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Introduction Astrocytes are a group of brain cells that plays a crucial role in brain metabolism. Even though these cells are well characterized, its mechanisms in brain glucose regulation remains unknown. Chemogenetics is a revolutionary technique, as it allows modulating different populations of cells through Drug Receptors Exclusively Activated by Designer Drugs (DREADDs). Our study aims to activate hippocampal astrocytes with DREADDs in different mutant animal models and evaluate changes in brain glucose kinetic. Methods Our study aimed to use chemogenetic to activate hippocampal astrocytes in wild type mice and in two animal models of knock out in astrocytes: Inositol 3 Phosphate KO (IP3-/-) and Glucose Transporter 1 KO (GLUT1-/-). Positron Emission Tomography (PET) combined with the glucose analog radiotracer 2-deoxy-2- [18F]-fluoro-D-glucose (FDG) imaging technique was used in dynamic studies to evaluate changes in glucose kinetics based on a 2-tissue-compartment model (2TC). FDG was injected 10 minutes after the activation drug, Clozapine-N-Oxide (CNO 3 mg/kg i.p.), or saline. Both conditions were performed in the same animals. Results/Discussion Our results in WT mice revealed that activation of astrocytes by CNO increased the uptake of FDG. Analysis through kinetic model showed that DREADDs activation with CNO increased glucose influx. Astrocyte activation in IP3-/- mice (animals with an impairment of calcium signaling) had no effect in FDG PET studies. Baseline GLUT1-/- mice showed higher levels of FDG uptake compared to WT animals in the kinetic model. When DREADDs were activated in GLUT1-/- mice there was no effect in 2TC model, suggesting that this glucose transporter is responsible of the increase in FDG uptake due to chemogenetics in astrocytes. Conclusions Activation of DREADDs with CNO induces an increase of glucose consumption in mouse brain. This effect is not observed in GLUT1-/- and IP3-/- mice. Thus, CNO is specifically activating astrocytes a

El Festival Pint Of Science es un evento de índole internacional que invita a los investigadores más punteros a compartir sus conocimientos en un ambiente relajado y distendido. Durante los 3 días en los que se desarrolla este, bien llamado, festival, los protagonistas y organizadores pretenden crear un formato accesible a todos los públicos. El escenario elegido para este evento son ¡LOS BARES DE TODO EL MUNDO! De esta forma se ofrece una plataforma que permite a la gente conocer y discutir la investigación directamente con las personas que la llevan a cabo. Este festival se celebra cada año de forma simultánea en coordinación con todos los países y ciudades participantes, y durante tres días consecutivos se llenan de ciencia los bares de todo el mundo. En España, la iniciativa se articula desde la Asociación de Divulgación Científica “Pint of Science España”, con sede en social en la localidad de Mojácar (Almería); una asociación creada con el único propósito de organizar este festival. La Asociación de Divulgación Científica “Pint of Science España” es una organización sin fines de lucro y está gestionado íntegramente por personal voluntario. Este equipo, durante los meses previos al festival, es el encargado de dar forma al evento en España y su trabajo se desarrolla desde acoger a las ciudades participantes, hasta contactar con los bares anfitriones, coordinar la participación de los científicos y la búsqueda de todo tipo de apoyo. Un trabajo realizado siempre en relación estrecha con el resto de países participantes.

Astrocytes are active cells involved in brain function through the bidirectional communication with neurons, in which the astrocyte calcium signal plays a crucial role. Synaptically-evoked calcium increases can be localized to independent subcellular domains or expand to the entire cell, i.e., calcium surge. In turn, astrocytes may regulate individual synapses by calcium-dependent release of gliotransmitters. Because a single astrocyte may contact ~100,000 synapses, the control of the intracellular calcium signal propagation may have relevant consequences on brain function by regulating the spatial range of astrocyte neuromodulation of synapses. Yet, the properties governing the spatial dynamics of the astrocyte calcium signal remains poorly defined. Imaging subcellular responses of cortical astrocytes to sensory stimulation in mice, we show that sensory-evoked astrocyte calcium responses originated and remained localized in domains of the astrocytic arborization, but eventually propagated to the entire cell if a spatial threshold of >23% of the arborization being activated was surpassed. Using transgenic IP3R2-/- mice, we found that type-2 IP3 receptors were necessary for the generation of the astrocyte calcium surge. We finally show using in situ electrophysiological recordings that the spatial threshold of the astrocyte calcium signal consequently determined the gliotransmitter release. Present results reveal a fundamental property of astrocyte calcium physiology, i.e., a spatial threshold for the astrocyte intracellular calcium signal propagation, which depends on astrocyte intrinsic properties and governs the astrocyte integration of local synaptic activity and the subsequent neuromodulation.

La dopamina (DA) es un neurotransmisor ampliamente distribuido en el cerebro que interviene en el control del movimiento, en el sistema de recompensa, sueño, atención y procesos de memoria y aprendizaje. Además, regula estados emocionales, motivación y toma de decisiones. La DA es el neurotransmisor que controla las neuronas estriatales de proyección (NEP), que son el principal tipo de neuronas del estriado y del núcleo accumbens (NAc). Estudios previos han mostrado el papel clave de la DA en la regulación de la plasticidad estructural y sináptica de las NEP. Los astrocitos, establecen una comunicación bidireccional con las neuronas, conocida como Sinapsis Tripartita. Sin embargo, debido a la complejidad de las interacciones de las NEP y los astrocitos en múltiples circuitos, muchos de estos mecanismos aún siguen siendo desconocidos. En esta tesis, se han establecido algunos de estos mecanismos mediante el estudio de los siguientes objetivos: I) relación entre la concentración de DA liberada en el estriado y la densidad de espinas dendríticas, II) papel de los receptores dopaminérgicos D1 y D2 en la regulación estructural y sináptica de las neuronas estriatales de proyección, III), relación entre la liberación de DA y la activación de diferentes grupos de astrocitos, IV), modulación de la plasticidad sináptica de las NEP por los astrocitos. Para el abordaje de estos objetivos se emplearon: registros de patch-clamp en la configuración célula entera in vitro en secciones coronales de estriado y NAc, estudios de optogenética, registros electroquímicos de medición en la liberación de DA y estudios morfológicos mediante microinyecciones por iontoforesis de las NEP. Nuestros resultados demuestran que la densidad de espinas dendríticas en las NEP está regulada por los niveles de DA en función del grado de inervación proveniente de la sustancia negra. Además, demostramos que el uso de drogas psicoestimulantes modifica la plasticidad sináptica de la vía dopaminérgica ATV-NAc

Dynamic signaling between the endocrine system (ES) and the nervous system (NS) is essential for brain and body homeostasis. In particular, reciprocal interaction occurs during pregnancy and motherhood that may involve changes in some brain plasticity processes. Prolactin (PRL), a hormone with pleiotropic effects on the NS, promotes maternal behavior and has been linked to modifications in brain circuits during motherhood; however, it is unclear whether PRL may regulate synaptic plasticity. Therefore, the main aim of the present work was to determine the cellular and molecular mechanisms triggered by PRL that regulate synaptic plasticity in the hippocampus. By analyzing extracellular recordings in CA3¿CA1 synapses of hippocampal slices, we report that PRL modifies short and long¿term synaptic plasticity in female mice of reproductive age, but not in sexually immature females or adult males. This effect is carried out through mechanisms that include participation of GABAA receptors and activation of the JAK2¿mediated signaling pathway. These findings show for the first time how PRL enhances the synaptic strength in hippocampal circuits and that this effect is sexually dimorphic, which would influence complex brain processes in physiological conditions like pregnancy and lactation.

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.

[Background]: Numerous studies indicate an association between neurodegenerative and metabolic diseases. Although still a matter of debate, growing evidence from epidemiological and animal studies indicate that preexisting diabetes increases the risk to develop Parkinson's disease. However, the mechanisms of such an association are unknown., [Objectives]: We investigated whether diabetes alters striatal dopamine neurotransmission and assessed the vulnerability of nigrostriatal neurons to neurodegeneration., [Methods]: We used streptozotocin‐treated and genetically diabetic db/db mice. Expression of oxidative stress and nigrostriatal neuronal markers and levels of dopamine and its metabolites were monitored. Dopamine release and uptake were assessed using fast‐scan cyclic voltammetry. 6‐Hydroxydopamine was unilaterally injected into the striatum using stereotaxic surgery. Motor performance was scored using specific tests., [Results]: Diabetes resulted in oxidative stress and decreased levels of dopamine and its metabolites in the striatum. Levels of proteins regulating dopamine release and uptake, including the dopamine transporter, the Girk2 potassium channel, the vesicular monoamine transporter 2, and the presynaptic vesicle protein synaptobrevin‐2, were decreased in diabetic mice. Electrically evoked levels of extracellular dopamine in the striatum were enhanced, and altered dopamine uptake was observed. Striatal microinjections of a subthreshold dose of the neurotoxin 6‐hydroxydopamine in diabetic mice, insufficient to cause motor alterations in nondiabetic animals, resulted in motor impairment, higher loss of striatal dopaminergic axons, and decreased neuronal cell bodies in the substantia nigra., [Conclusions]: Our results indicate that diabetes promotes striatal oxidative stress, alters dopamine neurotransmission, and increases vulnerability to neurodegenerative damage leading to motor impairment.

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.Corkrum et al. report that astrocyte activity is required for dopamine- and amphetamine-evoked synaptic regulation and amphetamine-induced locomotor effects. Their study reveals astrocytes as active components of dopaminergic signaling and the brain reward system.

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes.