revealed an inward rectification. Voltage-clamp study indicated that a slow, hyperpolarization-activated cation conductance was responsible for the inward rectification. We then confirmed that this slow conductance had properties of the hyperpolarization-activated cation conductance described in other cell types. The slow conductance was insensitive to 10 mM tetraethylammonium and 0.5 mM 4-aminopyridine, but was largely blocked by 1-1.5 mM Cs+. It was permeable to both K+ and Na+ ions and had a reversal potential of -44 mV. The voltage dependence of the hyperpolarization-activated cation conductance in interneurons was also studied: the activation threshold was about -55 mV, half-activation potential was about -80 mV and maximal conductance was about 1 nS. The activation and deactivation time constants of the conductance ranged from 100 to 1000 ms, depending on membrane potential. The depolarizing voltage sags and I-V relationship were further simulated in a model interneuron, using the parameters of the hyperpolarization-activated cation conductance obtained from the voltage-clamp study. The time-course and voltage dependence of the depolarizing voltage sags and I-V relationship in the model cell were very similar to those found in geniculate interneurons in current clamp. Taken together, the results of the present study suggest that thalamic local interneurons possess a prominent hyperpolarization-activated cation conductance, which may play important roles in determining basic membrane properties and in modulating firing patterns.

Animals↗
PubMed1999

An intrinsic oscillation in interneurons of the rat lateral geniculate nucleus.

By using the whole cell patch recording technique in vitro, we examined the voltage-dependent firing patterns of 69 interneurons in the rat dorsal lateral geniculate nucleus (LGN). When held at a hyperpolarized membrane potential, all interneurons responded with a burst of action potentials. In 48 interneurons, larger current pulses produced a bursting oscillation. When relatively depolarized, some interneurons produced a tonic train of action potentials in response to a depolarizing current pulse. However, most interneurons produced only oscillations, regardless of polarization level. The oscillation was insensitive to the bath application of a combination of blockers to excitatory and inhibitory synaptic transmission, including 30 microM 6,7-dinitroquinoxaline-2,3-dione, 100 microM (+/-)-2-amino-5-phosphonopentanoic acid, 20 microM bicuculline, and 2 mM saclofen, suggesting an intrinsic event. The frequency of the oscillation in interneurons was dependent on the intensity of the injection current. Increasing current intensity increased the oscillation frequency. The maximal frequency of the oscillation was 5-15 Hz for most cells, with some ambiguity caused by the difficulty of precisely defining a transition from oscillatory to regular firing behavior. In contrast, the interneuron oscillation was little affected by preceding depolarizing and hyperpolarizing pulses. In addition to being elicited by depolarizing current injections, the oscillation could also be initiated by electrical stimulation of the optic tract when the interneurons were held at a depolarized membrane potential. This suggests that interneurons may be recruited into thalamic oscillations by synaptic inputs. These results indicate that interneurons may play a larger role in thalamic oscillations than was previously thought.

Action Potentials↗
PubMed1998

Computer model of antiepileptic effects mediated by alterations in GABA(A)-mediated inhibition.

Results from a computer model of a thalamic network predict that agents augmenting GABA(A)-mediated inhibition in the reticular thalamic (RE) nucleus will be antiepileptic or desynchronizing. This provides support for the hypothesis that antiepileptics like benzodiazepines may exert their effects through an isolated increase of inhibition in the RE nucleus. When desynchronized, the model thalamocortical neurons showed a decreased probability of firing a low threshold spike, a decreased secondary inhibitory postsynaptic potential and a higher frequency of oscillations. The transition to desynchrony was also accompanied by an increased frequency in the firing of the model RE neurons.

Anticonvulsants↗
PubMed1998

Computer models of hippocampal circuit changes of the kindling model of epilepsy.

Abnormalities in the organization of brain circuits may underlie many types of epilepsy. This hypothesis can best be evaluated in the case of temporal lobe epilepsy, where evidence of rewiring (synaptic reorganization) can be found in the dentate gyrus. Computer modeling of normal and reorganized dentate gyrus was used to understand the functional consequences of these structural changes. Hyperexcitability appeared to be largely limited by the powerful intrinsic adaptation characteristic of granule cells, the principal cells in this area. Combining disinhibition with new recurrent excitatory circuitry was necessary to produce repeated firing of these cells. Paradoxically, continuing regenerative activity was only seen with a large reduction in the strength of the inciting stimulus. Validation of these findings will require further physiological correlation.

Computer Simulation↗
PubMed1998

Adapting a feedforward heteroassociative network to Hodgkin-Huxley dynamics.

Using the original McCulloch-Pitts notion of simple on and off spike coding in lieu of rate coding, an Anderson-Kohonen artificial neural network (ANN) associative memory model was ported to a neuronal network with Hodgkin-Huxley dynamics. In the ANN, the use of 0/1 (no-spike/spike) units introduced a cross-talk term that had to be compensated by introducing balanced feedforward inhibition. The resulting ANN showed good capacity and fair selectivity (rejection of unknown input vectors). Translation to the Hodgkin-Huxley model resulted in a network that was functional but not at all robust. Evaluation of the weaknesses of this network revealed that it functioned far better using spike timing, rather than spike occurrence, as the code. The algorithm requires a novel learning algorithm for feedforward inhibition that could be sought physiologically.

Action Potentials↗
PubMed1997

Computer model of clonazepam's effect in thalamic slice.

In the thalamus, paradoxical changes in response to augmentation of inhibition can occur as a result of either cellular or network effects. Clonazepam, a GABA(A) agonist, produces a paradoxical reduction in evoked thalamocortical neuron inhibitory postsynaptic potential (IPSP) in thalamic slice. This has been hypothesized to be a result of augmentation in inhibitory to inhibitory connections. In a computer model, orthodromic simulation produced an increase in initial IPSP, a result contrary to that found experimentally. This failure was traced to the inability of orthodromic activation to produce fast enough recurrent inhibition to alter initial reticularis neuron firing. Simulated antidromic stimulation was able to reduce this initial spike train and reproduced the experimental finding.

Animals↗
PubMed1997

Inhibition can disrupt hypersynchrony in model neuronal networks.

1. Model neuronal network simulations were performed using a reduced Traub neuronal network model. In the absence of inhibition the network produced synchronous population bursting. 2. Bursting of individual neurons was dependent on 1 or more of the following: build-up of charge in the dendritic compartment, prolonged current flow through simulated NMDA associated channels, current flow through T channels. Interburst interval duration and consequent burst frequency was dependent on the density of slow after-hyperpolarizing potassium channels. 3. Addition of an inhibitory interneuron population projecting to GABAA receptors resulted in rapid desynchronization of the population, generally after only 1-2 cycles. This effect was found to be due to reduced participation in the individual population burst and to the need for multi-synaptic activation of the individual neuron in the presence of inhibition. 4. This desynchronizing effect could be offset by increasing the strength of interburst hyperpolarization either through increased density of IAHP, or through the addition of a separate inhibitory interneuron pool projected to GABAB receptors. 5. These data suggest that the synchronizing effects of inhibition may vary depending on circumstances-with desynchronization being dominant in cases characterized by large population bursts such as those seen in epilepsy.

Excitatory Amino Acid Agonists↗
PubMed1997

Dynamic interactions determine partial thalamic quiescence in a computer network model of spike-and-wave seizures.

In vivo intracellular recording from cat thalamus and cortex was performed during spontaneous spike-wave seizures characterized by synchronously firing cortical neurons correlated with the electroencephalogram. During these seizures, thalamic reticular (RE) neurons discharged with long spike bursts riding on a depolarization, whereas thalamocortical (TC) neurons were either entrained into the seizures (40%) or were quiescent (60%). During quiescence, TC neurons showed phasic inhibitory postsynaptic potentials (IPSPs) that coincided with paroxysmal depolarizing shifts in the simultaneously recorded cortical neuron. Computer simulations of a reciprocally connected TC-RE pair showed two major modes of TC-RE interaction. In one mode, a mutual oscillation involved direct TC neuron excitation of the RE neuron leading to a burst that fed back an IPSP into the TC neuron, producing a low-threshold spike. In the other, quiescent mode, the TC neuron was subject to stronger coalescing IPSPs. Simulated cortical stimulation could trigger a transition between the two modes. This transition could go in either direction and was dependent on the precise timing of the input. The transition did not always follow the stimulation immediately. A larger, multicolumnar simulation was set up to assess the role of the TC-RE pair in the context of extensive divergence and convergence. The amount of TC neuron spiking generally correlated with the strength of total inhibitory input, but large variations in the amount of spiking could be seen. Evidence for mutual oscillation could be demonstrated by comparing TC neuron firing with that in reciprocally connected RE neurons. An additional mechanism for TC neuron quiescence was assessed with the use of a cooperative model of gamma-aminobutyric acid-B (GABA(B))-mediated responses. With this model, RE neurons receiving repeated strong excitatory input produced TC neuron quiescence due to burst-duration-associated augmentation of GABA(B) current. We predict the existence of spatial inhomogeneity in apparently generalized spike-wave seizures, involving a center-surround pattern. In the center, intense cortical and RE neuron activity would be associated with TC neuron quiescence. In the surround, less intense hyperpolarization of TC neurons would allow low-threshold spikes to occur. This surround, an "epileptic penumbra," would be the forefront of the expanding epileptic wave during the process of initial seizure generalization. Therapeutically, we would then predict that agents that reduce TC neuron activity would have a greater effect on seizure onset than on ongoing spike-wave seizures or other thalamic oscillations.

Action Potentials↗
PubMed1997

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells.

GABAA-mediated IPSCs in piriform cortex have fast and slow components with different properties and locations on pyramidal cells. J. Neurophysiol. 78: 2531-2545, 1997. A recent study in piriform (olfactory) cortex provided evidence that, as in hippocampus and neocortex, gamma-aminobutyric acid-A (GABAA)-mediated inhibition is generated in dendrites of pyramidal cells, not just in the somatic region as previously believed. This study examines selected properties of GABAA inhibitory postsynaptic currents (IPSCs) in dendritic and somatic regions that could provide insight into their functional roles. Pharmacologically isolated GABAA-mediated IPSCs were studied by whole cell patch recording in slices. To compare properties of IPSCs in distal dendritic and somatic regions, local stimulation was carried out with tungsten microelectrodes, and spatially restricted blockade of GABAA-mediated inhibition was achieved by pressure-ejection of bicuculline from micropipettes. The results revealed that largely independent circuits generate GABAA inhibition in distal apical dendritic and somatic regions. With such independence, a selective decrease in dendritic-region inhibition could enhance integrative or plastic processes in dendrites while allowing feedback inhibition in the somatic region to restrain system excitability. This could allow modulatory fiber systems from the basal forebrain or brain stem, for example, to change the functional state of the cortex by altering the excitability of interneurons that mediate dendritic inhibition without increasing the propensity for regenerative bursting in this highly epileptogenic system. As in hippocampus, GABAA-mediated IPSCs were found to have fast and slow components with time constants of decay on the order of 10 and 40 ms, respectively, at 29 degrees C. Modeling analysis supported physiological evidence that the slow time constant represents a true IPSC component rather than an artifactual slowing of the fast component from voltage clamp of a dendritic current. The results indicated that, whereas both dendritic and somatic-region IPSCs have both fast and slow GABAA components, there is a greater proportion of the slow component in dendrites. In a companion paper, the hypothesis is explored that the resulting slower time course of the dendritic IPSC increases its capacity to regulate the N-methyl--aspartate component of EPSPs. Finally, evidence is presented that the slow GABAA-mediated IPSC component is regulated by presynaptic GABAB inhibition whereas the fast is not. Based on the requirement for presynaptic GABAB-mediated block of inhibition for expression of long-term potentiation, this finding is consistent with participation of the slow GABAA component in regulation of synaptic plasticity. The lack of susceptibility of the fast GABAA component to the long-lasting, activity-induced suppression mediated by presynaptic GABAB receptors is consistent with a protective role for this process in preventing seizure activity.

Animals↗
PubMed1997

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex.

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex. J. Neurophysiol. 78: 2546-2559, 1997. Physiological analysis in the companion paper demonstrated that gamma-aminobutyric acid-A (GABAA)-mediated inhibition in piriform cortex is generated by circuits that are largely independent in apical dendritic and somatic regions of pyramidal cells and that GABAA-mediated inhibitory postsynaptic currents (IPSCs) in distal dendrites have a slower time course than those in the somatic region. This study used modeling methods to explore these characteristics of GABAA-mediated inhibition with respect to regulation of the N-methyl--aspartate (NMDA) component of excitatory postsynaptic potentials. Such regulation is relevant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NMDA component as well as pathological processes that can be activated by overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and other dendritic processes can be controlled by way of GABAergic tone without substantially altering system excitability. The analysis was performed on a branched compartmental model of a pyramidal cell in piriform cortex constructed with physiological and anatomic data derived by whole cell patch recording. Simulations with the model revealed that NMDA expression is more effectively blocked by the slow GABAA component than the fast. Because the slow component is present in greater proportion in apical dendritic than somatic regions, this characteristic would increase the capacity of dendritic IPSCs to regulate NMDA-mediated processes. The simulations further revealed that somatic-region GABAergic inhibition can regulate the generation of action potentials with little effect on the NMDA component generated by afferent fibers in apical dendrites. As a result, if expression of the NMDA component or other dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulate learning and memory, the somatic-region IPSC could preserve system stability through feedback regulation of firing without counteracting the effect of the dendritic-region block. Simulations with paired inputs revealed that the dendritic GABAA-mediated IPSC can regulate the extent to which a strong excitatory input facilitates the NMDA component of a concurrent weak input, providing a possible mechanism for control of "associative LTP" that has been demonstrated in this system. Postsynaptic GABAB-mediated inhibition had less effect on the NMDA component than either the fast or slow GABAA components. Depolarization from a concomitant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component also was found to have comparatively little effect on current through the NMDA channel because of its brief time course.

2-Amino-5-phosphonovalerate↗
PubMed1997

Receptive field changes after strokelike cortical ablation: a role for activation dynamics.

The reorganization of neural activity that takes place after stroke is of paramount importance in producing functional recovery. Experimental stroke models have suggested that this reorganization may have two phases, but physiology alone cannot fully resolve what causes each phase. Computer modeling suggests that these phases might involve an initial change in dynamics occurring immediately, followed by synaptic plasticity. We combined physiological recording from macaque middle temporal cortex (area MT) with a neural network computer model to examine this first phase of altered cortical function after a small, experimentally induced cortical lesion. Major receptive field (RF) changes seen in the first few days postlesion included both expansion and contraction of receptive fields. Although only expansion could be reproduced in an initial model, addition of inhibitory interneuron loss in a ring around the primary ablation, suggested by immunohistochemical examination, permitted contraction to be replicated as well. We therefore predict that this immunochemical observation reflects an immediate extension of the lesion rather than a late response. Additionally our model successfully predicted a correlation between increased firing rate and RF size. Our model suggests that activation dynamics alone, without anatomic remodeling, can cause the large receptive field changes that allow the rapid behavioral recovery seen after middle temporal lesions.

Animals↗
PubMed1996

Optimizing synaptic conductance calculation for network simulations.

High computational requirements in realistic neuronal network simulations have led to attempts to realize implementation efficiencies while maintaining as much realism as possible. Since the number of synapses in a network will generally far exceed the number of neurons, simulation of synaptic activation may be a large proportion of total processing time. We present a consolidating algorithm based on a recent biophysically-inspired simplified Markov model of the synapse. Use of a single lumped state variable to represent a large number of converging synaptic inputs results in substantial speed-ups.

Algorithms↗
PubMed1996

Control of slow oscillations in the thalamocortical neuron: a computer model.

We investigated computer models of a single thalamocortical neuron to assess the interaction of intrinsic voltage-sensitive channels and cortical synaptic input in producing the range of oscillation frequencies observed in these cells in vivo. A morphologically detailed model with Hodgkin-Huxley-like ion channels demonstrated that intrinsic properties would be sufficient to readily produce 3 to 6 Hz oscillations. Hyperpolarization of the model cell reduced its oscillation frequency monotonically whether through current injection or modulation of a potassium conductance, simulating the response to a neuromodulatory input. We performed detailed analysis of highly reduced models to determine the mechanism of this frequency control. The interburst interval was controlled by two different mechanisms depending on whether or not the pacemaker current, IH, was present. In the absence of IH, depolarization during the interburst interval occurred at the same rate with different current injections. The voltage difference from the nadir to threshold for the low-threshold calcium current, IT, determined the interburst interval. In contrast, with IH present, the rate of depolarization depended on injected current. With the full model, simulated repetitive cortical synaptic input entrained oscillations up to approximately double the natural frequency. Cortical input readily produced phase resetting as well. Our findings suggest that neither ascending brainstem control altering underlying hyperpolarization, nor descending drive by repetitive cortical inputs, would alone be sufficient to produce the range of oscillation frequencies seen in thalamocortical neurons. Instead, intrinsic neuronal mechanisms would dominate for generating the delta range (0.5-4 Hz) oscillations seen during slow wave sleep, whereas synaptic interactions with cortex and the thalamic reticular nucleus would be required for faster oscillations in the frequency range of spindling (7-14 Hz).

Cerebral Cortex↗
PubMed1992

Computer model of ethosuximide's effect on a thalamic neuron.

Ethosuximide appears to have a specific effect on the low-threshold calcium current in thalamic cells. This may be related to its efficacy in the treatment of absence epilepsy. We used a computer model of an individual thalamocortical neuron to better understand the alteration in the low-threshold calcium current under voltage clamp and to predict response to current injection in the presence of ethosuximide. The full model included nine voltage-sensitive ionic channels and a realistic dendritic morphology. The model reproduced the two major responses seen in tissue slices: repetitive spiking with depolarization and the low-threshold calcium spike elicited on release from hyperpolarization. The alteration in low-threshold calcium current with ethosuximide can be explained by a 10-mV depolarizing shift in the steady-state activation curve for this channel with a 10% reduction in maximum channel permeability. Simulations of current injection showed that ethosuximide diminished the low-threshold calcium spike while leaving the tonic firing pattern unaffected. Our results support the hypothesis that ethosuximide's effects on low-threshold calcium current might selectively alter the dynamics of slow bursting in thalamic cells.

Action Potentials↗