Transient dynamics and rhythm coordination of inferior olive spatio-temporal patterns

This Document is protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission.The inferior olive (IO) is a neural network belonging to the olivo-cerebellar system whose neurons are coupled with electrical synapses and display subthreshold oscillations and spiking activity. The IO is frequently proposed as the generator of timing signals to the cerebellum. Electrophysiological and imaging recordings show that the IO network generates complex spatio-temporal patterns. The generation and modulation of coherent spiking activity in the IO is one key issue in cerebellar research. In this work, we build a large scale IO network model of electrically coupled conductance-based neurons to study the emerging spatio-temporal patterns of its transient neuronal activity. Our modeling reproduces and helps to understand important phenomena observed in IO in vitro and in vivo experiments, and draws new predictions regarding the computational properties of this network and the associated cerebellar circuits. The main factors studied governing the collective dynamics of the IO network were: the degree of electrical coupling, the extent of the electrotonic connections, the presence of stimuli or regions with different excitability levels and the modulatory effect of an inhibitory loop (IL). The spatio-temporal patterns were analyzed using a discrete wavelet transform to provide a quantitative characterization. Our results show that the electrotonic coupling produces quasi-synchronized subthreshold oscillations over a wide dynamical range. The synchronized oscillatory activity plays the role of a timer for a coordinated representation of spiking rhythms with different frequencies. The encoding and coexistence of several coordinated rhythms is related to the different clusterization and coherence of transient spatio-temporal patterns in the network, where the spiking activity is commensurate with the quasi-synchronized subthreshold oscillations. In the presence of stimuli, different rhythms are encoded in the spiking activity of the IO neurons that nevertheless remains constrained to a commensurate value of the subthreshold frequency. The stimuli induced spatio-temporal patterns can reverberate for long periods, which contributes to the computational properties of the IO. We also show that the presence of regions with different excitability levels creates sinks and sources of coordinated activity which shape the propagation of spike wave fronts. These results can be generalized beyond IO studies, as the control of wave pattern propagation is a highly relevant problem in the context of normal and pathological states in neural systems (e.g., related to tremor, migraine, epilepsy) where the study of the modulation of activity sinks and sources can have a potential large impact.Roberto Latorre, Carlos Aguirre, and Pablo Varona were supported by MINECOTIN 2012-30883 and MikhailI. Rabinovich by ONRGrantN00014310205

Rebuilding Cerebellar Network Computations from Cellular Neurophysiology

This schematic drawing shows the most relevant connections within a cerebellar module. The mossy fibers contact granule cells (GrC) and deep cerebellar nuclei (DCN) cells which, in turn, receive inhibition from the same common set of Purkinje cells (PC). Moreover, the interior olive (IO) cells emit climbing fibers that contact DCN cells and Purkinje cells (PC), which also project to the same DCN cells. An activate group of GrCs is in (red), while others (yellow) are laterally inhibited by the GoCs. The active GrCs excite the overlaying PCs (dark red) according to a vertical organization pattern (Bower and Woolston, 1983). The PCs inhibit DCN neurons which in turn inhibit the IO neurons. Note that, within a cerebellar module, different circuit elements communicate in closed loops. The mossy fibers contact granule cells and DCN cells which, in turn, receive inhibition from the same common set of Purkinje cells. Moreover, the IO cells emit climbing fibers that contact DCN and PC, which also project to the same DCN cells

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate realistic models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems

Excitatory postsynaptic potentials in rat neocortical neurons in vitro. III. Effects of a quinoxalinedione non-NMDA receptor antagonist

1. Intracellular microelectrodes were used to obtain recordings from neurons in layer II/III of rat frontal cortex. A bipolar electrode positioned in layer IV of the neocortex was used to evoke postsynaptic potentials. Graded series of stimulation were employed to selectively activate different classes of postsynaptic responses. The sensitivity of postsynaptic potentials and iontophoretically applied neurotransmitters to the non-N-methyl-D-asparate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) was examined. 2. As reported previously, low-intensity electrical stimulation of cortical layer IV evoked short-latency early excitatory postsynaptic potentials (eEPSPs) in layer II/III neurons. CNQX reversibly antagonized eEPSPs in a dose-dependent manner. Stimulation at intensities just subthreshold for activation of inhibitory postsynaptic potentials (IPSPs) produced long-latency (10 to 40-ms) EPSPs (late EPSPs or 1EPSPs). CNQX was effective in blocking 1EPSPs. 3. With the use of stimulus intensities at or just below threshold for evoking an action potential, complex synaptic potentials consisting of EPSP-IPSP sequences were observed. Both early, Cl(-)-dependent and late, K(+)-dependent IPSPs were reduced by CNQX. This effect was reversible on washing. This disinhibition could lead to enhanced excitability in the presence of CNQX. 4. Iontophoretic application of quisqualate produced a membrane depolarization with superimposed action potentials, whereas NMDA depolarized the membrane potential and evoked bursts of action potentials. At concentrations up to 5 microM, CNQX selectively antagonized quisqualate responses. NMDA responses were reduced by 10 microM CNQX. D-Serine (0.5-2 mM), an agonist at the glycine regulatory site on the NMDA receptor, reversed the CNQX depression of NMDA responses

Spike burst-pause dynamics of Purkinje cells regulate sensorimotor adaptation

Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.This work was supported by the European Union (www.europa.eu), Project SpikeControl 658479 (recipient NL), the Spanish Agencia Estatal de Investigacio´n and European Regional Development Fund (www.ciencia.gob.es/ portal/site/MICINN/aei), Project CEREBROT TIN2016-81041-R (recipient ER), and the French National Research Agency (www.agence-nationalerecherche. fr) – Essilor International (www.essilor. com), Chair SilverSight ANR-14-CHIN-0001 (recipient AA)

Interplay between subthreshold oscillations and depressing synapses in single neurons

Latorre R, Torres JJ, Varona P (2016) Interplay between Subthreshold Oscillations and Depressing Synapses in Single Neurons. PLoS ONE 11(1): e0145830. doi:10.1371/journal.pone.0145830In this paper we analyze the interplay between the subthreshold oscillations of a single neuron conductance-based model and the short-term plasticity of a dynamic synapse with a depressing mechanism. In previous research, the computational properties of subthreshold oscillations and dynamic synapses have been studied separately. Our results show that dynamic synapses can influence different aspects of the dynamics of neuronal subthreshold oscillations. Factors such as maximum hyperpolarization level, oscillation amplitude and frequency or the resulting firing threshold are modulated by synaptic depression, which can even make subthreshold oscillations disappear. This influence reshapes the postsynaptic neuron's resonant properties arising from subthreshold oscillations and leads to specific input/output relations. We also study the neuron's response to another simultaneous input in the context of this modulation, and show a distinct contextual processing as a function of the depression, in particular for detection of signals through weak synapses. Intrinsic oscillations dynamics can be combined with the characteristic time scale of the modulatory input received by a dynamic synapse to build cost-effective cell/channel-specific information discrimination mechanisms, beyond simple resonances. In this regard, we discuss the functional implications of synaptic depression modulation on intrinsic subthreshold dynamics.This work was supported by MINECO TIN2012-30883 (RL and PV) and FIS2013-43201-P (JJT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Gap junctions and emergent rhythms

Gap junction coupling is ubiquitous in the brain, particularly between the dendritic trees of inhibitory interneurons. Such direct non-synaptic interaction allows for direct electrical communication between cells. Unlike spike-time driven synaptic neural network models, which are event based, any model with gap junctions must necessarily involve a single neuron model that can represent the shape of an action potential. Indeed, not only do neurons communicating via gaps feel super-threshold spikes, but they also experience, and respond to, sub-threshold voltage signals. In this chapter we show that the so-called absolute integrate-and-fire model is ideally suited to such studies. At the single neuron level voltage traces for the model may be obtained in closed form, and are shown to mimic those of fast-spiking inhibitory neurons. Interestingly in the presence of a slow spike adaptation current the model is shown to support periodic bursting oscillations. For both tonic and bursting modes the phase response curve can be calculated in closed form. At the network level we focus on global gap junction coupling and show how to analyze the asynchronous firing state in large networks. Importantly, we are able to determine the emergence of non-trivial network rhythms due to strong coupling instabilities. To illustrate the use of our theoretical techniques (particularly the phase-density formalism used to determine stability) we focus on a spike adaptation induced transition from asynchronous tonic activity to synchronous bursting in a gap-junction coupled network

Analysis of HOXA5 expression and function in development of the central nervous system

The Hox genes encode transcription factors that are indispensable for proper spatio-temporal patterning of the vertebrate body axes. In mouse, Hoxa5 transcripts are differentially expressed in specific mesoderm-derived structures and in the most anterior domain of expression in the central nervous system (CNS). However, the functional significance of any pattern of protein-coding RNAs must be verified by correlating the presence of the protein(s) and RNAs. Here we describe the dynamic pattern of HOXA5 protein during mouse embryogenesis. The HOXA5 protein is detected as early as embryonic day (E) 9.0, and is found, as development proceeds, in several mesoderm-derived structures. In addition, the protein shows a strikingly restricted and dynamic expression pattern in the developing CNS, and is detected in both motor neurons and interneurons between E10.5-E13.5. In many mesoderm-derived tissues affected by the Hoxa5 mutation, the expression pattern of HOXA5 protein corresponds to that of the putative functional Hoxa5 transcript. However, in the CNS, this correlation is exclusively demonstrated in the most anterior domain of expression. We next focused on a complex HOXA5 expression pattern in the caudal hindbrain. In this structure, we show that HOXA5 expression is confined to the caudal region of the developing inferior olivary nucleus (ION) and dorsal lamella of the dorsal accessory olive (DAO) subnucleus. Furthermore, the ION can be transiently defined by a combinatorial expression of BRN3A and LIM1/2 transcription factors that may belong to a new dorsal neuron cell type in the caudal hindbrain defined in this study. Although HOXA5 is dispensable for the transcriptional code of ION up to embryonic day (E) 16.5, the protein expression is crucial to preserve BRN3A expression in the dorsal lamella of DAO at E18.5. To date, this is the first report for expression of any Hox5 paralog in ION. Our results suggest that HOXA5 plays a strong role in maintaining the normal transcriptional code for ION, which may affect establishment of connectivity, maturation, and synaptic stabilization of climbing fibers developed postnatally. Overall, the HOXA5 protein pattern is consistent with its proposed role in positional specification in mesodermal structures, as well as in the embryonic neuraxis

Editorial: The olivo-cerebellar system

Investigation on the olivo-cerebellum system has attained a high level of sophistication leading to define several structural and functional properties of neurons, synapses, connections and circuits. Research has expanded and deepened in so many directions, and so many theories and models have been proposed, that an ensemble review of the matter is now neede