Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex

El pdf del artículo es la versión post-print.The systemic administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists has been considered as a pharmacological model of schizophrenia. In the present work, we used in vivo microdialysis to examine: first, the effects of MK-801, on the efflux of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC) of the rat; second, whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by atypical (clozapine and olanzapine) and classical (haloperidol and chlorpromazine) antipsychotic drugs given intra-mPFC; and third, the role of local blockade of dopamine D2/D3/D4, serotonin 5-HT2A and α1-adrenergic receptors as well as agonism at dopamine D1/D5 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The four antipsychotic drugs blocked the MK-801-induced increase in glutamate, whereas only clozapine and olanzapine were able to block the increased efflux of 5-HT. Furthermore, M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (α1-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. In contrast, raclopride (D2/D3 antagonist) and L-745,870 (D4 antagonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. SKF-38393 (dopamine D1/D5 agonist) also prevented the MK-801-induced increase of glutamate in the mPFC, but the same effect on cortical 5-HT was reached only at the highest concentration tested. We suggest that the blockade of an exacerbated 5-HT release in the mPFC induced by NMDA antagonists can be a characteristic of atypical antipsychotic drugs. Moreover, we propose that D 2/D3/D4 receptor antagonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus enhancing cortical inhibition, which would prevent an excessive glutamatergic transmission. Dopamine D1/D5 agonists would further stimulate GABA release from other subpopulation of interneurons controlling cortical output to the dorsal raphe nucleus. Atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and α1- adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells. © 2010 Bentham Science Publishers Ltd.This work was supported by the Spanish Ministry of Health (FIS Grant PI070111 to A. A.), the Spanish Ministry of Education and Science (Grant SAF 2007-62378 to F.A.), and the Generalitat de Catalunya (SGR2005/00758). X.L.- G. is the recipient of a predoctoral fellowship from the Consejo Superior de Investigaciones Cientificas (CSIC).Peer Reviewe

Caracterització de l'anisotropia dels acers inoxidables dúplex mitjançant assaigs micromecànics

Els acers inoxidables dúplex posseeixen una microestructura bifàsica composta de ferrita i austenita, presents en proporcions similars. El seu interès industrial rau en el bon compromís entre propietats mecàniques i resistència a la corrosió que ofereixen, presentant un comportament general que ni els acers inoxidables ferrítics ni els austenítics poden igualar. Per aquest motiu el seu ús s’ha estès, esdevenint un material molt emprat en components de plantes de dessalinització, intercanviadors de calor i plantes petroquímiques. La necessitat de caracteritzar les propietats mecàniques dels materials a escales locals ha anat en augment i ha motivat el desenvolupament d’equips de nanoindentació instrumentada, els quals mesuren la duresa i el mòdul d’elasticitat a mesura que la profunditat d’indentació augmenta. En aquest Treball Final de Grau, tal com indica el seu títol, es pretén caracteritzar la microestructura i l’anisotropia mecànica de cadascuna de les fases constituents dels acers inoxidables dúplex mitjançant la tècnica de difracció d’electrons retrodispersats i la nanoindentació, respectivament, amb l’objectiu de poder-les correlacionar. S’ha pogut observar com l’acer dúplex presenta una forta textura a causa del procés de laminació així com una elevada anisotropia mecànica tant en termes de duresa com de mòdul d’elasticitat. La majoria dels grans de ferrita es troben orientats segons el pla (001) mentre que per als grans d’austenita és el pla (111). El valor de duresa, així com el mòdul d’elasticitat, augmenta per a ambdues fases a mesura que els grans s’orienten en el pla (111)

Is the acute NMDA receptor hypofunction a valid model of schizophrenia?

El pdf del artículo es la versión post-print.Several genetic, neurodevelopmental, and pharmacological animal models of schizophrenia have been established. This short review examines the validity of one of the most used pharmacological model of the illness, ie, the acute administration of N-methyl-D-aspartate (NMDA) receptor antagonists in rodents. In some cases, data on chronic or prenatal NMDA receptor antagonist exposure have been introduced for comparison. The face validity of acute NMDA receptor blockade is granted inasmuch as hyperlocomotion and stereotypies induced by phencyclidine, ketamine, and MK-801 are regarded as a surrogate for the positive symptoms of schizophrenia. In addition, the loss of parvalbumin-containing cells (which is one of the most compelling finding in postmortem schizophrenia brain) following NMDA receptor blockade adds construct validity to this model. However, the lack of changes in glutamic acid decarboxylase (GAD67) is at variance with human studies. It is possible that changes in GAD67 are more reflective of the neurodevelopmental condition of schizophrenia. Finally, the model also has predictive validity, in that its behavioral and transmitter activation in rodents are responsive to antipsychotic treatment. Overall, although not devoid of drawbacks, the acute administration of NMDA receptor antagonists can be considered as a good model of schizophrenia bearing a satisfactory degree of validity. © 2011 The Author.This work was supported by the Spanish Ministry of Health (Grant FIS PI070111), by the grant Proyecto Intramural Especial CSIC 201020E046, and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. XL-G and LJ-S are recipients of a postdoctoral fellowship from the Consejo Superior de Investigaciones Científicas (CSIC) and a predoctoral fellowship from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), respectively.Peer Reviewe

Brain connectivity during Alzheimer's disease progression and its cognitive impact in a transgenic rat model

The research of Alzheimer's disease (AD) in its early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph metrics to identify differences between the groups in connectivity, its evolution with age, and its influence on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, while the structural brain network influenced cognitive outcome in transgenic animals, functional network impacted how control subjects performed. TgF344-AD brain network alterations were present from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in these animals, involving structural network reorganization and its effects on cognition, opens a window to evaluate new treatments for the disease

Spatio-temporal metabolic rewiring in the brain of TgF344-AD rat model of Alzheimer's disease

Brain damage associated with Alzheimer's disease (AD) occurs even decades before the symptomatic onset, raising the need to investigate its progression from prodromal stages. In this context, animal models that progressively display AD pathological hallmarks (e.g. TgF344-AD) become crucial. Translational technologies, such as magnetic resonance spectroscopy (MRS), enable the longitudinal metabolic characterization of this disease. However, an integrative approach is required to unravel the complex metabolic changes underlying AD progression, from early to advanced stages. TgF344-AD and wild-type (WT) rats were studied in vivo on a 7 Tesla MRI scanner, for longitudinal quantitative assessment of brain metabolic profile changes using MRS. Disease progression was investigated at 4 time points, from 9 to 18 months of age, and in 4 regions: cortex, hippocampus, striatum, and thalamus. Compared to WT, TgF344-AD rats replicated common findings in AD patients, including decreased N-acetylaspartate in the cortex, hippocampus and thalamus, and decreased glutamate in the thalamus and striatum. Different longitudinal evolution of metabolic concentration was observed between TgF344-AD and WT groups. Namely, age-dependent trajectories differed between groups for creatine in the cortex and thalamus and for taurine in cortex, with significant decreases in Tg344-AD animals; whereas myo-inositol in the thalamus and striatum showed greater increase along time in the WT group. Additional analysis revealed divergent intra- and inter-regional metabolic coupling in each group. Thus, in cortex, strong couplings of N-acetylaspartate and creatine with myo-inositol in WT, but with taurine in TgF344-AD rats were observed; whereas in the hippocampus, myo-inositol, taurine and choline compounds levels were highly correlated in WT but not in TgF344-AD animals. Furthermore, specific cortex-hippocampus-striatum metabolic crosstalks were found for taurine levels in the WT group but for myo-inositol levels in the TgF344-AD rats. With a systems biology perspective of metabolic changes in AD pathology, our results shed light into the complex spatio-temporal metabolic rewiring in this disease, reported here for the first time. Age- and tissue-dependent imbalances between myo-inositol, taurine and other metabolites, such as creatine, unveil their role in disease progression, while pointing to the inadequacy of the latter as an internal reference for quantification

Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat

The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.This work was supported by the Spanish Ministry of Education and Science Grants SAF 2004-05525 and SAF 2003-04930 and by the Generalitat de Catalunya (SGR2005/00758 and SGR2005/00826). XL-G, ZB, and MA-B were recipients of predoctoral fellowships from the Consejo Superior de Investigaciones Científicas (CSIC), Spanish Ministry of Education and Science, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), respectively.Peer reviewe

Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine

Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.Funding: This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13-00038 and PI16-00217) that were cofunded by the European Regional Development Fund (“A way to build Europe”). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)

Effects of Orientation and Anisometry of Magnetic Resonance Imaging Acquisitions on Diffusion Tensor Imaging and Structural Connectomes

Diffusion-weighted imaging (DWI) quantifies water molecule diffusion within tissues and is becoming an increasingly used technique. However, it is very challenging as correct quantification depends on many different factors, ranging from acquisition parameters to a long pipeline of image processing. In this work, we investigated the influence of voxel geometry on diffusion analysis, comparing different acquisition orientations as well as isometric and anisometric voxels. Diffusion-weighted images of one rat brain were acquired with four different voxel geometries (one isometric and three anisometric in different directions) and three different encoding orientations (coronal, axial and sagittal). Diffusion tensor scalar measurements, tractography and the brain structural connectome were analyzed for each of the 12 acquisitions. The acquisition direction with respect to the main magnetic field orientation affected the diffusion results. When the acquisition slice-encoding direction was not aligned with the main magnetic field, there were more artifacts and a lower signal-to-noise ratio that led to less anisotropic tensors (lower fractional anisotropic values), producing poorer quality results. The use of anisometric voxels generated statistically significant differences in the values of diffusion metrics in specific regions. It also elicited differences in tract reconstruction and in different graph metric values describing the brain networks. Our results highlight the importance of taking into account the geometric aspects of acquisitions, especially when comparing diffusion data acquired using different geometries

Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease

Background: Animal models of Alzheimer's disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present. Methods: Cognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats. Results: The results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes. Conclusions: In this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks have not yet been detected. Structural and functional network metrics of regions related to reward, memory, and sensory performance were strongly correlated with the cognitive outcome. The use of animal models is essential for the early identification of these alterations and can contribute to the development of early biomarkers of the disease based on MRI connectomics

HA del castillo!! Historia y Acción social en torno a la las fortalezas españolas

[EN] The historic neighborhoods located on the slopes of the defensive buildings of the cities have often been excluded from urban and social advances (unhealthy housing, few public services, nonexistent facilities, low incomes) undergoing a process of emptying and social degradation. On the other hand, castles that top the majority of Spanish populations continue to be the main focus of tourist attraction, thus creating a physical and social barrier between the two spaces, historically related. Focused on children and with the intention of making public in a playful way their immediate environment, and the unprotected or lacked of interest areas, we have developed a cultural and pedagogical program developed around cultural assets within from a place at risk of social exclusion, making it belong to them and inviting the rest of society to be interested in that historically rich neighbourhood of life.[ES] Los barrios históricos situados en las faldas de las construcciones defensivas de las ciudades se han quedado, a menudo, excluidas de los avances urbanísticos y sociales (viviendas insalubres, escasos servicios públicos, inexistentes equipamientos, rentas bajas) sufriendo un proceso de vaciado y degradación social. Por otro lado, los castillos que coronan la mayoría de las poblaciones españolas siguen siendo el mayor foco de atracción turística, creándose así una barrera física y social entre ambos espacios, históricamente relacionados. Enfocado a los niños y con la intención de dar a conocer de una manera lúdica su entorno más inmediato, zonas desprotegidas o con escaso interés turísticos por la lacra social que les envuelve, se ha desarrollado un programa pedagógico cultural en torno a los bienes culturales dentro de un lugar con riesgo de exclusión social, haciendo que les pertenezca e invitando al resto de la sociedad a interesarse por ese barrio históricamente rico de vida.López Sabater, Á.; Laumain, XA.; García López De Andújar, V.; Gil García, JE. (2021). HA del castillo!! Historia y Acción social en torno a la las fortalezas españolas. En I Simposio anual de Patrimonio Natural y Cultural ICOMOS España. Editorial Universitat Politècnica de València. 307-314. https://doi.org/10.4995/icomos2019.2019.11736OCS30731