Section: New Results

From the microscopic to the mesoscopic scale

Participants: Laure Buhry, Amélie Aussel, Nathalie Azevedo Carvalho, Dominique Martinez (CNRS), Radu Ranta (Univ. Lorraine, CRAN).

In collaboration with Harry Tran (Univ. Lorraine, CRAN), Louise Tyvaert (Univ. Lorraine, CRAN, CHRU Nancy), Olivier Aron (Univ. Lorraine, CRAN, CHRU Nancy), Sylvain Contassot-Vivier (Univ. Lorraine),

Hippocampal oscillatory activity

Healthy hippocampus

We proposed a detailed anatomical and mathematical model of the hippocampal formation for the generation of healthy hippocampal activity, especially sharp-wave ripples and theta-nested gamma oscillations [24], [25]. Indeed, the mechanisms underlying the broad variety of oscillatory rhythms measured in the hippocampus during the sleep-wake cycle are not yet fully understood. We proposed a computational model of the hippocampal formation based on a realistic topology and synaptic connectivity, and we analyzed the effect of different changes on the network, namely the variation of synaptic conductances, the variations of the CAN channel conductance and the variation of inputs. By using a detailed simulation of intracerebral recordings, we showed that this model is able to reproduce both the theta-nested gamma oscillations that are seen in awake brains and the sharp-wave ripple complexes measured during slow-wave sleep. The results of our simulations support the idea that the functional connectivity of the hippocampus, modulated by the sleep-wake variations in Acetylcholine concentration, is a key factor in controlling its rhythms [24].

We further extended this work with an extensive study of the parameter range of the healthy hippocampus activity and showed that the "healthy model" was unable to reproduce pathological hippocampal oscillations observed in temporal lobe epilepsy.

Modeling LFP measures

The development of this model was also the opportunity to extend our model of the measure of the local field potential (LFP) and to study the contribution of spikes (not only synaptic currents) to the generation of the LFP. Indeed, simulating extracellular recordings of neuronal populations is a challenging task for understanding the nature of extracellular field potentials (LFPs), investigating specific brain structures and mapping cognitive functions. In general, it is assumed that extracellular recording devices (micro and/or macro-electrodes) record a mixture of low frequency patterns, mainly attributed to the synaptic currents and high-frequency components reflecting action potential (APs) activity. Simulating such signals often requires a high computational burden due to the multicompartmental neuron models used. Therefore, different LFP proxies coexist in the literature, most of them only reproducing some of the features of experimental signals. This may be an issue in producing and validating computational models of phenomena where the fast and slow components of neural activity are equally important, such as hippocampal oscillations. In this part of the work, we proposed an original approach for simulating large-scale neural networks efficiently while computing a realistic approximation of the LFP signal including extracellular signatures of both synaptic and action potentials [26]. We applied this method on the hippocampal network we developed earlier and compared the simulated signal with intracranial measurements from human patients.

Epilepsy of the mesial temporal lobe

The model described above has then been extended to include pathological changes observed in temporal lobe epilepsy, the future goal being to better understand the generation and propagation of epileptic activity throughout the brain, and therefore to investigate new potential therapeutic targets.

The mechanisms underlying the generation of hippocampal epileptic seizures and interictal events during the sleep-wake cycle are not yet fully understood. In this article, based on our previous computational modeling work of the hippocampal formation based on realistic topology and synaptic connectivity, we study the role of network specificity and channel pathological conditions of the epileptic hippocampus in the generation and maintenance of seizures and interictal oscillations. Indeed, the epilepsies of the mesial temporal lobe are associated with hippocampal neuronal and axonal loss, mossy fiber sprouting and channelopathies, namely impaired potassium and chlore dynamics. We show, through the simulations of hippocampal activity during slow-wave sleep and wakefulness that: (i) both mossy fiber sprouting and sclerosis account for epileptic seizures, (ii) high hippocampal sclerosis with low sprouting suppresses seizures, (iii) impaired potassium and chloride dynamics have little influence on the generation of seizures, (iv) but do have an influence on interictal spikes that decreases with high mossy fiber sprouting. A manuscript is in preparation for the Journal of Neuroscience.

Synchronization phenomena in neuronal network models

From a more computational point of view, we got interested in interneuronal gamma oscillations and synchronization in hippocampus-like networks via different models, especially in adaptive exponential integrate-and-fire neurons. Fast neuronal oscillations in gamma frequencies are observed in neocortex and hippocampus during essential arousal behaviors. Through a four-variable Hodgkin–Huxley type model, Wang and Buzsáki have numerically demonstrated that such rhythmic activity can emerge from a random network of GABAergic interneurons via minimum synaptic inputs. In this case, the intrinsic neuronal characteristics and network structure act as the main drive of the rhythm. We investigate inhibitory network synchrony with a low complexity, two-variable adaptive exponential integrate-and-fire (AdEx) model, whose parameters possess strong physiological relevances, and provide a comparison with the two-variable Izhikevich model and Morris–Lecar model. Despite the simplicity of these three models, the AdEx model shares two important results with the previous biophysically detailed Hodgkin–Huxley type model: the minimum number of synaptic inputs necessary to initiate network gamma-band rhythms remains the same, and this number is weakly dependent on the network size. Meanwhile, Izhikevich and Morris–Lecar neurons demonstrate different results in this study. We further investigated the necessary neuronal, synaptic and connectivity properties, including gap junctions and shunting inhibitions, for AdEx model leading to sparse and random network synchrony in gamma rhythms and nested theta gamma rhythms. These findings suggest a computationally more tractable framework for studying synchronized networks in inducing cerebral gamma band activities.

Event-driven simulation of large scale neural models with on-demand connectivity generation

Accurate simulations of brain structures is a major problem in neuroscience. Many works are dedicated to design better models or to develop more efficient simulation schemes. In this work, we propose to combine time-stepping numerical integration of Hodgkin-Huxley type neurons with event-driven updating of the synaptic currents. A spike detection method was also developed to determine the spike time more precisely in order to preserve the second-order Runge-Kutta methods. This hybrid approach allows us to regenerate the outgoing connections at each event, thereby avoiding the storage of the connectivity. Consequently, memory consumption and execution time are significantly reduced while preserving accurate simulations, especially spike times of detailed point neuron models. The efficiency of the method has been demonstrated on the simulation of ${10}^6$ interconnected MSN neurons with Parkinson disease (an article has been submitted to Frontiers in Neuroinformatics) [23].