Browsing by UCM subject "Neurociencias (Biológicas)"
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Publication2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons(springer, 2015-08) Llorente Berzal, Álvaro; Terzian, Ana Luisa B.; Di Marzo, Vincenzo; Micale, Vincenzo; Viveros, María Paz; Wotjak, Carsten T.Rationale The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. Objectives We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means. Results The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 μg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1- deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear-promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO. Conclusions Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons. PublicationA Red-Berry mixture as a Nutraceutical: detailed composition and neuronal protective effect(MDPI, 2021-05-27) Carballeda-Sangiao, Noelia; Chamorro Francisco, Susana; Pascual-Teresa, Sonia deRecommendations towards increased consumption of fresh fruit and vegetables are well supported by epidemiological and clinical trials. However, in some specific cases, it is difficult to follow these recommendations and the use of nutraceuticals or, in the present work, a freezedried fruits mixture can be recommended in order to afford the optimal consumption of dietary polyphenols naturally present in fruits and vegetables. In this work we have carefully characterized a red-berry mixture in terms of polyphenol composition, encountering mainly anthocyanins, which account for a total of 2.8 mg/g as cyanidin-3-glucoside equivalents. Additionally, we have assayed the red-berry blend in a cell model of neurological damage by differentiating the cells and measuring the effect of red-berry polyphenols on cell viability and redox state by flow cytometry. The berry-fruit extract showed an inhibitory effect on differentiated SH-SY5Y ROS formation at a concentration as low as 250 µg/mL (33% inhibition). The results show the potential of this berry-fruit blend for its nutraceutical use in the prevention of the neurodegeneration associated with age or environmental agents. PublicationAge-Dependent Effects of Cannabinoids on Neurophysiological, Emotional, and Motivational States(Springer, 2015) Viveros, María Paz; Marco López, Eva MaríaCannabis sativa preparations are among the illicit drugs most commonly used by young people, including pregnant women. The endocannabinoid (eCB) system, which is involved in the regulation of emotional and motivational homeostasis, synaptic plasticity and cognitive functions, also plays a critical role in diverse phases of brain development. Both perinatal and periadolescent periods are critical for brain eCB system development. Thus, interference of endocannabinoid signalling by cannabis exposure may contribute to explain the enduring negative impact of cannabis on neurodevelopmental processes and the resulting psycho-physio-pathological consequences. In the present chapter we describe and discuss published data dealing with the long-term neurobehavioural effects of cannabis exposure during the prenatal and adolescent periods. Human studies have demonstrated that marijuana consumption by pregnant women critically affects the neurobehavioural development of their children. Investigations using animal models provide useful information for a better understanding of the long-lasting deleterious consequences of cannabis exposure during pregnancy and lactation. Increasing use of cannabis among adolescents is a matter of great public concern that has led to a parallel increase in research on appropriate animal models. Chronic administration of cannabinoid agonists during the periadolescent period causes persistent behavioural alterations related to cognitive deficits, increased risk of psychosis, mood disorders and addiction to cannabis and other drugs of abuse. The underlying mechanisms by which cannabis use may lead to these disorders, including genetic vulnerability and the increasing content of the main psychoactive ingredient in cannabis preparations, delta-9-tetrahydrocannabinol (THC), will be discussed. To conclude, prevention and therapeutic strategies based on scientific knowledge will be proposed. PublicationAgustín González, an inspirational leader in spanish comparative neuroanatomy(Karger, 2021-10-13) Marín, Oscar; Moreno García, NereaIt is our pleasure to open this Festschrift dedicated to our mentor Prof. Agustín González (Fig. 1) on his retirement after more than 40 years of academic work at the Universidad Complutense de Madrid. Agustín is a key figure in the field of comparative neuroanatomy, essential to understanding the evolution of this field in Spain and beyond over the last decades. This special issue collects a rich number of contributions by collaborators, pupils, and colleagues from all over the world, reflecting the impact of their achievements and the respect and admiration of the entire international community. The volume also serves as a homage to Prof. Luis Puelles, an occasional collaborator of Agustín and another giant of Spanish neuroscience. In this commentary, we summarize Agustín’s work as a researcher, teacher, mentor, and member of the scientific community. We also consider the broader impact of Agustín’s activity, primarily when it comes to its ability to influence others. As alumni from his laboratory, we do this from a very personal point of view, reflecting on our imperfect memories of the time we spent together. We wish that this imperfect historical glimpse on Agustín’s professional career will bring a smile to the face of the many colleagues who have worked with Agustín over the past few decades and inspire those who have not personally known him. PublicationAltered neocortical dynamics in a mouse model of Williams–Beuren Syndrome(Springer, 2019-08-30) Dasilva, Miguel; Navarro-Guzman, Alvaro; Ortiz-Romero, Paula; Camassa, Alessandra; Muñoz-Cespedes, Alberto; Campuzano, Victoria; Sanchez-Vives, María V.Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by moderate intellectual disability and learning difficulties alongside behavioral abnormalities such as hypersociability. Several structural and functional brain alterations are characteristic of this syndrome, as well as disturbed sleep and sleeping patterns. However, the detailed physiological mechanisms underlying WBS are mostly unknown. Here, we characterized the cortical dynamics in a mouse model of WBS previously reported to replicate most of the behavioral alterations described in humans. We recorded the laminar local field potential generated in the frontal cortex during deep anesthesia and characterized the properties of the emergent slow oscillation activity. Moreover, we performed micro-electrocorticogram recordings using multielectrode arrays covering the cortical surface of one hemisphere. We found significant differences between the cortical emergent activity and functional connectivity between wild-type mice and WBS model mice. Slow oscillations displayed Up states with diminished firing rate and lower high-frequency content in the gamma range. Lower firing rates were also recorded in the awake WBS animals while performing a marble burying task and could be associated with the decreased spine density and thus synaptic connectivity in this cortical area. We also found an overall increase in functional connectivity between brain areas, reflected in lower clustering and abnormally high integration, especially in the gamma range. These results expand previous findings in humans, suggesting that the cognitive deficits characterizing WBS might be associated with reduced excitability, plus an imbalance in the capacity to functionally integrate and segregate information. PublicationAltered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease(IOS Press, 2019-09-03) Martínez de Toda Cabeza, Irene; Miguélez, Lara; Vida, Carmen; Carro, Eva; Fuente del Rey, Mónica de laOxidative stress plays an essential and early role in the pathophysiology of Alzheimer’s disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression. PublicationAmphibian thalamic nuclear organization during larval development and in the adult frog Xenopus laevis: genoarchitecture and hodological analysis(Wiley, 2020-03-11) Morona Arribas, Ruth; Bandín Carazo, Sandra; López Redondo, Jesús María; Moreno García, Nerea; González Gallegos, AgustínThe early patterning of the thalamus during embryonic development defines rostral and caudal progenitor domains, which are conserved from fishes to mammals. However, the subsequent developmental mechanisms that lead to the adult thalamic configuration have only been investigated for mammals and other amniotes. In this study, we have analyzed in the anuran amphibian Xenopus laevis (an anamniote vertebrate), through larval and postmetamorphic development, the progressive regional expression of specific markers for the rostral (GABA, GAD67, Lhx1, and Nkx2.2) and caudal (Gbx2, VGlut2, Lhx2, Lhx9, and Sox2) domains. In addition, the regional distributions at different developmental stages of other markers such as calcium binding proteins and neuropeptides, helped the identification of thalamic nuclei. It was observed that the two embryonic domains were progressively specified and compartmentalized during premetamorphosis, and cell subpopulations characterized by particular gene expression combinations were located in periventricular, intermediate and superficial strata. During prometamorphosis, three dorsoventral tiers formed from the caudal domain and most pronuclei were defined, which were modified into the definitive nuclear configuration through the metamorphic climax. Mixed cell populations originated from the rostral and caudal domains constitute most of the final nuclei and allowed us to propose additional subdivisions in the adult thalamus, whose main afferent and efferent connections were assessed by tracing techniques under in vitro conditions. This study corroborates shared features of early gene expression patterns in the thalamus between Xenopus and mouse, however, the dynamic changes in gene expression observed at later stages in the amphibian support mechanisms different from those of mammals. PublicationArtificial stimulation of the peripheral nerves to generate natural-like activity in the central nervous system(IEEE, 2004) Bonacasa, V.; Cepeda, I. R.; Makarov, Valeri A.; Panetsos, FivosIn the present work we study how sensory inputs conveyed by nerve fibers in the form of spatiotemporal patterns generate different responses in the central nervous system (CNS) depending on the physical characteristics of the stimulus applied and then we reproduce similar responses by means of electrical stimulation of the nervous fibers PublicationAstroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons(Elsevier, 2019-05-15) Ruiz Calvo, Andrea; Bajo-Grañeras, Raquel; Maroto, Irene B.; Zian, Debora; Grabner, Gernot F.; García-Taboada, Elena; Resel, Eva; Zechner, Rudolf; Zimmermann, Robert; Ortega-Gutiérrez, Silvia; Galve Roperh, Ismael; Bellocchio, Luigi; Guzmán, ManuelCannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1 receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington's disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoid system in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration. PublicationBenchmarking of tools for axon length measurement in individually-labeled projection neurons(Public Library of Science, 2021-12-08) Rubio Teves, Mario; Díez Hermano, Sergio; Porrero, César; Sánchez Jiménez, Abel; Prensa Sepúlveda, Lucía; Clascá, Francisco; García Amado, María; Villacorta Atienza, José AntonioProjection neurons are the commonest neuronal type in the mammalian forebrain and their individual characterization is a crucial step to understand how neural circuitry operates. These cells have an axon whose arborizations extend over long distances, branching in complex patterns and/or in multiple brain regions. Axon length is a principal estimate of the functional impact of the neuron, as it directly correlates with the number of synapses formed by the axon in its target regions; however, its measurement by direct 3D axonal tracing is a slow and labor-intensive method. On the contrary, axon length estimations have been recently proposed as an effective and accessible alternative, allowing a fast approach to the functional significance of the single neuron. Here, we analyze the accuracy and efficiency of the most used length estimation tools—design-based stereology by virtual planes or spheres, and mathematical correction of the 2D projected-axon length—in contrast with direct measurement, to quantify individual axon length. To this end, we computationally simulated each tool, applied them over a dataset of 951 3D-reconstructed axons (from NeuroMorpho.org), and compared the generated length values with their 3D reconstruction counterparts. The evaluated reliability of each axon length estimation method was then balanced with the required human effort, experience and know-how, and economic affordability. Subsequently, computational results were contrasted with measurements performed on actual brain tissue sections. We show that the plane-based stereological method balances acceptable errors (~5%) with robustness to biases, whereas the projection-based method, despite its accuracy, is prone to inherent biases when implemented in the laboratory. This work, therefore, aims to provide a constructive benchmark to help guide the selection of the most efficient method for measuring specific axonal morphologies according to the particular circumstances of the conducted research. PublicationBlockage of the neonatal leptin surge affects the gene expression of growth factors, glial proteins and neuropeptides involved in the control of metabolism and reproduction in peri-pubertal male and female rats(Oxford University Press, 2015-07) Mela Rivas, Virginia; Díaz, Francisca; López Rodríguez, Ana Belén; Vázquez, María Jesús; Gertler, Arieh; Argente, Jesús; Tena-Sempere, Manuel; Viveros, María Paz; Chowen, Julie A.Leptin is important in the development of neuroendocrine circuits involved in metabolic control. As both leptin and metabolism influence pubertal development, we hypothesized that early changes in leptin signaling could also modulate hypothalamic systems involved in reproduction. We previously demonstrated that a single injection of a leptin antagonist on postnatal day (PND) 9, coincident with the neonatal leptin peak, induced sexually dimorphic modifications in trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus on PND13. Here our aim was to investigate if the alterations induced by leptin antagonism persist into puberty. Accordingly, male and female rats were treated with a pegylated super leptin antagonist from PND5 to 9 and killed just before the normal appearance of external signs of puberty (PND 33 in females and PND 43 in males). There was no effect on body weight, but in males food intake increased, subcutaneous adipose tissue decreased and hypothalamic NPY and AgRP mRNA levels were reduced, with no effect in females. In both sexes, the antagonist increased hypothalamic mRNA levels of the kisspeptin receptor, Gpr54. Expression of the leptin receptor, trophic factors and glial markers were differently affected in the hypothalamus of peri-pubertal males and females. Leptin production in adipose tissue was decreased in antagonist treated rats of both sexes, with production of other cytokines being differentially regulated between sexes. In conclusion, in addition to the long-term effects on metabolism, changes in neonatal leptin levels modifies factors involved in reproduction that could possibly affect sexual maturation. PublicationBMP8 and activated brown adipose tissue in human newborns(Nature Publishing Group, 2021) Urisarri, Adela; González García, Ismael; Estévez Salguero, Ánxela; Pata, María P.; Milbank, Edward; López, Noemí; Mandiá, Natalia; Grijota Martínez, Carmen; Salgado, Carlos A.; Nogueiras, Rubén; Diéguez, Carlos; Villarroya, Francesc; Fernández Real, José-Manuel; Couce, María L.; López, MiguelThe classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns. PublicationBrain Mapping of Ghrelin O-Acyltransferase in Goldfish (Carassius Auratus): Novel Roles for the Ghrelinergic System in Fish?(Wiley Periodicals, 2016) Blanco Imperiali, Ayelén M.; Sánchez Bretano, Aída; Delgado Saavedra, María Jesús; Valenciano González, Ana IsabelGhrelin O-acyltransferase (GOAT) is the enzyme responsible for acylation of ghrelin, a gut-brain hormone with important roles in many physiological functions in vertebrates. Many aspects of GOAT remain to be elucidated, especially in fish, and particularly its anatomical distribution within the different brain areas has never been reported to date. The present study aimed to characterize the brain mapping of GOAT using RT-qPCR and immunohistochemistry in a teleost, the goldfish (Carassius auratus). Results show that goat transcripts are expressed in different brain areas of the goldfish, with the highest levels in the vagal lobe. Using immunohistochemistry, we also report the presence of GOAT immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, pineal gland, optic tectum and cerebellum, although they are especially abundant in the hindbrain. Particularly, an important signal is observed in the vagal lobe and some fiber tracts of the brainstem, such as the medial longitudinal fasciculus, Mauthneri fasciculus, secondary gustatory tract and spinothalamic tract. Most of the forebrain areas where GOAT is detected, particularly the hypothalamic nuclei, also express the ghs-r1a ghrelin receptor and other appetite-regulating hormones (e.g., orexin and NPY), supporting the role of ghrelin as a modulator of food intake and energy balance in fish. Present results are the first report on the presence of GOAT in the brain using imaging techniques. The high presence of GOAT in the hindbrain is a novelty, and point to possible new functions for the ghrelinergic system in fish. PublicationCambios cronobiológicos de la actividad del eje hipotálamo-hipofisario en función de la edad : variaciones en la secreción adenohipofisaria(Universidad Complutense de Madrid, Servicio de Publicaciones, 2004) Cano Barquilla, María del Pilar; Esquifino Parras, Ana IsabelLos ritmos biológicos, particularmente los ritmos circadianos, son esenciales en la organización temporal de los seres vivos. En mamíferos envejecidos, todas las características rítmicas cambian, aunque no todos al mismo tiempo ni de forma simultánea. Como consecuencia, la organización temporal interna está alterada aunque en condiciones estables y probablemente desincronizada con el medio ambiente cambiante (como por ejemplo, las estaciones). El objetivo de este estudio ha sido analizar el efecto de la edad sobre la actividad diaria del eje hipotálamo-hipofisario. Para ello, se estudia el contenido de catecolaminas, serotonina, GABA, taurina y somatostatina, así como el metabolismo de dopamina y serotonina en el hipotálamo anterior y mediobasal, en la eminencia media y en la adenohipófisis y los niveles plasmáticos de prolactina y GH, en ratas jóvenes (2 meses de vida) y envejecidas (18 meses de vida), sacrificadas en seis intervalos distintos a lo largo de un ciclo de 24 horas. Además, se analizaron las correlaciones existentes entre estos parámetros neuroendocrinos. Los resultados muestran que el envejecimiento modifica diferencialmente el funcionamiento cronobiológico del eje hipotálamo-hipofisario. Se demuestra una disminución en la capacidad biosintética de las neuronas de los neuromodulares estudiados con la edad, que puede explicar al menos en parte los cambios descritos en las variaciones diarias de prolactina o GH PublicationCan we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics(Medknow Publications, 2022-02-08) Herrera Rincón, Celia; Murciano-Brea, Julia; Geuna, Stefano PublicationCannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in Mice(Oxford University Press, 2015-01-24) Gomes, Felipe V.; Issy, Ana Carolina; Ferreira, Frederico R.; Viveros, María Paz; Del Bel, Elaine A.; Guimarães, Francisco S.Background: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. Methods: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calciumbinding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Results: MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. PublicationCannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice(Springer Nature, 2022-07-07) Sánchez De La Torre, Aníbal; Aguado Sánchez, Tania; Huerga-Gómez, Alba; Santamaría, Silvia; Gentile, Antonietta; Chara, Juan Carlos; Matute, Carlos; Monory, Krisztina; Mato, Susana; Guzmán Pastor, Manuel; Lutz, Beat; Galve Roperh, Ismael; Palazuelos Diego, JavierCannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptordeficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cellautonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids. PublicationCannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders(Elsevier, 2018-08-15) Sagredo Ezquioga, Onintza; Palazuelos Diego, Javier; Gutierrez-Rodriguez, Ana; Satta, Valentina; Galve Roperh, Ismael; Martínez Orgado, José AntonioThe endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases. In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds. This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity. PublicationCannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke(American Heart Association, 2017-01) Bravo Ferrer, Isbel; Cuartero Desviat, María Isabel; Zarruk, Juan G.; Pradillo, Jesús M.; Hurtado Moreno, Olivia; Romera, Victor G.; Díaz Alonso, Javier; García Segura, Juan Manuel; Guzmán, Manuel; Lizasoaín, Ignacio; Galve Roperh, Ismael; Moro, María A.Background and Purpose—Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms. However, its role in chronic stroke is still unknown. Methods—Stroke was induced by permanent middle cerebral artery occlusion in mice; CB2R modulation was assessed by administering the CB2R agonist JWH133 ((6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6Hdibenzo[b,d]pyran) or the CB2R antagonist SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]-heptan-2-yl]-5-(4- chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) once daily from day 3 to the end of the experiment or by CB2R genetic deletion. Analysis of immunofluorescence-labeled brain sections, 5-bromo-2´-deoxyuridine (BrdU) staining, fluorescence-activated cell sorter analysis of brain cell suspensions, and behavioral tests were performed. Results—SR144528 decreased neuroblast migration toward the boundary of the infarct area when compared with vehicletreated mice 14 days after middle cerebral artery occlusion. Consistently, mice on this pharmacological treatment, like mice with CB2R genetic deletion, displayed a lower number of new neurons (NeuN+ /BrdU+ cells) in peri-infarct cortex 28 days after stroke when compared with vehicle-treated group, an effect accompanied by a worse sensorimotor performance in behavioral tests. The CB2R agonist did not affect neurogenesis or outcome in vivo, but increased the migration of neural progenitor cells in vitro; the CB2R antagonist alone did not affect in vitro migration. Conclusions—Our data support that CB2R is fundamental for driving neuroblast migration and suggest that an endocannabinoid tone is required for poststroke neurogenesis by promoting neuroblast migration toward the injured brain tissue, increasing the number of new cortical neurons and, conceivably, enhancing motor functional recovery after stroke. PublicationCapilares cerebelosos y su microambiente : estudio ultraestructural e inmunocitoquímico(Universidad Complutense de Madrid, Servicio de Publicaciones, 2002) Gragera Martínez, Raquel de los Reyes; Martínez Rodríguez, Ricardo; Muñiz Hernando, EnriquetaLos capilares cerebelosos constituyen la principal estructura constituyente de la barrera hematoencefalica en esta región cerebral, junto con el envoltorio glial perivascular. Las técnicas de microscopia electrónica convencional nos han permitido demostrar que la vaina glial no constituye una estructura continua, de forma que estas discontinuidades permiten el contacto entre elementos de naturaleza nerviosa y la pared de los vasos. En este sentido, todas las estirpes celulares de la corteza cerebelosa pueden entrar en contacto con la pared vascular. Las técnicas inmunohistoquimicas del pap nos han permitido demostrar la presencia de diversos neuromediadores (gaba, taurina, gilcina, serotonina, tiamina) y enzimas implicadas en su sintesis (gad, aat) en los capilares cerebelosos y su microambiente (glia perivascular y estructuras nerviosas asociadas a la pared vascular). Asi mismo, hemos puesto de manifiesto moleculas con una importante implicación funcional en los capilares y su microambiente (atpasa na+/k+, clatrina, alfa-actina). Estos hechos constituyen un importante reflejo morfológico del control glial y nervioso de la permeabilidad capilar y del flujo sanguíneo en los capilares de la corteza cerebelosa de la rata