The introduced silver Pheasant (Lophura Nycthemera) in Patagonia Abundance, group structure, activity patterns and association to human disturbance

Los fasiánidos son uno de los grupos de aves introducidas con mayor impacto en los ecosistemas nativos. En la Patagonia varias especies de fasiánidos están establecidas o en proceso de establecimiento, por lo que es relevante conocer sus impactos sobre los ecosistemas. El Faisán Plateado (Lophura nycthemera) fue introducido en Isla Victoria en la década de 1950 y se estableció exitosamente en toda la isla. El objetivo de este trabajo es estudiar la población de esta especie en Isla Victoria en términos de abundancia y su asociación con el disturbio humano como un primer paso para conocer su impacto potencial en el ecosistema. Se realizaron capturas fotográficas mediante fototrampeo y observaciones directas en transectas lineales ubicadas en áreas con niveles alto y bajo de disturbio humano. Con los datos de las capturas fotográficas se estimó un índice de abundancia relativa para comparar el uso de hábitat entre las dos áreas. Se utilizó la técnica de muestreo a distancia para estimar la densidad poblacional a partir de las observaciones directas. El Faisán Plateado usó más las áreas con un alto nivel de disturbio, lo que sugiere que la presencia de hábitats modificados podría facilitar su establecimiento y dispersión en la Patagonia. Las densidades poblacionales, tanto en las áreas con alto como con bajo nivel de disturbio, fueron mayores que las reportadas en su área de distribución nativa, mostrando que esta especie ha tenido un gran éxito en Isla Victoria. La alta abundancia, junto con características distintivas tales como el gran tamaño, los hábitos de alimentación y el comportamiento social, pueden moldear las interacciones con las especies nativas e influenciar su impacto sobre las comunidades nativas.Phasianids are one of the groups of introduced birds with highest impact on native ecosystems. In Patagonia several phasianids are established or in process of establishment, thus it is relevant to know their impacts on ecosystems. The Silver Pheasant (Lophura nycthemera) was introduced to Isla Victoria in the 1950’s and successfully established all over the island. The aim of this work is to study the population of this species on Isla Victoria in terms of abundance and association to human disturbance as a first step to know its potential impact in the ecosystem. We conducted camera-trapping and direct observations in linear transects located in highly disturbed and in lowly disturbed areas. Using camera-trapping data we estimated an index of relative abundance to compare habitat use between areas. We used the distance-sampling approach to estimate population density with the data from direct observations. The Silver Pheasant used much more frequently areas with a high level of disturbance, suggesting that the presence of disturbed habitats could facilitate establishment and spread of this species in Patagonia. Population densities in areas with high and with low levels of disturbance were higher than those reported from the native distribution area, showing that the Silver Pheasant had a great success on Isla Victoria. The high abundance, together with distinctive characteristics such as a large body size, foraging habits and social behaviour can shape the interactions with native species and influence its impact on native communities

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)

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

Stress, depression and the hippocampus: modulatory effects of continuous LPA treatment

The LPA1, one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts may be involved in promoting normal emotional behaviors. Evidence also imply a role for the LPA1 receptor in mediating the consequences of stress on the hippocampus. However, to date, there is not available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. Changes in glutamate/GABA cycling could be one possible mechanism. To gain further insight into how LPA-LPA1 may prevent the negative consequences of chronic stress, we assessed the effects of chronic ICV administration of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Then, gene expression for molecular markers for excitatory and inhibitory neurotransmission was determined. In addition, the hippocampal expression of mineralocorticoid receptor and glucocorticoid receptor genes and proteins were determined, as well as plasma corticosterone levels. Contrary to expectations, the continuous delivery of LPA in chronically stressed animals instead of inhibiting, potentiated some, though not all, negative effects of stress. Furthermore, this treatment induced as well altered the excitatory/inhibitory balance in the ventral hippocampus. In conclusion, the results of this study reinforce the assumption that LPA, mainly through the LPA1 receptor, regulates hippocampal-dependent behaviour and functions.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Funding: This study was supported by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (SEJ1863 to C.P.; CTS-643 to G.E.-T), Ministerio de Economía y Competitividad and the European Regional Development Fund (PSI2017-83408-P to C.P.), Consejería de Salud de la Junta de Andalucía (NICOLÁS MONARDE Program to G.E:T) Ministerio de Educación, Cultura y Deporte (FPU14/01610 to R.D.M.-F.; FPDI2010 to C.R-V. (Junta de Andalucía) and intramural funding from the EPFL to C.S. I Plan propio de investigación y transferencia de la Universidad de Málaga (Congress attendance of C.P)

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)

The limbic brain under stress: a role for the LPA1 receptor

Adverse events can impact brain structure and function and are considered primary sources of risk for depression, anxiety, and other psychiatric disorders. In this sense, the neurobiological circuitry in charge of dealing with stressors has been widely studied in animal models. Our group has demonstrated a role for lysophosphatidic acid (LPA) through the LPA1-receptor in controlling anxious and depressive states, owing to aggravation of the detrimental consequences of stress in the brain. Indeed, our group has recently proposed the variant maLPA1-null mice, i.e. mice lacking the LPA1 receptor, as an endophenotype for anxious depression. In addition, we have previously reported hyperactivation of key stress-related brain areas after stress, such as basolateral amygdala. Here, we seek to further examine the engagement of the LPA1 receptor in the regulation of the limbic circuit following an acute stressor, tail suspension test, in wildtype and knockout animals. To that end, c-Fos expression was evaluated as a measure of functional activity in both basal and stress conditions, followed by interregional correlation matrices to establish the brain map of functional activation. Additionally, we observed whether one single dose of the antidepressant treatment with desipramine is able to normalize the functional brain map. Results revealed that the absence of the LPA1 receptor induce an anomalous pattern of brain functional activity after TST, which was reverted by desipramine administration.These results provide further insight to the involvement of the LPA1 receptor in stress regulation and shed light on divergent brain pathways under normal and vulnerability conditions that can be implicated in depressive symptoms. Finally, how this pattern might be reverted by antidepressant treatment can be useful for developing new pharmaceutical targets regarding the LPA1 receptor.Funding: Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863 to C.P) and of Health (Nicolas Monardes programme, to G.E-T); the Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to L.J.S. and C.P.). Author R.D. M-F holds a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610). Author S.T. holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment (FPDI 2014). I Plan Propio de Investigación y Transferencia, Universidad de Málaga. Campus de Excelencia. Andalucía Tech

Stress coping behaviour, brain connectivity and LPA1 receptor: similarities and differences between the genetic and the pharmacological approach

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 recently proposed that this receptor has a key role in controlling depression-like behaviours and in the detrimental consequences of stress. Here, we sought to establish the involvement of the LPA1 receptor in brain activity after an acute stressor. To this end, we examined behavioural despair in mice with a constitutive depletion of the LPA1 receptor (maLPA1-null mice), wild-type mice and mice receiving one single icv dose of the LPA1 receptor antagonist Ki16425 or vehicle. Furthermore, the expression of c-Fos protein in stress-related brain areas and the corticosterone response following acute stress were examined. Our data indicated that, contrary to the knockout model, the antagonism of the LPA1 receptor significantly increased immobility in the Forced Swim Test. However, latency to first immobility was reduced in both experimental conditions. Immunohistochemistry studies revealed an increased in activity in key limbic structures such as medial prefrontal cortex in both the LPA1 antagonist-treated mice and maLPA1-null mice, with an interesting opposed effect on hippocampal activity. Following acute stress, the sole infusion of Ki16425 in the cerebral ventricle increased corticosterone levels. In conclusion, the alteration of LPA1 receptor function, through both genetic deletion or pharmacological antagonism, is involved in behavioural despair and hyperactivity of brain stress systems, thus contributing to explore specific susceptibility mechanisms of stress as targets for therapeutic recovery.Funding by the Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863) and the Spanish Ministry of Education, Culture and Sports ( PSI2017 - 83408 - P). Authors RD. M-F and A. N-Q hold a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610 and FPU16/05308, respectively). Author S.T. holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment C. R. (FPDI 2016); Andalucía Tech. I Plan Propio de Investiga ción y Transferencia de la Universidad de Málaga. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Social avoidance and altered stress axis in a mouse model of anxious depression

Prevalence of stress-related disorders, such as depression, is raising in modern societies. Indeed, current neurobiological research aims to elucidate the link between deregulation of the hypothalamic-pituitary-adrenal (HPA) axis among vulnerable individuals and the onset of depressive symptoms, such as social withdrawal. Herein, we seek to determine the role of LPA1 receptor in social behaviour and the performance of maLPA1-null mice, a model of anxious depression, in the dexamethasone (DEX) suppression test. For that purpose, we used the three-chamber test for social preference. Also, we administered vehicle or DEX 0.1mg/kg to wild-type (WT) mice and maLPA1-null mice, analysed corticosterone (CORT) response by ELISA method and determine glucocorticoid receptor (GR) expression and serum/glucocorticoid regulated kinase 1 (SGK1) in the hippocampus by Western-Blot analysis. We found that maLPA1-null mice lack preference for the social chamber as compared to WT animals. Additionally, mice lacking the LPA1 receptor did not suppress CORT after DEX treatment and increased significantly hippocampal SGK1 expression despite unaltered GR protein levels. These results provide further insight on the role of LPA1 receptors in depressive-like behavior and the pathological intracellular signals involved in stress regulation.Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ1863 to CP and CTS-643 to GE-T) and of Health (Nicolas Monardes Programme to GE-T). Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to LJS and CP; and co-financed with Funds of the European Commission “FEDER” PSI2017-83408-P to CP). Author AN-Q and RDM-F hold Grants of the Spanish Ministry of Education, Culture and Sports (FPU 16/05308; FPU14/01610, respectively). Author FJG-S held a Grant of the First Research and Transfer Plan of the University of Malaga. University of Malaga, Campus de Excelencia Internacional Andalucía Tech, and I Plan Propio de Investigación y Transferencia of the University of Malaga

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkbl alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1(K781), was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination

Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study

[Background]: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.[Methods]: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes.[Findings]: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum β2-microglobulin ≥2·5 μg/mL, and serum baseline tryptase ≥125 μg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87–0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76–0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89–0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66–0·78], vs 0·64 to 0·73 for pre-existing models).[Interpretation]: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide.Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund