Cajal Institute CSIC

Madrid, Spain

Cajal Institute CSIC

Madrid, Spain
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Richardson H.E.,La Trobe University | Portela M.,Cajal Institute CSIC
Current Opinion in Cell Biology | Year: 2017

Cell polarity regulation is critical for defining membrane domains required for the establishment and maintenance of the apical-basal axis in epithelial cells (apico-basal polarity), asymmetric cell divisions, planar organization of tissues (planar cell polarity), and the formation of the front-rear axis in cell migration (front-rear polarity). In the vinegar fly, Drosophila melanogaster, cell polarity regulators also interact with the Hippo tissue growth control signaling pathway. In this review we survey the recent Drosophila literature linking cell polarity regulators with the Hippo pathway in epithelial tissue growth, neural stem cell asymmetric divisions and in cell migration in physiological and tumorigenic settings. © 2017 Elsevier Ltd

Fernandez-Ruiz A.,Cajal Institute CSIC | Herreras O.,Cajal Institute CSIC
Frontiers in Computational Neuroscience | Year: 2013

Although intracerebral field potential oscillations are commonly used to study information processing during cognition and behavior, the cellular and network processes underlying such events remain unclear. The limited spatial resolution of standard single-point recordings does not clarify whether field oscillations reflect the activity of one or many afferent presynaptic populations. However, multi-site recording devices now provide high-resolution spatial profiles of local field potentials and when coupled to modern mathematical analyses that discriminate signals with distinct but overlapping spatial distributions, they open the door to better understand these potentials. Here we review recent insights that help disentangle certain pathway-specific activities. Accordingly, some oscillatory patterns can now be viewed as a periodic succession of synchronous synaptic currents that reflect the time envelope of spiking activity in given presynaptic populations. These analyses modify our concept of brain rhythms as abstract entities, molding them into mechanistic representations of network activity and allowing us to work in the time domain, reducing the loss of information inherent to data-chopping frequency treatment. © 2013 Fernández-ruiz and Herreras.

Fernandez-Ruiz A.,Cajal Institute CSIC | Makarov V.A.,Complutense University of Madrid | Herreras O.,Cajal Institute CSIC
Frontiers in Neural Circuits | Year: 2012

Long-term potentiation (LTP) is commonly used to study synaptic plasticity but the associated changes in the spontaneous activity of individual neurons or the computational properties of neural networks in vivo remain largely unclear. The multisynaptic origin of spontaneous spikes makes it difficult to estimate the impact of a particular potentiated input. Accordingly, we adopted an approach that isolates pathway-specific postsynaptic activity from raw local field potentials (LFPs) in the rat hippocampus in order to study the effects of LTP on ongoing spike transfer between cell pairs in the CA3-CA1 pathway. CA1 Schaffer-specific LFPs elicited by spontaneous clustered firing of CA3 pyramidal cells involved a regular succession of elementary micro-field-EPSPs (gamma-frequency) that fired spikes in CA1 units. LTP increased the amplitude but not the frequency of these ongoing excitatory quanta. Also, the proportion of Schaffer-driven spikes in both CA1 pyramidal cells and interneurons increased in a cell-specific manner only in previously connected CA3-CA1 cell pairs, i.e., when the CA3 pyramidal cell had shown pre-LTP significant correlation with firing of a CA1 unit and potentiated spike-triggered average (STA) of Schaffer LFPs following LTP. Moreover, LTP produced subtle reorganization of presynaptic CA3 cell assemblies. These findings show effective enhancement of pathway-specific ongoing activity which leads to increased spike transfer in potentiated segments of a network. They indicate that plastic phenomena induced by external protocols may intensify spontaneous information flow across specific channels as proposed in transsynaptic propagation of plasticity and synfire chain hypotheses that may be the substrate for different types of memory involving multiple brain structures. © 2012 Herreras, Makarov and Fernández-ruiz.

Martin-Vazquez G.,Cajal Institute CSIC | Benito N.,Cajal Institute CSIC | Benito N.,CNRS Pascal Institute | Makarov V.A.,Complutense University of Madrid | And 3 more authors.
Cerebral Cortex | Year: 2016

Identifying the pathways contributing to local field potential (LFP) events and oscillations is essential to determine whether synchronous interregional patterns indicate functional connectivity. Here, we studied experimentally and numerically how different target structures receiving input from a common population shape their LFPs. We focused on the bilateral CA3 that sends gamma-paced excitatory packages to the bilateral CA1, the lateral septum, and itself (recurrent input). The CA3-specific contribution was isolated from multisite LFPs in target regions using spatial discrimination techniques. We found strong modulation of LFPs by target-specific features, including the morphology and population arrangement of cells, the timing of CA3 inputs, volume conduction from nearby targets, and co-activated inhibition. Jointly they greatly affect the LFP amplitude, profile, and frequency characteristics. For instance, ipsilateral (Schaffer) LFPs occluded contralateral ones, and septal LFPs arise mostly from remote sources while local contribution from CA3 input was minor. In the CA3 itself, gamma waves have dual origin from local networks: in-phase excitatory and nearly antiphase inhibitory. Also, waves may have different duration and varying phase in different targets. These results indicate that to explore the cellular basis of LFPs and the functional connectivity between structures, besides identifying the origin population/s, target modifiers should be considered. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved.

Herreras O.,Cajal Institute CSIC
Frontiers in Neural Circuits | Year: 2016

The intracerebral local field potential (LFP) is a measure of brain activity that reflects the highly dynamic flow of information across neural networks. This is a composite signal that receives contributions from multiple neural sources, yet interpreting its nature and significance may be hindered by several confounding factors and technical limitations. By and large, the main factor defining the amplitude of LFPs is the geometry of the current sources, over and above the degree of synchronization or the properties of the media. As such, similar levels of activity may result in potentials that differ in several orders of magnitude in different populations. The geometry of these sources has been experimentally inaccessible until intracerebral high density recordings enabled the co-activating sources to be revealed. Without this information, it has proven difficult to interpret a century’s worth of recordings that used temporal cues alone, such as event or spike related potentials and frequency bands. Meanwhile, a collection of biophysically ill-founded concepts have been considered legitimate, which can now be corrected in the light of recent advances. The relationship of LFPs to their sources is often counterintuitive. For instance, most LFP activity is not local but remote, it may be larger further from rather than close to the source, the polarity does not define its excitatory or inhibitory nature, and the amplitude may increase when source’s activity is reduced. As technological developments foster the use of LFPs, the time is now ripe to raise awareness of the need to take into account spatial aspects of these signals and of the errors derived from neglecting to do so. © 2016 Herreras.

Makarova J.,Cajal Institute CSIC | Ortuno T.,University of La Coruña | Korovaichuk A.,Cajal Institute CSIC | Korovaichuk A.,Max Planck Institute for Biophysical Chemistry | And 4 more authors.
Frontiers in Systems Neuroscience | Year: 2014

Deciphering how the brain encodes the continuous flow of information contained in natural stimuli requires understanding the spontaneous activity of functional assemblies in multiple neuronal populations. A promising integrative approach that combines multisite recordings of local field potentials (LFP) with an independent component analysis (ICA) enables continuous readouts of population specific activities of functionally different neuron groups to be obtained. We previously used this technique successfully in the hippocampus, a single-layer neuronal structure. Here we provide numerical evidence that the cytoarchitectonic complexity of other brain structures does not compromise the value of the ICA-separated LFP components, given that spatial sampling of LFP is representative. The spatial distribution of an LFP component may be quite complex due to folded and multilayered structure of the neuronal aggregate. Nevertheless, the time course of each LFP component is still a reliable postsynaptic convolution of spikes fired by a homogeneous afferent population. This claim is supported by preliminary experimental data obtained in the lateral geniculate nucleus of the awake monkey. © 2014 Makarova, Ortuño, Korovaichuk, Cudeiro, Makarov, Rivadulla and Herreras.

Perez-Domper P.,Cajal Institute CSIC | Perez-Domper P.,CIBER ISCIII | Gradari S.,Cajal Institute CSIC | Trejo J.L.,Cajal Institute CSIC
Ageing Research Reviews | Year: 2013

The decision between cellular survival and death is governed by a balance between proapoptotic versus antiapoptotic signaling cascades. Growth factors are key actors, playing two main roles both at developmental and adult stages: a supporting antiapoptotic role through diverse actions converging in the mitochondria, and a promoter role of cell maturation and plasticity through dendritogenesis and synaptogenesis, especially relevant for the adult hippocampal neurogenesis, a case of development during adulthood. Here, both parallel roles mutually feed forward each other (the success in avoiding apoptosis lets the cell to grow and differentiate, which in turn lets the cell to reach new targets and form new synapses accessing new sources of growth factors to support cell survival) in a circular cause and consequence, or a "the chicken or the egg" dilemma. While identifying the first case of this dilemma makes no sense, one possible outcome might have biological relevance: the decision between survival and death in the adult hippocampal neurogenesis is mainly concentrated at a specific time window, and recent data suggest some divergences between the survival and the maturational promoter effect of growth factors. This review summarizes these evidences suggesting how growth factors might contribute to the live-or-die decision of adult-born immature granule neurons through influencing the maturation of the young neuron by means of its connectivity into a mature functional circuit. © 2013 Elsevier B.V.

Suarez L.M.,Cajal Institute CSIC | Suarez L.M.,CIBER ISCIII | Solis O.,Cajal Institute CSIC | Solis O.,CIBER ISCIII | And 7 more authors.
Biological Psychiatry | Year: 2014

Background L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is an incapacitating complication of L-DOPA therapy that affects most patients with Parkinson's disease. Previous work indicating that molecular sensitization to dopamine receptor D1 (D1R) stimulation is involved in dyskinesias prompted us to perform electrophysiological recordings of striatal projection "medium spiny neurons" (MSN). Moreover, because enhanced D1R signaling in drug abuse induces changes in spine density in striatum, we investigated whether the dyskinesia is related to morphological changes in MSNs. Methods Wild-type and bacterial artificial chromosome transgenic mice (D1R-tomato and D2R-green fluorescent protein) mice were lesioned with 6-hydroxydopamine and subsequently treated with L-DOPA to induce dyskinesia. Functional, molecular, and structural changes were assessed in corticostriatal slices. Individual MSNs injected with Lucifer-Yellow were detected by immunohistochemistry for three-dimensional reconstructions with Neurolucida software. Intracellular current-clamp recordings with high-resistance micropipettes were used to characterize electrophysiological parameters. Results Both D1R-MSNs and D2R-MSNs showed diminished spine density in totally denervated striatal regions in parkinsonian mice. Chronic L-DOPA treatment, which induced dyskinesia and aberrant FosB expression, restored spine density in D2R-MSNs but not in D1R-MSNs. In basal conditions, MSNs are more excitable in parkinsonian than in sham mice, and excitability decreases toward normal values after L-DOPA treatment. Despite this normalization of basal excitability, in dyskinetic mice, the selective D1R agonist SKF38393 increased the number of evoked action potentials in MSNs, compared with sham animals. Conclusions Chronic L-DOPA induces abnormal spine re-growth exclusively in D2R-MSNs and robust supersensitization to D1R-activated excitability in denervated striatal MSNs. These changes might constitute the anatomical and electrophysiological substrates of dyskinesia. © 2014 Society of Biological Psychiatry.

Dreier J.P.,Charité - Medical University of Berlin | Isele T.,TU Berlin | Reiffurth C.,Charité - Medical University of Berlin | Offenhauser N.,Charité - Medical University of Berlin | And 3 more authors.
Neuroscientist | Year: 2013

In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs-Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death. © The Author(s) 2013.

Lolo F.-N.,Spanish National Cancer Center | Lolo F.-N.,Spanish National Cardiovascular Center | Tinto S.C.,Spanish National Cancer Center | Tinto S.C.,Cajal Institute CSIC | And 2 more authors.
BioEssays | Year: 2013

Recent results show that, during the process known as cell competition, winner cells identify and kill viable cells from a growing population without requiring engulfment. The engulfment machinery is mainly required in circulating macrophages (hemocytes) after the discrimination between winners and losers is completed and the losers have been killed and extruded from the epithelium. Those new results leave us with the question as to which molecules allow winner cells to recognize and impose cell death on the loser cells during cell competition. During cell competition, winner cells induce apoptosis in loser cells by unknown mechanisms. Apoptotic debris is extruded basally from the epithelium to be cleared by hemocytes. © 2013 WILEY Periodicals, Inc.

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