Acebes A.,Cajal Institute
Reviews in the Neurosciences | Year: 2012
PI3K activation is the starting point of signaling pathways relaying on changes in the phosphorylation levels of membrane phosphoinositides. These pathways have been involved in several neuronal processes, including cellular growth and survival, differentiation, neuroprotection, dendritic growing, and synaptic plasticity among others. Recent data from Drosophila and rodents have demonstrated an unexpected role of PI3K controlling synapse number that lead to functional and behavioral effects. In the short-term, PI3K is also required for maintaining AMPA receptor clustering at the postsynaptic membranes. We review here the PI3K roles regulating synapse number and functionality. © 2012 by Walter de Gruyter Berlin Boston.
Rodriguez-Munoz M.,Cajal Institute |
Rodriguez-Munoz M.,Instituto Cajal CSIC MINECO |
Garzon J.,Cajal Institute
Molecular Neurobiology | Year: 2013
Opioids are among the most effective analgesics in controlling the perception of intense pain, although their continuous use decreases their potency due to the development of tolerance. The glutamate N-methyl-d-aspartate (NMDA) receptor system is currently considered to be the most relevant functional antagonist of morphine analgesia. In the postsynapse of different brain regions the C terminus of the mu-opioid receptor (MOR) associates with NR1 subunits of NMDARs, as well as with a series of signaling proteins, such as neural nitric oxide synthase (nNOS)/nitric oxide (NO), protein kinase C (PKC), calcium and calmodulin-dependent kinase II (CaMKII) and the mitogen-activated protein kinases (MAPKs). NO is implicated in redox signaling and PKC falls under the regulation of zinc metabolism, suggesting that these signaling elements might participate in the regulation of MOR activity by the NMDAR. In this review, we discuss the influence of redox signaling in the mechanisms whose plasticity triggers opioid tolerance. Thus, the MOR C terminus assembles a series of signaling proteins around the homodimeric histidine triad nucleotide-binding protein 1 (HINT1). The NMDAR NR1 subunit and the regulator of G protein signaling RGSZ2 bind HINT1 in a zinc-independent manner, with RGSZ2 associating with nNOS and regulating MOR-induced production of NO. This NO acts on the RGSZ2 zinc finger, providing the zinc ions that are required for PKC/Raf-1 cysteine-rich domains to simultaneously bind to the histidines present in the HINT1 homodimer. The MOR-induced activation of phospholipase β (PLCβ) regulates PKC, which increases the reactive oxygen species (ROS) by acting on NOX/NADPH, consolidating the long-term PKC activation required to regulate the Raf-1/MAPK cascade and enhancing NMDAR function. Thus, RGSZ2 serves as a Redox Zinc Switch that converts NO signals into Zinc signals, thereby modulating Redox Sensor Proteins like PKCγ and Raf-1. Accordingly, redox-dependent and independent processes weave together to situate the MOR under the negative control of the NMDAR. © 2013 Springer Science+Business Media New York.
Herreras O.,Cajal Institute |
Makarova J.,Cajal Institute |
Makarov V.A.,Complutense University of Madrid
Neuroscience | Year: 2015
Local field potentials (LFPs) reflect the coordinated firing of functional neural assemblies during information coding and transfer across neural networks. As such, it was proposed that the extraordinary variety of cytoarchitectonic elements in the brain is responsible for the wide range of amplitudes and for the coverage of field potentials, which in most cases receive contributions from multiple pathways and populations. The influence of spatial factors overrides the bold interpretations of customary measurements, such as the amplitude and polarity, to the point that their cellular interpretation is one of the hardest tasks in Neurophysiology. Temporal patterns and frequency bands are not exclusive to pathways but rather, the spatial configuration of the voltage gradients created by each pathway is highly specific and may be used advantageously. Recent technical and analytical advances now make it possible to separate and then reconstruct activity for specific pathways. In this review, we discuss how spatial features specific to cells and populations define the amplitude and extension of LFPs, why they become virtually indecipherable when several pathways are co-activated, and then we present the recent advances regarding their disentanglement using spatial discrimination techniques. The pathway-specific threads of LFPs have a simple cellular interpretation, and the temporal fluctuations obtained can be applied to a variety of new experimental objectives and improve existing approaches. Among others, they facilitate the parallel readout of activity in several populations over multiple time scales correlating them with behavior. Also, they access information contained in irregular fluctuations, facilitating the testing of ongoing plasticity. In addition, they open the way to unravel the synaptic nature of rhythmic oscillations, as well as the dynamic relationships between multiple oscillatory activities. The challenge of understanding which waves belong to which populations, and the pathways that provoke them, may soon be overcome. © 2015 IBRO.
Torres-Aleman I.,Cajal Institute |
Torres-Aleman I.,CIBER ISCIII
Developmental Neurobiology | Year: 2010
Insulin-like growth factor I (IGF-I) belongs to an ancient family of hormones already present in early invertebrates. The insulin family is well characterized in mammals, although new members have been described recently. Since its characterization over 50 years ago, IGF-I has been considered a peptide mostly involved in the control of body growth and tissue remodeling. Currently, its most prominent recognized role is as a quasi-universal cytoprotectant. This role connects IGF-I with regulation of lifespan and with cancer, two areas of very active research in relation to this peptide. In the brain, IGF-I was formerly considered a neurotrophic factor involved in brain growth, as many other neurotrophic factors. Other aspects of the neurobiology of IGF-I are gradually emerging and suggest that this growth factor has a prominent role in brain function as a whole. During development IGF-I is abundantly expressed in many areas, whereas once the brain is formed its expression is restricted to a few regions and in very low quantities. However, the adult brain appears to have an external input from serum IGF-I, where this anabolic peptide is abundant. Thus, serum IGF-I has been proven to be an important modulator of brain activity, including higher functions such as cognition. Many of these functions can be ascribed to its tissue-remodeling activity as IGF-I modulates adult neurogenesis and angiogenesis. Other activities are cytoprotective; indeed, IGF-I can be considered a key neuroprotective peptide. Still others pertain to the functional characteristics of brain cells, such as cell excitability. Through modulation of membrane channels and neurotransmission, IGF-I impinges directly on neuronal plasticity, the cellular substrate of cognition. However, to fully understand the role of IGF-I in the brain, we have to sum the actions of locally produced IGF-I to those of serum IGF-I, and this is still pending. Thus, an integrated view of the role played by IGF-I in the brain is not yet possible. An operational approach to overcome this limitation would be to consider IGF-I as a signal coupling environmental influences on body metabolism with brain function. Or in a more colloquial way, we may say that IGF-I links body "fitness" with brain fitness, providing a mechanism to the roman saying "mens sana in corpore sano". © 2010 Wiley Periodicals, Inc.
Ortega-Martinez S.,Cajal Institute |
Trejo J.L.,Cajal Institute
Behavioural Brain Research | Year: 2015
The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety-like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior. © 2014 Elsevier B.V.
Fernandez-Ruiz A.,Cajal Institute |
Makarov V.A.,Complutense University of Madrid |
Benito N.,Cajal Institute |
Herreras O.,Cajal Institute
Journal of Neuroscience | Year: 2012
Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing ofCA3pyramidal cells to which individual units contribute variably.Afraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies. © 2012 the authors.
Lopez-Sanchez N.,Cajal Institute |
Frade J.M.,Cajal Institute
Journal of Neuroscience | Year: 2013
A subpopulation of chick retinal projection neurons becomes tetraploid during development, an event prevented by blocking antibodies against p75 neurotrophin receptor (p75NTR).Wehave used an optimized flow cytometric assay, based on the analysis of unfixed brain cell nuclei, to study whether p75NTR-dependent neuronal tetraploidization takes place in the cerebral cortex, giving rise to projection neurons as well. We show that 3% of neurons in both murine neocortex and chick telencephalic derivatives are tetraploid, and that in the mouse ~85%of these neurons express the immediate early genes Erg-1 and c-Fos, indicating that they are functionally active. Tetraploid cortical neurons (65-80%) express CTIP2, a transcription factor specific for subcortical projection neurons in the mouse neocortex. During the period in which these neurons are born, p75NTR- is detected in differentiating neurons undergoing DNA replication. Accordingly, p75NTRdeficient mice contain a reduced proportion of both NeuN and CTIP2-positive neocortical tetraploid neurons, thus providing genetic evidence for the participation of p75NTR- in the induction of neuronal tetraploidy in the mouse neocortex. In the striatum tetraploidy is mainly associated with long-range projection neurons as well since ~80% of tetraploid neurons in this structure express calbindin, a marker of neostriatal-matrix spiny neurons, known to establish long-range projections to the substantia nigra and globus pallidus. In contrast, only 20% of tetraploid cortical neurons express calbindin, which is mainly expressed in layers II-III, where CTIP2 is absent.We conclude that tetraploidy mainly affects long-range projection neurons, being facilitated by p75NTR in the neocortex. © 2013 the authors.
Fernandez A.M.,Cajal Institute |
Torres-Aleman I.,Cajal Institute
Nature Reviews Neuroscience | Year: 2012
Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis - they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation. © 2012 Macmillan Publishers Limited. All rights reserved.
Torres Aleman I.,Cajal Institute
Endocrinology and Metabolism Clinics of North America | Year: 2012
The previously undisputed neuroprotective role of insulin-like growth factor 1 (IGF-1) has been challenged by recent observations in IGF-1 receptor (IGF-1R) defective mutants. As new ligand-dependent and ligand-independent roles for IGF-1R are now emerging, new insights into the biologic role of brain IGF-1R and its connection with serum and brain IGF-1 function are urgently required. In the meantime, treatment of specific neurodegenerative diseases with IGF-1 may still be explored using adequate preclinical procedures. © 2012 Elsevier Inc.
News Article | December 21, 2016
Within a consortium, led by Oryzon, that will have a 1.3M USD aggregated budget BARCELONA, SPAIN and CAMBRIDGE, MA--(Marketwired - December 21, 2016) - Oryzon Genomics ( : ORY) (ISIN Code: ES0167733015), a public clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the Company will receive a new grant in the form of a loan with interest rate granted, from the Ministry of Economy and Competitiveness, Government of Spain and FEDER Funds from the European Union and included under the RETOS Collaboration 2016 program. Oryzon will receive approximately 0.8M USD (multiyear disbursements) for further development of its epigenetic inhibitors against inflammatory indications. This grant (RTC-2016-4955-1) will cover the partial funding of a project entitled "Epigenetic regulation of the inflammatory response" that is currently being carried out under the leadership of Oryzon in collaboration with various well renowned academic institutions such as the Cajal Institute (National Spanish Research Council, CSIC, Madrid), the López Neira Institute (CSIC, Granada), Bosch i Gimpera Foundation (University of Barcelona) and the Autonomous University of Barcelona. The project has a 33 month duration, starting April 1, 2016 and ending December 31, 2018, and the aggregated budget of the project is approximately 1.3M USD. The public institutions will receive a non-reimbursable grant to develop different activities to assess the potential of Oryzon's drugs on inflammatory diseases for a total amount exceeding 0.4 M USD. Carlos Buesa, President and Chief Executive Officer of Oryzon, commented: "This private-public consortium will set up useful tools and approaches to assess the therapeutic potential of LSD1 inhibitors and other epigenetic modulators in inflammatory and autoimmune diseases, a field that Oryzon is already exploring with ORY-2001, its first in class epigenetic program in Multiple Sclerosis. ORY-2001 is expected to finish Phase I in the next months." Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company considered as the European champion in Epigenetics. The company has one of the strongest portfolios in the field and a clinical asset already partnered with Roche. Oryzon's LSD1 program is currently covered by +20 patent families and has rendered two compounds in clinical trials. In addition, Oryzon has ongoing programs for developing inhibitors against other epigenetic targets. The company has a strong technological platform for biomarker identification and performs biomarker and target validation for a variety of malignant and neurodegenerative diseases. Oryzon's strategy is to develop first in class compounds against novel epigenetic targets through Phase II clinical trials, at which point it is decided on a case-by-case basis to either keep the development in-house or to partner or out-license the compound for late stage development and commercialization. The company has offices in Barcelona and Cambridge, Massachusetts. For more information, visit www.oryzon.com. This communication contains forward-looking information and statements about Oryzon Genomics, S.A., including financial projections and estimates and their underlying assumptions, statements regarding plans, objectives and expectations with respect to future operations, capital expenditures, synergies, products and services, and statements regarding future performance. Forward-looking statements are statements that are not historical facts and are generally identified by the words "expects", "anticipates", "believes", "intends", "estimates" and similar expressions. Although Oryzon Genomics, S.A. believes that the expectations reflected in such forward-looking statements are reasonable, investors and holders of Oryzon Genomics, S.A. shares are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Oryzon Genomics, S.A., that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include those discussed or identified in the documents sent by Oryzon Genomics, S.A. to the Comisión Nacional del Mercado de Valores, which are accessible to the public. Forward-looking statements are not guarantees of future performance. The auditors of Oryzon Genomics, S.A, have not reviewed them. You are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date they were made. All subsequent oral or written forward-looking statements attributable to Oryzon Genomics, S.A. or any of its members, directors, officers, employees or any persons acting on its behalf are expressly qualified in their entirety by the cautionary statement above. All forward-looking statements included herein are based on information available to Oryzon Genomics, S.A. on the date hereof. Except as required by applicable law, Oryzon Genomics, S.A. does not undertake any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.