Role of the LPA1 receptor in mood and emotional regulation

Depression is a debilitating psychiatric condition characterized by anhedonia and behavioural despair among others symptoms. Despite the high prevalence and devastating impact of depression, underlying neurobiological mechanisms of mood disorders are still not well known. Regardless its complexity, central features of this disease can be modelled in rodents in order to better understand the potential mechanisms underlying. On the other hand, the lack of LPA1 receptor compromises the morphological and functional integrity of the limbic circuit and the neurogenesis in hippocampus, induces cognitive alterations on hippocampal-dependent tasks and dysfunctional coping of chronic stress, provokes exaggerated endocrine responses to emotional stimuli and impairs adaptation of the hypothalamic-pituitary-adrenal axis after chronic stress. Factors, which all have been related with depression. Here, we sought to establish the involvement of the LPA1 receptor in regulation of mood and emotion. To this end, in wild-type and maLPA1-null mice active coping responses to stress were examined using the forced swimming test (FST). To assess hedonic behaviour saccharine preference test and female urine sniffing test were used. Our data indicated that the absence of the LPA1 receptor significantly affected to coping strategies. Thus, while null mice displayed less immobility than wt in FST, exhibited more climbing and less swimming behaviour, responses that could be interpreted as an emotional over-reaction (i.e., a panic-like response) to stress situations. Concerning hedonic behaviour, the lack of the LPA1 receptor diminished saccharin preference and female urine sniffing time. Overall, these data supports the role of LPA1 receptor in mood and emotional regulation. Specially, the lack of this receptor induced emotional dysregulation and anhedonic behaviour, a core symptom of depression.Universidad de Málaga, Campus de Excelencia Andalucía Tech. Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ-1863; CTS643) and of Health (PI-0234-2013; Nicolas Monardes Programme), MINECO (PSI2013-44901-P) and National Institute of Health Carlos III (Sara Borrel)

Enhancing adult hippocampal neurogenesis with lysophosphatidic acid: a proposal for erasing cocaine contextual memory

Stimulating adult hippocampal neurogenesis (AHN) has been uncovered as a promising approach in the manipulation of retrograde memories. This work aims to study whether increasing AHN with lysophosphatidic acid (LPA, an endogenous lysophospholipid with proneurogenic actions) promotes the forgetting of previously established cocaine-contextual associations. C57BL/6J mice previously trained in a cocaine-induced conditioned place preference (CPP) paradigm were submitted to 23 days of withdrawal, during which they received repeated intracerebroventricular infusions of LPA, ki16425 (a selective LPA1/3 receptors antagonist), or vehicle solution. Then, CPP maintenance was assessed, and the causal role of AHN in this process was evaluated using a mediation analysis. In a complementary experiment, wild-type and LPA1-null mice were acutely infused with LPA or ki16425 to determine the involvement of the LPA1 receptor in the in vivo proneurogenic actions of LPA. The chronic LPA treatment significantly weakened the long-term retention of a previously acquired cocaine-CPP memory, an effect clearly mediated by a LPA-induced increase in the number of adult-born dentate granule cells. In contrast, the ki16425-treated mice displayed aberrant responses of initially decreased CPP retention that progressively increased CPP across the extinction sessions, in absence of effects on AHN. The histological studies suggested that the proneurogenic actions of LPA were related to the enhancement of cell proliferation and critically depended on the LPA1 receptor function. Our results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN, and highlight the usefulness of a post-learning increase of adult-born hippocampal neurons as a strategy to promote the forgetting of cocaine-context associations.Plan Propio de Investigación y Transferencia. Campus de Excelencia Internacional Andalucía Tech. Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), co‐funded by the European Research Development Fund (AEI/FEDER, UE) (PSI2013‐44901‐P and PSI2017‐82604‐R to L.J.S. and PSI2015‐73156‐JIN to E.C.O.); by the National System of Health‐Instituto de Salud Carlos III, which is co‐funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to F.R.d.F.); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to G.E.T.). D.L.G.M. hold a FPU grant from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 ). F.R.d.F. and G.E.T. are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. E.C.O. holds a ‘Jóvenes Investigadores’ grant (code: PSI2015‐73156‐JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is co‐funded by the AEI/FEDER, UE

AO-4025 ITT ESA - Surface treatments and coatings for reduction of multipactor and Passive InterModulation (PIM) effect in RF components

This is the electronic version of a paper presented at the 4th International Workshop on Multipactor, Corona and Passive Intermodulation in Space RF Hardware (MULCOPIM 2003) held in Noordwijk, The Netherlands.ESA has initiated several activities with the aim to reduce the risk of multipaction and corona effects in space hardware. Within the activity Surface Treatment and Coating for the Reduction of Multipactor and Passive Intermodulation (PIM) Effects in RF Components a European group has been formed to investigate new surface coatings / treatments to improve the power handling capability of passive equipment with respect to multipactor and passive intermodulation. This paper presents an overview of the activities to be performed within this project and describes the first results

More adult-born dentate gyrus neurons to weaken cocaine-related retrograde memories: an in vivo strategy employing exogenous lysophosphatidic acid

The post-training enhancement of adult hippocampal neurogenesis (AHN) has been receiving growing interest as a potential method to manipulate retrograde memories. Recent hypothesis suggest that the addition of adult-born dentate granule cells might promotes remodeling of pre-existing hippocampal circuits, which might both clear cocaine-related memories and facilitate the learning of new adaptive information. Here, we study the effect of stimulating AHN in vivo with exogenous lysophosphatidic acid (LPA) on the maintenance of retrograde cocaine-contextual associative memories. Male C57BL/6J mice trained in a cocaine-induced Conditioned Place Preference (CPP) model were later submitted to repeated intracerebroventricular (i.c.v.) injections of LPA, Ki16425 or vehicle solution during withdrawal. Afterwards, the long-term persistence of the cocaine-CPP was assessed and the mediational role of AHN in this process was evaluated. In addition, wild-type and mice lacking the LPA1 receptor received a single i.c.v. injection of LPA, Ki16425 or vehicle to assess the role of the LPA1 receptor in the LPA-induced increase of AHN. Our results revealed that the chronic administration of LPA decreased the retention of a previously acquired cocaine-induced CPP. This effect was mediated by an LPA-induced increase of AHN. In contrast, mice treated with Ki16425 showed reduced cocaine-CPP retention, but they increased their preference for the cocaine-paired compartment throughout CPP extinction. Besides, no effects of Ki16425 on AHN were found. Immunohistochemical studies suggested that LPA stimulated cell proliferation and promoted neuronal maturation with a key role of the LPA1 receptor. These findings emphasize the relevance of LPA and its LPA1 receptor as an in vivo modulator of AHN and the utility of the post-training increase of adult-born hippocampal neurons to weaken cocaine-context associations.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory

Author manuscriptErasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (a LPA1/3 receptor antagonist), or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an ~two-fold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 receptor-deficient mice were acutely infused with LPA, which revealed that LPA1-mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1-pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación), which is cofunded by the European Research Development Fund AEI/FEDER, UE- (PSI2013-44901-P and PSI2017-82604-R to LJS and PSI2015-73156-JIN to ECO); by the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE (Red de Trastornos Adictivos; RD16/0017/0001 to FRdF); and by the Andalusian R&D&I Programme, Regional Ministry of Economy and Knowledge (PAIDI CTS643 to GET). DLGM and RDMF hold FPU grants from the Spanish Ministry of Education, Culture and Sports (FPU13/04819 and FPU14-01610, respectively). CRV received a ‘Plan Propio’ grant from the University of Malaga. FJP and AS hold ‘Miguel Servet’ grants (CP14/00212 and CP14/00173, respectively) from the National System of Health-Instituto de Salud Carlos III, which is co-funded by AEI/FEDER, UE. FRdF and GET are supported by Nicolas Monardes Programme, from the Andalusian Regional Ministry of Health. ECO holds a ‘Jóvenes Investigadores’ grant (code: PSI2015- 73156-JIN) from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) which is co-funded by the European Research Development Fund (AEI/FEDER, UE)

What role does the LPA1 receptor play in regulating emotional-like behaviours?

The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts as an intercellular signalling molecule. It has been proposed that this receptor has a role in controlling anxiety-like behaviours and in the detrimental consequences of stress. In general, the neurobiological mechanism of fear extinction is strikingly similar to that of the adaptative stress response (distress regulation), sharing similar neuroanatomical, neuroendocrine, and neurochemical basis. Inadequate control of the stress response could precipitate or provoke anxiety disorders. In this context, we tried to elucidate the LPA1 receptor involvement in emotional regulation. For this purpose, we first examined fear extinction, a type of emotional regulation, in normal wild-type (wt) and maLPA1-null mice using two different extinction procedures (cued fear extinction and contextual fear extinction). Additionally, to study the role of the LPA1 receptor in the absence of developmental abnormalities induced by its permanent loss, the effect of the LPA1 antagonist Ki16425 administration was examined in contextual fear extinction on wild-type mice. Next, we studied the consequences of the absence of the LPA1 receptor in two key areas involved in emotional regulation, characterizing the structure and GABAergic composition of the medial prefrontal cortex (mPFC) and the amygdala by immunohistochemical detection of neuron specific nuclear protein (NeuN), GABA-positive cells and calcium-binding proteins (calretinin (CR), parvalbumin (PV), and calbindin (CB)). Lastly, we examined the corticosterone response and the expression of a marker of neuronal activity, c-Fos protein, in the amygdala and the mPFC after acute stress. Our results revealed that lack of the LPA1-receptor induces exaggerated amygdala reactivity and endocrine responses to emotional stimuli (e.g., an acute episode of stress), revealing a role of the LPA1 receptor in regulating emotional-like behaviours. Considering that a reduction of GABAergic inhibitory control in the amygdala may be a common mechanism to generate a heightened emotional state, the abnormal emotional response reported in LPA1-null mice could be explained, at least in part, by a significant reduction of GABAérgic composition of the amygdala observed in these animals. Taking together, the LPA1 receptor is involved in emotional behaviours and in the anatomical integrity of the corticolimbic circuit, the deregulation of which may be a susceptibility factor for anxiety disorders and a potential therapeutic target for the treatment of these diseases.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The absence of LPA1 receptor results in lipidome dysregulation and Neuropeptide-Y underexpression

LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intercellular signaling molecule. It has been shown that the LPA1 receptor is involved in emotional regulation and, when depleted, has a key role in vulnerability to stress. In this sense, maLPA1-null mice, a knockout model for LPA1 receptor has been recently proposed as a model of anxious depression. Here, we sought to elucidate the effect of the genetic depletion of this receptor of LPA1 receptor in both lipidome and Neuropeptide-Y (NPY) signaling, two factors associated with adaptive stress regulation. For that purpose, we measured the lipidomic profile of wild-type mice and maLPA1-null mice in both hippocampus and serum. In addition, through immunohistochemical procedures we quantified NPY+ cells in hippocampus, basolateral amygdala (BLA) and central amygdala (CeA). Interestingly, the comparative lipidomics analysis revealed differences in certain subspecies which are related to LPA1 receptor functionality. Regarding NPY, we found a reduction in BLA, but not in hippocampus. Overall, both lipid abnormalities and amygdalar dysfunction of NPY can be related to lower resources in stress coping and, in turn, higher vulnerability to the noxious effect of stress that might lead to anxiety and depressive-like states.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis.

Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, Trained mice reduced the number of proliferating hippocampal cells but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole-board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is an useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This study was funded by grants from the Spanish Ministry of Economy and Competitiveness (Agencia Estatal de Investigación) co-funded by the European Research Development Fund -AEI/FEDER, UE- (PSI2015-73156-JIN ‘Jóvenes Investigadores grant’ to E.C.O. and PSI2013-44901-P to L.J.S. and C.P.), from ‘Junta de Andalucía’ SEJ1863 to C.P. and from University of Málaga (Plan Propio 2017 – ‘Ayudas para proyectos puente’) to M.G.F. Author P.S.P. holds a ‘Juan de la Cierva-formación‘grant from the Spanish Ministry of Economy, Industry and Competitiveness (code: FJCI-2015-23925) and a ‘D.3. Estancia de investigadores de reconocido prestigio en la UMA‘ grant from the University of Málaga. Authors R.D.M.F. and D.L.G.M. hold ‘FPU’ grants from the Spanish Ministry of Education, Culture and Sports (code: FPU14-01610 and FPU13/04819, respectively). Author F.J.P. holds a ‘Miguel Servet’ grant (code: CP14/00212) from the National System of Health-Instituto de Salud Carlos-III co-funded by FEDER, UE

Revista de Vertebrados de la Estación Biológica de Doñana

Contribución al estudio de la bermejuela Rutilus arcasi, Steindachner, 1866 de la cuenca del Júcar (Osteichthyes: Cyprinidae)II. Edad y crecimientoSobre la taxonomía de Barbus comiza Steindachner, 1865 (Ostariophysi: Cyprinidae)Fenología de una comunidad de anfibios asociada a cursos fluviales temporales.Nueva especie para la ciencia de Anolis (Lacertilia: Iguanidae) de Cuba pertenecient eal complejo argillaceusSegregación ecológica en una comunidad de ofidios.El Aguila Imperial (Aquila adalberti): dispersión de los jóvenes, estructura de edades y mortalidaSobre diferencias individuales en la alimentación de Tyto albaInfluencia de las condiciones ambientales sobre la organización de la comunidad de aves invernantes en un bosque subalpino mediterráneoVariaciones en la agregación y distribución de la cabra montés (Capra pyrenaica Schinz,1838) detectadas con un muestreo de excrementosAlimentación del conejo (Oryctolagus cuniculus L. 1758) en Doñana. SO, EspañaSobre la distribución de Barbus meridionales Risso, 1826 (Ostariophysi: Cyprinidae) en la Península IbéricaSobre la distribución de Barbus meridionales Risso, 1826 (Ostariophysi: Cyprinidae) en la Península IbéricaNueva cita de Barbus microcephalus Almaça (Pisces, Cyprinidae) en España.Revisión taxonómica y distribución de Cobitis maroccana Pellegrin, 1929 (Osteichthyes, Cobitidae)Datos sobre una población de Lacerta viviparaSobre la presencia de Emys orbicularis en la provincia de León.Algunas observaciones sobre la captura de quirópteros por Falco subbuteo y Falco tinunculusNyctalus leisleri (Kuhk, 1818) (Mammalia: Chiroptera). Una nueva especie para las islas CanariaNuevos datos acerca de la distribución del topillo campesino Microtus arvalis, PALLAS 1778, en la Península IbéricaPeer reviewe

Absence of LPA1 receptor results in altered pattern of limbic activation after tail suspension test

Stress serves as an adaptive mechanism and helps organisms to cope with life-threatening situations. However, individual vulnerability to stress and dysregulation of this system may precipitate stress-related disorders such as depression. The neurobiological circuitry in charge of dealing with stressors has been widely studied in animal models. Recently our group has demonstrated a role for lysophosphatidic acid (LPA) through the LPA1 receptor in vulnerability to stress, in particular the lack of this receptor relates to robust decrease of adult hippocampal neurogenesis and induction of anxious and depressive states. Nevertheless, the specific abnormalities in the limbic circuit in reaction to stress remains unclear. The aim of this study is to examine the differences in the brain activation pattern in the presence or absence of LPA1 receptor after acute stress. For this purpose, we have studied the response of maLPA1-null male mice and normal wild type mice to an intense stressor: Tail Suspension Test. Activation induced by behaviour of brain regions involved in mood regulation was analysed by stereological quantification of c-Fos immunoreactive positive cells. We also conducted multidimensional scaling analysis in order to unravel coativation between structures. Our results revealed hyperactivity of stress-related structures such as amygdala and paraventricular nucleus of the hypothalamus in the knockout model and different patterns of coactivation in both genotypes using a multidimensional map. This data provides further evidence to the engagement of the LPA1 receptors in stress regulation and sheds light on different neural pathways under normal and vulnerability conditions that can lead to mood disorders.Universidad de Malaga, Campus de Excelencia internacional Andalucía Tech. Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863); Postdoctoral Fellowship ‘Sara Borrell’ of the National Institute of Health Carlos III E. C.; Grant of the Andalusian Ministry of Economy, Innovation , Science and Employment C. R. (FPDI 2010). Grant of the Spanish Ministry of Education, Culture and Sport s (FPU14/01610)