Institute Of Neurociencies

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Institute Of Neurociencies

Spain
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Gutierrez-Sacristan A.,GRIB | Bravo A.,GRIB | Portero M.,GReNeC | Valverde O.,GReNeC | And 19 more authors.
CEUR Workshop Proceedings | Year: 2016

During the last years there has been a growing research in the genetics of psychiatric diseases. However, there is still a limited understanding of the cellular and molecular mechanisms leading to these diseases, which has hampered the application of this wealth of knowledge into the clinical practice to improve diagnosis and treatment of psychiatric patients. PsyGeNET (http:// www.psygenet.org/) has been developed to improve the understanding of psychiatric diseases, by facilitating the access to the vast amount of their genetic information in a structured manner, providing a set of analysis and visualization tools. In this communication we describe the protocol we put in place for the sustainable update of this knowledge resource. It includes the recruitment of a team of experts to perform the curation of the data previously extracted by text mining. Annotation guidelines and a webbased annotation tool were developed to support curators tasks. A curation workflow was designed including a pilot phase, and two rounds of curation and analysis phases. We report the results of the application of this workflow to the task of curation of gene-disease associations for PsyGeNET, including the analysis of the inter-annotator agreement, and suggest that this model is a suitable approach for the sustainable development and update of knowledge resources.


Carriba P.,Lhospital Universitari Of La Vall Dhebron Vhir | Carriba P.,Institute Of Neurociencies | Carriba P.,CIBER ISCIII | Jimenez S.,CIBER ISCIII | And 22 more authors.
Cell Death and Disease | Year: 2015

The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1M146LxAPP751sl) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells. © 2015 Macmillan Publishers Limited. All rights reserved.


Parra-Damas A.,Institute Of Neurociencies | Parra-Damas A.,Autonomous University of Barcelona | Chen M.,Institute Of Neurociencies | Chen M.,Autonomous University of Barcelona | And 12 more authors.
Biological Psychiatry | Year: 2017

Background Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)–regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions. Methods We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease–linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses. PS cDKO mice display classical features of neurodegeneration occurring in Alzheimer's disease including age-dependent cortical atrophy, neuron loss, dendritic degeneration, and memory deficits. Results Context-associative learning, but not single context or unconditioned stimuli, induces rapid dephosphorylation (Ser151) and translocation of CRTC1 from the cytosol/dendrites to the nucleus of hippocampal neurons in the mouse brain. Accordingly, context-associative learning induces differential CRTC1-dependent transcription of c-fos and the nuclear receptor subfamily 4 (Nr4a) genes Nr4a1-3 in the hippocampus through a mechanism that involves CRTC1 recruitment to CRE promoters. Deregulation of CRTC1 dephosphorylation, nuclear translocation, and transcriptional function are associated with long-term contextual memory deficits in PS cDKO mice. Importantly, CRTC1 gene therapy in the hippocampus ameliorates context memory and transcriptional deficits and dendritic degeneration despite ongoing cortical degeneration in this neurodegeneration mouse model. Conclusions These findings reveal a critical role of CRTC1 in the hippocampus during associative memory, and provide evidence that CRTC1 deregulation underlies memory deficits during neurodegeneration. © 2016 Society of Biological Psychiatry


Cardenas M.-I.,Polytechnic University of Catalonia | Cardenas M.-I.,Institute Of Neurociencies | Vellido A.,Polytechnic University of Catalonia | Vellido A.,CIBER ISCIII | Giraldo J.,Institute Of Neurociencies
Frontiers in Artificial Intelligence and Applications | Year: 2014

G-Protein-Coupled Receptors (GPCRs) are cell membrane proteins with a key role in biological processes. GPCRs of class C, in particular, are of great interest in pharmacology. The lack of knowledge about their 3-D structures means they must be investigated through their primary amino acid sequences. Sequence visualization can help to explore the existing receptor sub-groupings at different partition levels. In this paper, we focus on Metabotropic Glutamate Receptors (mGluR), a subtype of class C GPCRs. Different versions of a probabilistic manifold learning model are employed to comparatively sub-group and visualize them through different transformations of their sequences.


Ortega-Martorell S.,Unitat de Biociencies | Ortega-Martorell S.,CIBER ISCIII | Olier I.,Institute Of Neurociencies | Vellido A.,Polytechnic University of Catalonia | And 4 more authors.
Proceedings of the 18th European Symposium on Artificial Neural Networks - Computational Intelligence and Machine Learning, ESANN 2010 | Year: 2010

Diagnosis in neuro-oncology can be assisted by non-invasive data acquisition techniques such as Magnetic Resonance Spectroscopy (MRS). From the viewpoint of computer-based brain tumour classification, the high dimensionality of MRS poses a difficulty, and the use of dimensionality reduction (DR) techniques is advisable. Despite some important limitations, Principal Component Analysis (PCA) is commonly used for DR in MRS data analysis. Here, we define a novel DR technique, namely Spectral Prototype Extraction, based on a manifold-constrained Hidden Markov Model (HMM). Its formulation within a variational Bayesian framework imbues it with regularization properties that minimize the negative effect of the presence of noise in the data. Its use for MRS pre-processing is illustrated in a difficult brain tumour classification problem.


Daviu N.,Institute Of Neurociencies | Daviu N.,Autonomous University of Barcelona | Rabasa C.,Institute Of Neurociencies | Rabasa C.,Autonomous University of Barcelona | And 5 more authors.
Stress | Year: 2014

Acute exposure to severe stressors causes marked activation of the hypothalamic-pituitary-adrenal (HPA) axis that is reflected on the day after higher resting levels of HPA hormones and sensitization of the HPA response to novel (heterotypic) stressors. However, whether a single exposure to a severe stressor or daily repeated exposure to the same (homotypic) stressor modifies these responses to the same extent has not been studied. In this experiment, we studied this issue in adult male Sprague-Dawley rats daily exposed for seven days to a severe stressor such as immobilization on boards (IMO). A first exposure to 1h IMO resulted in a marked activation of the HPA axis as reflected in plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, and such activation was significantly reduced after the seventh IMO. On the day after the first IMO, higher resting levels of ACTH and corticosterone and sensitization of their responses to a short exposure to an open-field (OF) were observed, together with a marked hypoactivity in this environment. Repeated exposure to IMO partially reduced hypoactivity, the increase in resting levels of HPA hormones and the ACTH responsiveness to the OF on the day after the last exposure to IMO. In contrast, corticosterone response was gradually increased, suggesting partial dissociation from ACTH. These results indicate that daily repeated exposure to the same stressor partially reduced the HPA response to the homotypic stressor as well as the sensitization of HPA axis activity observed the day after chronic stress cessation. © 2014 Informa UK Ltd.


Modol L.,Autonomous University of Barcelona | Casas C.,Institute Of Neurociencies | Llido A.,Autonomous University of Barcelona | Navarro X.,Institute Of Neurociencies | And 2 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014

The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K+/Cl- co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20 mg/kg) or Finasteride (5α-reductase inhibitor, 50 mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development. © 2014 Elsevier Ltd.


Marques-Fernandez F.,Fundacio Institute Of Recerca Of Lhospital Universitari Of La Vall Dhebron | Marques-Fernandez F.,Institute Of Neurociencies | Marques-Fernandez F.,Research Center Biome Dica en Red Sobre Enfermedades Neurodegenerativas | Planells-Ferrer L.,Fundacio Institute Of Recerca Of Lhospital Universitari Of La Vall Dhebron | And 21 more authors.
Cell Death and Disease | Year: 2013

Activation of tumor necrosis factor receptor-1 can trigger survival or apoptosis pathways. In many cellular models, including the neuronal cell model PC12, it has been demonstrated that inhibition of protein synthesis is sufficient to render cells sensitive to apoptosis induced by TNFα. The survival effect is linked to the translocation of the transcription factor nuclear factor-kappa B (NF-κB) to the nucleus and activation of survival-related genes such as FLICE-like inhibitory protein long form (FLIP-L) or IAPs. Nonetheless, we previously reported an NF-κB-independent contribution of Bcl-xL to cell survival after TNFα treatment. Here, we demonstrate that NF-κB-induced increase in FLIP-L expression levels is essential for mitogen-activated protein kinases/ extracellular signal-regulated kinases (MAPK/ERK) activation. We demonstrate that FLIP-L behaves as a Raf-1 activator through both proteinprotein interaction and Raf-1 kinase activation, without the requirement of the classical Ras activation. Importantly, prevention of FLIP-L increase by NF-κB inhibition or knockdown of endogenous FLIP-L blocks MAPK/ERK activation after TNFα treatment. From a functional point of view, we show that inhibition of the MAPK/ERK pathway and the NF-κB pathway are equally relevant to render PC12 cells sensitive to cell death induced by TNFα. Apoptosis induced by TNFα under these conditions is dependent on jun nuclear kinase1/2 JNK1/2-dependent Bim upregulation. Therefore, we report a previously undescribed and essential role for MAPK/ERK activation by FLIP-L in the decision between cell survival and apoptosis upon TNFα stimulation. © 2013 Macmillan Publishers Limited All rights reserved.


Romeo A.,University of Barcelona | Super H.,University of Barcelona | Super H.,Institute Of Neurociencies | Super H.,Catalan Institution for Research and Advanced Studies
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

We introduce a two layer network of spiking neurons with a regulated feedback between both layers determined by a unit functioning as a gating element. Its activity, which ultimately influences the synchrony regime, depends on the processing of the sensory inputs through a receptive field of time-varying radius. The time evolution of this scale affects the length of the intervals which are relevant to attentional effects. Attention can be regarded as an attempt to reduce variability in the difference between expected and actual sensory input. Cognitive processing of sensory stimuli is represented by spike rate as well as by spike timing and the ensuing degree of synchrony. The fact that feedback modifies spike rates by changing spike timing may highlight new aspects of the neural correlates in cognitive processing. That was one of the motivations for the present network, after realizing that the synchrony of global oscillation can be described by changes in feedback signals. We try to model the degree of readiness for success in an visual attentional task using a changing length scale, i.e., a single variable with dimension of length which evolves in time. Our considered stimuli are circles and the internal states of the system are represented by the radius of a visual receptive field (RF), which is also circular and evolves in time. Next, going on to neurons themselves, time oscillation and synchrony properties supply pictures of their global states, and may reflect the variations which take place during a cognitive task. Taking advantage of a gated feedback mechanism, we propose a model for how oscillations can occur sooner at cued regions, and also, with longer delays, at uncued regions. A two-layer network causes a delay in global oscillations when the cue is ‘invalid’, i.e., occurs at a different region than the target. Further, an evolution rate parameter for the RF scale determines the efficiency of the system’s adaptation to new stimuli, to the extent that different degrees of success depend on the value of that rate, which we may interpret as an indirect measure of attention. Our obtained values show rough agreement with experimental measures of typical ‘consolidation’ times. The model provides changing pictures when evolution rates increase by an order of magnitude. On top of lapse lengths, differences in global oscillation onsets between ‘valid-cue’ and ‘invalid-cue’ cases are present. These differences may vary from 200 ms to 25–50 ms when applying such modifications. © Springer International Publishing Switzerland 2016.


Bolea I.,Institute Of Neurociencies | Juarez-Jimenez J.,Institute Of Biomedicina Ibub | De Los Rios C.,Laboratorio Of Radicales Libres Y Quimica Computacional | Chioua M.,Hospital Universitario Of La Princesa | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2- yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC 50 = 5.2 ± 1.1 nM) and MAO-B (IC 50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC 50 = 0.35 ± 0.01 μM) and BuChE (IC 50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy. (Figure presented) © 2011 American Chemical Society.

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