Dop1R1, a type 1 dopaminergic receptor expressed in Mushroom Bodies, modulates Drosophila larval locomotion

As in vertebrates, dopaminergic neural systems are key regulators of motor programs in insects, including the fly Drosophila melanogaster. Dopaminergic systems innervate the Mushroom Bodies (MB), an important association area in the insect brain primarily associated to olfactory learning and memory, but that has been also implicated with the execution of motor programs. The main objectives of this work is to assess the idea that dopaminergic systems contribute to the execution of motor programs in Drosophila larvae, and then, to evaluate the contribution of specific dopaminergic receptors expressed in MB to these programs. Our results show that animals bearing a mutation in the dopamine transporter show reduced locomotion, while mutants for the dopaminergic biosynthetic enzymes or the dopamine receptor Dop1R1 exhibit increased locomotion. Pan-neuronal expression of an RNAi for the Dop1R1 confirmed these results. Further studies show that animals expressing the RNAi for Dop1R1 in the entire MB neuronal population or only in the MB γ-lobe forming neurons, exhibit an increased motor output, as well. Interestingly, our results also suggest that other dopaminergic receptors do not contribute to larval motor behavior. Thus, our data support the proposition that CNS dopamine systems innervating MB neurons modulate larval locomotion and that Dop1R1 mediates this effect

Colombian consensus on the treatment of Placenta Accreta Spectrum (PAS)

Introducción: el espectro de acretismo placentario (EAP) es una condición asociada a sangrado masivo posparto y mortalidad materna. Las guías de manejo publicadas en países de altos ingresos recomiendan la participación de grupos interdisciplinarios en hospitales con recursos suficientes para realizar procedimientos complejos. Sin embargo, algunas de las recomendaciones de estas guías resultan difíciles de aplicar en países de bajos y medianos ingresos. Objetivos: este consenso busca formular recomendaciones generales para el tratamiento del EAP en Colombia. Materiales y métodos: en el consenso participaron 23 panelistas, quienes respondieron 31 preguntas sobre el tratamiento de EAP. Los panelistas fueron seleccionados con base en la participación en dos encuestas realizadas para determinar la capacidad resolutiva de hospitales en el país y la región. Se utilizó la metodología Delphi modificada, incorporando dos rondas sucesivas de discusión. Para emitir las recomendaciones el grupo tomó en cuenta la opinión de los participantes, que lograron un consenso mayor al 80 %, así como las barreras y los facilitadores para su implementación. Resultados: el consenso formuló cinco recomendaciones integrando las respuestas de los panelistas. Recomendación 1. Las instituciones de atención primaria deben realizar búsqueda activa de EAP en pacientes con factores de riesgo: placenta previa e historia de miomectomía o cesárea en embarazo previo. En caso de haber signos sugestivos de EAP por ecografía, las pacientes deben ser remitidas de manera inmediata, sin tener una edad gestacional mínima, a hospitales reconocidos como centros de referencia. Las modalidades virtuales de comunicación y atención en salud pueden facilitar la interacción entre las instituciones de atención primaria y los centros de referencia para EAP. Se debe evaluar el beneficio y riesgo de las modalidades de telemedicina. Recomendación 2. Es necesario que se definan hospitales de referencia para EAP en cada región de Colombia, asegurando el cubrimiento de la totalidad del territorio nacional. Es aconsejable concentrar el flujo de pacientes afectadas por esta condición en unos pocos hospitales, donde haya equipos de cirujanos con entrenamiento específico en EAP, disponibilidad de recursos especializados y un esfuerzo institucional por mejorar la calidad de atención, en busca de tener mejores resultados en la salud de las gestantes con esta condición. Para lograr ese objetivo los participantes recomiendan que los entes reguladores de la prestación de servicios de salud a nivel nacional, regional o local vigilen el proceso de remisión de estas pacientes, facilitando rutas administrativas en caso de que no exista contrato previo entre el asegurador y el hospital o la clínica seleccionada (IPS). Recomendación 3. En los centros de referencia para pacientes con EAP se invita a la creación de equipos que incorporen un grupo fijo de especialistas (obstetras, urólogos, cirujanos generales, radiólogos intervencionistas) encargados de atender todos los casos de EAP. Es recomendable que esos grupos interdisciplinarios utilicen el modelo de “paquete de intervención” como guía para la preparación de los centros de referencia para EAP. Este modelo consta de las siguientes actividades: preparación de los servicios, prevención e identificación de la enfermedad, respuesta ante la presentación de la enfermedad, aprendizaje luego de cada evento. La telemedicina facilita el tratamiento de EAP y debe ser tenida en cuenta por los grupos interdisciplinarios que atienden esta enfermedad. Recomendación 4. Los residentes de Obstetricia deben recibir instrucción en maniobras útiles para la prevención y el tratamiento del sangrado intraoperatorio masivo por placenta previa y EAP, tales como: la compresión manual de la aorta, el torniquete uterino, el empaquetamiento pélvico, el bypass retrovesical y la maniobra de Ward. Los conceptos básicos de diagnóstico y tratamiento de EAP deben incluirse en los programas de especialización en Ginecología y Obstetricia en Colombia. En los centros de referencia del EAP se deben ofrecer programas de entrenamiento a los profesionales interesados en mejorar sus competencias en EAP de manera presencial y virtual. Además, deben ofrecer soporte asistencial remoto (telemedicina) permanente a los demás hospitales en su región, en relación con pacientes con esa enfermedad. Recomendación 5. La finalización de la gestación en pacientes con sospecha de EAP y placenta previa, por imágenes diagnósticas, sin evidencia de sangrado vaginal activo, debe llevarse a cabo entre las semanas 34 y 36 6/7. El tratamiento quirúrgico debe incluir intervenciones secuenciales que pueden variar según las características de la lesión, la situación clínica de la paciente y los recursos disponibles. Las opciones quirúrgicas (histerectomía total y subtotal, manejo quirúrgico conservador en un paso y manejo expectante) deben incluirse en un protocolo conocido por todo el equipo interdisciplinario. En escenarios sin diagnóstico anteparto, es decir, ante un hallazgo intraoperatorio de EAP (evidencia de abultamiento violáceo o neovascularización de la cara anterior del útero), y con participación de personal no entrenado, se plantean tres situaciones: Primera opción: en ausencia de indicación de nacimiento inmediato o sangrado vaginal, se recomienda diferir la cesárea (cerrar la laparotomía antes de incidir el útero) hasta asegurar la disponibilidad de los recursos recomendados para llevar a cabo una cirugía segura. Segunda opción: ante indicación de nacimiento inmediato (por ejemplo, estado fetal no tranquilizador), pero sin sangrado vaginal o indicación de manejo inmediato de EAP, se sugiere realizar manejo en dos tiempos: se realiza la cesárea evitando incidir la placenta, seguida de histerorrafia y cierre de abdomen, hasta asegurar la disponibilidad de los recursos recomendados para llevar a cabo una cirugía segura. Tercera opción: en presencia de sangrado vaginal que hace imposible diferir el manejo definitivo de EAP, es necesario extraer el feto por el fondo del útero, realizar la histerorrafia y reevaluar. En ocasiones, el nacimiento del feto disminuye el flujo placentario y el sangrado vaginal se reduce o desaparece, lo que hace posible diferir el manejo definitivo de EAP. Si el sangrado significativo persiste, es necesario continuar con la histerectomía haciendo uso de los recursos disponibles: compresión manual de la aorta, llamado inmediato a los cirujanos con mejor entrenamiento disponible, soporte de grupos expertos de otros hospitales a través de telemedicina. Si una paciente con factores de riesgo para EAP (por ejemplo, miomectomía o cesárea previa) presenta retención de placenta posterior al parto vaginal, es recomendable confirmar la posibilidad de dicho diagnóstico (por ejemplo, realizando una ecografía) antes de intentar la extracción manual de la placenta. Conclusiones: esperamos que este primer consenso colombiano de EAP sirva como base para discusiones adicionales y trabajos colaborativos que mejoren los resultados clínicos de las mujeres afectadas por esta enfermedad. Evaluar la aplicabilidad y efectividad de las recomendaciones emitidas requerirá investigaciones adicionales.Q4Pacientes con Espectro de Acretismo Placentario (EAP)Introduction: Placenta accreta spectrum (PAS) is a condition associated with massive postpartum bleeding and maternal mortality. Management guidelines published in high income countries recommend the participation of interdisciplinary teams in hospitals with sufficient resources for performing complex procedures. However, some of the recommendations contained in those guidelines are difficult to implement in low and medium income countries. Objectives: The aim of this consensus is to draft general recommendations for the treatment of PAS in Colombia. Materials and Methods: Twenty-three panelists took part in the consensus with their answers to 31 questions related to the treatment of PAS. The panelists were selected based on participation in two surveys designed to determine the resolution capabilities of national and regional hospitals. The modified Delphi methodology was used, introducing two successive discussion rounds. The opinions of the participants, with a consensus of more than 80 %, as well as implementation barriers and facilitators, were taken into consideration in order to issue the recommendations. Results: The consensus drafted five recommendations, integrating the answers of the panelists. Recommendation 1. Primary care institutions must undertake active search of PAS in patients with risk factors: placenta praevia and history of myomectomy or previous cesarean section. In case of ultrasound signs suggesting PAS, patients must be immediately referred, without a minimum gestational age, to hospitals recognized as referral centers. Online communication and care modalities may facilitate the interaction between primary care institutions and referral centers for PAS. The risks and benefits of telemedicine modalities must be weighed. Recommendation 2. Referral hospitals for PAS need to be defined in each region of Colombia, ensuring coverage throughout the national territory. It is advisable to concentrate the flow of patients affected by this condition in a few hospitals with surgical teams specifically trained in PAS, availability of specialized resources, and institutional efforts at improving quality of care with the aim of achieving better health outcomes in pregnant women with this condition. To achieve this goal, participants recommend that healthcare regulatory agencies at a national and regional level should oversee the process of referral for these patients, expediting administrative pathways in those cases in which there is no prior agreement between the insurer and the selected hospital or clinic.Recommendation 3. Referral centers for patients with PAS are urged to build teams consisting of a fixed group of specialists (obstetricians, urologists, general surgeons, interventional radiologists) entrusted with the care of all PAS cases. It is advisable for these interdisciplinary teams to use the “intervention bundle” model as a guidance for building PAS referral centers. This model comprises the following activities: service preparedness, disease prevention and identification, response to the occurrence of the disease, and debriefing after every event. Telemedicine facilitates PAS treatment and should be taken into consideration by interdisciplinary teams caring for this disease. Recommendation 4. Obstetrics residents must be instructed in the performance of maneuvers that are useful for the prevention and treatment of massive intraoperative bleeding due to placenta praevia and PAS, including manual aortic compression, uterine tourniquet, pelvic packing, retrovesical bypass, and Ward maneuver. Specialization Obstetrics and Gynecology programs in Colombia must include the basic concepts of the diagnosis and treatment of PAS. Referral centers for PAS must offer online and in-person training programs for professionals interested in improving their competencies in PAS. Moreover, they must offer permanent remote support (telemedicine) to other hospitals in their region for patients with this condition. Recommendation 5. Patients suspected of having PAS and placenta praevia based on imaging, with no evidence of active vaginal bleeding, must be delivered between weeks 34 and 36 6/7. Surgical treatment must include sequential interventions that may vary depending on the characteristics of the lesion, the clinical condition of the patient and the availability of resources. The surgical options (total and subtotal hysterectomy, one-stage conservative surgical management and watchful waiting) must be included in a protocol known by the entire interdisciplinary team. In situations in which an antepartum diagnosis is lacking, that is to say, in the face of intraoperative finding of PAS (evidence of purple bulging or neovascularization of the anterior aspect of the uterus), and the participation of untrained personnel, three options are considered: Option 1: In the absence of indication of immediate delivery or of vaginal delivery, the recommendation is to postpone the cesarean section (close the laparotomy before incising the uterus) until the recommended resources for safe surgery are secured. Option 2: If there is an indication for immediate delivery (e.g., non-reassuring fetal status) but there is absence of vaginal bleeding or indication for immediate PAS management, a two-stage management is suggested: cesarean section avoiding placental incision, followed by uterine repair and abdominal closure, until the availability of the recommended resources for safe surgery is ascertained. Option 3: In the event of vaginal bleeding that prevents definitive PAS management, the fetus must be delivered through the uterine fundus, followed by uterine repair and reassessment of the situation. Sometimes, fetal delivery diminishes placental flow and vaginal bleeding is reduced or disappears, enabling the possibility to postpone definitive management of PAS. In case of persistent significant bleeding, hysterectomy should be performed, using all available resources: manual aortic compression, immediate call to the surgeons with the best available training, telemedicine support from expert teams in other hospitals.If a patient with risk factors for PAS (e.g., myomectomy or previous cesarean section) has a retained placenta after vaginal delivery, it is advisable to confirm the possibility of such diagnosis (by means of ultrasound, for example) before proceeding to manual extraction of the placenta.Conclusions: It is our hope that this first Colombian consensus on PAS will serve as a basis for additional discussions and collaborations that can result in improved clinical outcomes for women affected by this condition. Additional research will be required in order to evaluate the applicability and effectiveness of these recommendations.https://orcid.org/0000-0001-6822-0374Revista Nacional - IndexadaCN

Roadmap on energy harvesting materials

Ambient energy harvesting has great potential to contribute to sustainable development and address growing environmental challenges. Converting waste energy from energy-intensive processes and systems (e.g. combustion engines and furnaces) is crucial to reducing their environmental impact and achieving net-zero emissions. Compact energy harvesters will also be key to powering the exponentially growing smart devices ecosystem that is part of the Internet of Things, thus enabling futuristic applications that can improve our quality of life (e.g. smart homes, smart cities, smart manufacturing, and smart healthcare). To achieve these goals, innovative materials are needed to efficiently convert ambient energy into electricity through various physical mechanisms, such as the photovoltaic effect, thermoelectricity, piezoelectricity, triboelectricity, and radiofrequency wireless power transfer. By bringing together the perspectives of experts in various types of energy harvesting materials, this Roadmap provides extensive insights into recent advances and present challenges in the field. Additionally, the Roadmap analyses the key performance metrics of these technologies in relation to their ultimate energy conversion limits. Building on these insights, the Roadmap outlines promising directions for future research to fully harness the potential of energy harvesting materials for green energy anytime, anywhere

Formation de mémoire sous privation de nourriture chez la Drosophile melanogaster : la glie alimente les neurones avec des corps cétoniques synthétisés localement

Food scarcity represents a major metabolic challenge for the brain and processesthat ensure its adequate functioning are considered crucial for organism survival (Mattsonet al, 2017). The brain is the central regulator of energy homeostasis, and it gives priority toits own supply over peripheral organs. However, the mechanisms through which theenergy status regulates brain plasticity remains largely unknown. We have previouslyrevealed using Drosophila melanogaster that the brain is subjected to adaptive plasticityand that under a metabolic challenge, such as starvation (i.e when the level of brain’smajor fuel, the glucose, scarce), the brain disables the costly formation of protein synthesisdependent long-term memory (LTM) to favor survival, but concomitantly upregulatedanother form of consolidated long-lasting memory called LT-ARM (Placais and Preat,2013). Recently, we have demonstrated that flies double their sugar intake and upregulatetheir mitochondrial pyruvate flux in the fly olfactory memory center, the Mushroom Body(MB), after LTM formation (Placais et al., 2017). Nevertheless, in absence of glucosederivatives, how does the brain regulate memory formation to withstands periods of foodscarcity? Moreover, what are the metabolic fuels used by the brain to sustain the formationof persistent memory upon starvation? And eventually which are the brain cell typesinvolved in this process?Ketone Bodies (KBs) are high-energy rich metabolites, derived from fatty acidmetabolism and used by the brain under metabolic challenging conditions such asstarvation (Owen et al. 1967). However, it is currently unknown whether neurons are able touse KBs to sustain neuronal physiology and in particular memory formation. In my thesis, Iaddressed the in vivo role of KBs metabolism in aversive olfactory memory formation uponstarvation (sLT-ARM), the metabolic pathways required and the cell types involved in thisprocess by combining genetics, behavioral assays, fluorescent lipid staining and in vivotwo photon imaging using the model organism Drosophila melanogaster.By using cell type specific gene knockdown restricted to adulthood associated tobehavioral and in vivo imaging experiments, I have demonstrated that KBs import andmitochondrial oxidation are required in MB neurons to sustain sLT-ARM formationspecifically. Then I have identified the cortex glia cells as the ones providing KBs toneurons upon sLT-ARM formation. Eventually using behavioral assays and fluorescent lipidstaining, I have shown that sLT-ARM formation is dependent on ketogenesis in cortex gliafrom their own lipid store and that this process is likely regulated by the master energysensor AMPK.Based on these data, we can propose a model of cortex glia-MB neuronsinteractions specific to starvation in which KB synthetized by glia from their own lipid storeare shuttled to neurons to sustain persistent memory formation. Our data suggest that, atleast in glial cells, AMPK could be one of the keys to activate this model upon starvation.This work presented here is of particular relevance in the frame of recent evidences thatfood deprivation periods such as caloric restriction or intermittent fasting might havebeneficial effects on cognition in age-related cognitive impairments.Le jeûne représente un défi métabolique majeur pour le cerveau et les processus qui assurent son bon fonctionnement sont considérés comme cruciaux pour la survie de l'organisme (Mattson et al, 2017). Le cerveau est le régulateur central de l'homéostasie énergétique et il donne la priorité à son propre apport par rapport aux organes périphériques.Cependant, les mécanismes par lesquels l'état énergétique régule la plasticité cérébrale restentlargement inconnus. Chez Drosophila melanogaster, nous avons précédemment montré que le cerveau est soumis à une plasticité adaptative et que lors d’un stress métabolique, comme le jeûne (i.e lorsque le niveau de carburant principal du cerveau, le glucose, est rare), le cerveau désactive la formation de la mémoire à long terme dépendante de la synthèse protéique (MLT)pour favoriser la survie, et parallèlement favorise une autre forme de mémoire à long terme consolidée appelée MRA (Placais et Preat, 2013). Récemment, nous avons démontré que les mouches doublent leur consommation de sucre et augmentent le flux de pyruvate mitochondrialdans le centre de mémoire olfactive, les Corps Pédonculés (CP), après la formation de la MLT (Placais et al., 2017). Néanmoins, en l'absence de glucose, comment le cerveau régule-t-il la formation de la mémoire pour résister aux périodes de pénurie alimentaire ? Quels sont les substrats métaboliques utilisés par le cerveau lors de la formation d'une mémoire persistante encas de jeûne ? Et finalement, quels sont les types de cellules cérébrales impliqués dans ce processus ?Les corps cétoniques (CC) sont des métabolites riches en énergie, dérivés du métabolisme des acides gras et utilisés par le cerveau lors de conditions de stress métabolique tel que le jeûne (Owen et al. 1967). Cependant, on ignore actuellement si les neurones sont capables d'utiliser les CC pour maintenir leur activité physiologique et en particulier la formation de la mémoire. Dans ma thèse, j'ai abordé le rôle in vivo du métabolisme des CC dans la formation de la mémoire olfactive aversive lors du jeûne (j-MRA), les voies métaboliques nécessaires et les types cellulaires impliqués dans ce processus en combinant la génétique, les tests comportementaux, des marquages fluorescents des lipides et de l’imagerie in vivo à 2-photons à l'aide de l'organisme modèle Drosophila melanogaster.En couplant la diminution de l’expression de gènes cibles de façon cellule-spécifique et uniquement à l’âge adulte, à des expériences de comportement et de l’imagerie in vivo, j'ai démontré que l'import de CC et leur oxydation mitochondriale dans les neurones des CP sont nécessaires à la formation de la j-MRA spécifiquement. Ensuite, j'ai identifié les cellules de la glie corticale comme celles qui fournissent des CC aux neurones lors de la formation de la j-MRA.Finalement, en utilisant des tests comportementaux et une coloration fluorescente des lipides,j'ai pu montrer que la formation de j-MRA dépend de la cétogenèse dans la glie corticale à partir de leur propre réserve lipidique et que ce processus est probablement régulé par l’AMPK,senseur majeur de l’état énergétique de la cellule.Sur la base de ces données, nous pouvons proposer un modèle d'interactions glie corticale-neurones des CP spécifiques aux conditions de jeûne dans lequel les CC synthétisés par la glie à partir de leur propre stock de lipides sont exportés vers les neurones pour soutenir la formation d’une mémoire persistante. Nos données suggèrent qu'au moins dans les cellules gliales, l'AMPK pourrait être l'une des clés pour activer ce modèle en cas de jeûne. Le travail présenté ici est particulièrement pertinent dans le cadre d’études récentes montrant que les périodes de privation alimentaire telles que la restriction calorique ou le jeûne intermittent pourraient avoir des effets bénéfiques sur la cognition dans les déficiences cognitives liées à l'âge

Formation de mémoire sous privation de nourriture chez la Drosophile melanogaster : la glie alimente les neurones avec des corps cétoniques synthétisés localement

Le jeûne représente un défi métabolique majeur pour le cerveau et les processus qui assurent son bon fonctionnement sont considérés comme cruciaux pour la survie de l'organisme (Mattson et al, 2017). Le cerveau est le régulateur central de l'homéostasie énergétique et il donne la priorité à son propre apport par rapport aux organes périphériques.Cependant, les mécanismes par lesquels l'état énergétique régule la plasticité cérébrale restentlargement inconnus. Chez Drosophila melanogaster, nous avons précédemment montré que le cerveau est soumis à une plasticité adaptative et que lors d’un stress métabolique, comme le jeûne (i.e lorsque le niveau de carburant principal du cerveau, le glucose, est rare), le cerveau désactive la formation de la mémoire à long terme dépendante de la synthèse protéique (MLT)pour favoriser la survie, et parallèlement favorise une autre forme de mémoire à long terme consolidée appelée MRA (Placais et Preat, 2013). Récemment, nous avons démontré que les mouches doublent leur consommation de sucre et augmentent le flux de pyruvate mitochondrialdans le centre de mémoire olfactive, les Corps Pédonculés (CP), après la formation de la MLT (Placais et al., 2017). Néanmoins, en l'absence de glucose, comment le cerveau régule-t-il la formation de la mémoire pour résister aux périodes de pénurie alimentaire ? Quels sont les substrats métaboliques utilisés par le cerveau lors de la formation d'une mémoire persistante encas de jeûne ? Et finalement, quels sont les types de cellules cérébrales impliqués dans ce processus ?Les corps cétoniques (CC) sont des métabolites riches en énergie, dérivés du métabolisme des acides gras et utilisés par le cerveau lors de conditions de stress métabolique tel que le jeûne (Owen et al. 1967). Cependant, on ignore actuellement si les neurones sont capables d'utiliser les CC pour maintenir leur activité physiologique et en particulier la formation de la mémoire. Dans ma thèse, j'ai abordé le rôle in vivo du métabolisme des CC dans la formation de la mémoire olfactive aversive lors du jeûne (j-MRA), les voies métaboliques nécessaires et les types cellulaires impliqués dans ce processus en combinant la génétique, les tests comportementaux, des marquages fluorescents des lipides et de l’imagerie in vivo à 2-photons à l'aide de l'organisme modèle Drosophila melanogaster.En couplant la diminution de l’expression de gènes cibles de façon cellule-spécifique et uniquement à l’âge adulte, à des expériences de comportement et de l’imagerie in vivo, j'ai démontré que l'import de CC et leur oxydation mitochondriale dans les neurones des CP sont nécessaires à la formation de la j-MRA spécifiquement. Ensuite, j'ai identifié les cellules de la glie corticale comme celles qui fournissent des CC aux neurones lors de la formation de la j-MRA.Finalement, en utilisant des tests comportementaux et une coloration fluorescente des lipides,j'ai pu montrer que la formation de j-MRA dépend de la cétogenèse dans la glie corticale à partir de leur propre réserve lipidique et que ce processus est probablement régulé par l’AMPK,senseur majeur de l’état énergétique de la cellule.Sur la base de ces données, nous pouvons proposer un modèle d'interactions glie corticale-neurones des CP spécifiques aux conditions de jeûne dans lequel les CC synthétisés par la glie à partir de leur propre stock de lipides sont exportés vers les neurones pour soutenir la formation d’une mémoire persistante. Nos données suggèrent qu'au moins dans les cellules gliales, l'AMPK pourrait être l'une des clés pour activer ce modèle en cas de jeûne. Le travail présenté ici est particulièrement pertinent dans le cadre d’études récentes montrant que les périodes de privation alimentaire telles que la restriction calorique ou le jeûne intermittent pourraient avoir des effets bénéfiques sur la cognition dans les déficiences cognitives liées à l'âge.Food scarcity represents a major metabolic challenge for the brain and processesthat ensure its adequate functioning are considered crucial for organism survival (Mattsonet al, 2017). The brain is the central regulator of energy homeostasis, and it gives priority toits own supply over peripheral organs. However, the mechanisms through which theenergy status regulates brain plasticity remains largely unknown. We have previouslyrevealed using Drosophila melanogaster that the brain is subjected to adaptive plasticityand that under a metabolic challenge, such as starvation (i.e when the level of brain’smajor fuel, the glucose, scarce), the brain disables the costly formation of protein synthesisdependent long-term memory (LTM) to favor survival, but concomitantly upregulatedanother form of consolidated long-lasting memory called LT-ARM (Placais and Preat,2013). Recently, we have demonstrated that flies double their sugar intake and upregulatetheir mitochondrial pyruvate flux in the fly olfactory memory center, the Mushroom Body(MB), after LTM formation (Placais et al., 2017). Nevertheless, in absence of glucosederivatives, how does the brain regulate memory formation to withstands periods of foodscarcity? Moreover, what are the metabolic fuels used by the brain to sustain the formationof persistent memory upon starvation? And eventually which are the brain cell typesinvolved in this process?Ketone Bodies (KBs) are high-energy rich metabolites, derived from fatty acidmetabolism and used by the brain under metabolic challenging conditions such asstarvation (Owen et al. 1967). However, it is currently unknown whether neurons are able touse KBs to sustain neuronal physiology and in particular memory formation. In my thesis, Iaddressed the in vivo role of KBs metabolism in aversive olfactory memory formation uponstarvation (sLT-ARM), the metabolic pathways required and the cell types involved in thisprocess by combining genetics, behavioral assays, fluorescent lipid staining and in vivotwo photon imaging using the model organism Drosophila melanogaster.By using cell type specific gene knockdown restricted to adulthood associated tobehavioral and in vivo imaging experiments, I have demonstrated that KBs import andmitochondrial oxidation are required in MB neurons to sustain sLT-ARM formationspecifically. Then I have identified the cortex glia cells as the ones providing KBs toneurons upon sLT-ARM formation. Eventually using behavioral assays and fluorescent lipidstaining, I have shown that sLT-ARM formation is dependent on ketogenesis in cortex gliafrom their own lipid store and that this process is likely regulated by the master energysensor AMPK.Based on these data, we can propose a model of cortex glia-MB neuronsinteractions specific to starvation in which KB synthetized by glia from their own lipid storeare shuttled to neurons to sustain persistent memory formation. Our data suggest that, atleast in glial cells, AMPK could be one of the keys to activate this model upon starvation.This work presented here is of particular relevance in the frame of recent evidences thatfood deprivation periods such as caloric restriction or intermittent fasting might havebeneficial effects on cognition in age-related cognitive impairments

Serotonin Receptors Expressed in <i>Drosophila</i> Mushroom Bodies Differentially Modulate Larval Locomotion

<div><p><i>Drosophila melanogaster</i> has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA) including serotonin (5HT) participate in motor control in <i>Drosophila</i>. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB). The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in <i>Drosophila</i> larvae (3^rd-instar) exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT_1AR, 5HT_1BR, 5HT₂R and 5HT₇R) were evaluated in their locomotion. Finally, RNAi directed to the <i>Drosophila</i> 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT_1BR, 5HT₂R and 5HT₇R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT_1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.</p></div

Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation.

During starvation, mammalian brains can adapt their metabolism, switching from glucose to alternative peripheral fuel sources. In the Drosophila starved brain, memory formation is subject to adaptative plasticity, but whether this adaptive plasticity relies on metabolic adaptation remains unclear. Here we show that during starvation, neurons of the fly olfactory memory centre import and use ketone bodies (KBs) as an energy substrate to sustain aversive memory formation. We identify local providers within the brain, the cortex glia, that use their own lipid store to synthesize KBs before exporting them to neurons via monocarboxylate transporters. Finally, we show that the master energy sensor AMP-activated protein kinase regulates both lipid mobilization and KB export in cortex glia. Our data provide a general schema of the metabolic interactions within the brain to support memory when glucose is scarce

Increased locomotion observed in animals pan-neuronally expressing RNAi for 5HT_1BR depends on MB γ-lobe forming neurons.

<p>A. Pan neuronal expression of RNAi for 5HT_1AR (Gal4-elav x UAS-RNAi 5HT_1BR, in green) increases larval locomotion compared to genetic controls (elav-Gal4/+, in blue, and UAS-RNAi 5HT_1AR/+, in gray). B. Expression of RNAi for 5HT_1AR in the entire MB neuronal population (in green) does not affect motor output, as compared to genetic controls. C. Expression of RNAi for 5HT_1AR in the γ-lobe forming neurons increases locomotion (in green) compared to genetic controls. D. No effect on locomotion is observed when the RNAi for 5HT_1AR ισ εξπρεσσεδ ιν τηε α’/β’ lobe-forming neurons compared to its genetic controls. In each case, genetic controls are animals bearing one copy of the Gal4 driver (in blue) or the undriven UAS-RNAi 5HT_1AR (in gray). Bars represent mean distance+SEM that at least 9 larvae covered over 140 sec, per experimental condition. *** indicates p<0.001 compared to genetic controls; ANOVA followed by Tukey post-hoc test.</p

Geração de cenários de conservação: importância da análise de sensibilidade dos parâmetros do modelo adotado

The efforts to minimize the loss of habitats and threats to conservation of biodiversity are increasingly based on objective criteria, which allow prioritizing areas and species in need of preservation, taking into account the limitations in both natural and economic resources. These criteria are fundamental for the reserve selection and design, mainly in regions severely affected by the intensification of land use. In particular, the use of mathematical modeling, enabling the identification of more efficient alternatives, is an important subsidy to conservation challenge. In this paper, we present a sensitivity analysis regarding the parameters of the non-linear model we developed for the selection of priority areas for conservation, which considers both the quality and ecological feasibility of the remnant vegetation in the Cerrado areas of the State of Goiás, as well as the practical and legal aspects regarding the use of watersheds for territorial management. The variation of the parameters used in such model maintains a direct relation to the social-economical and environmental interests, thus generating distinct solutions and scenarios. Among the possible outcomes, we highlight as an "optimum" solution, the one with a large number remnant vegetation areas within riparian environments, which serves the purpose of strengthening spatial connectivity and natural corridors.Pages: 5949-595