Mouse breeding facilities in Argentina: Current state, challenges, and strengths in relation to animal welfare.

The science and technology of laboratory animals has come a long way worldwide, but for reasons related to the development of the countries, this journey started later in some Latin American countries, as is the case of Argentina. Without a specific legal framework to conduct animal experimentation, local strengths to promote animal welfare are based on professionals specifically trained in the care of laboratory animals as well as an extended network of ethics committees that ensures compliance with the ethical principles applied to animal experimentation. Nevertheless, there are no updated reports showing welfare indicators in rodent facilities. Therefore, we conducted a survey on mice breeding facilities enrolled in a national record elaborated by the National Ministry of Science. Questions related to four of the Five Domains Model of Mellor, concerning (1) nutrition, (2) physical environment, (3) health, and (4) behavioral interactions with the environment, other animals, and humans, were included as well as information concerning general aspects of the establishments. Data obtained from 25 mice breeder facilities localized all over the country were summarized, providing for the first time a clear picture of the national situation about the welfare of laboratory mice in these establishments. This data will be essential to design future policy as well as for deciding priorities aiming to improve the welfare of mice bred in Argentinian facilities.

Edinger-Westphal peptidergic neurons enable maternal preparatory nesting.

Optimizing reproductive fitness in mammalians requires behavioral adaptations during pregnancy. Maternal preparatory nesting is an essential behavior for the survival of the upcoming litter. Brain-wide immediate early gene mapping in mice evoked by nesting sequences revealed that phases of nest construction strongly activate peptidergic neurons of the Edinger-Westphal nucleus in pregnant mice. Genetic ablation, bidirectional neuromodulation, and in vitro and in vivo activity recordings demonstrated that these neurons are essential to modulate arousal before sleep to promote nesting specifically. We show that these neurons enable the behavioral effects of progesterone on preparatory nesting by modulating a broad network of downstream targets. Our study deciphers the role of midbrain CART+ neurons in behavioral adaptations during pregnancy vital for reproductive fitness.

Hemophagocytic lymphohistiocytosis as a presentation of T-cell lymphoma. / [Linfohistiocitosis hemofagocítica como presentación de Linfoma de células-T.]

Introduction: Hemophagocytic lymphohistiocytosis (HHL), a severe hyperinflammatory syndrome caused by aberrant activation of macrophages and cytotoxic T cells, is clinically manifested as a febrile onset along with cytopenias, high ferritin serum level and splenomegaly. In adult patients, secondary causes of it should be looked for, such as autoimmune and infectious diseases and neoplasms. Prompt initiation of treatment is important due to the high mortality of this syndrome. Methods: A case of a 53-year-old patient diagnosed with HHL associated with T-cell lymphoma is presented as a sudden onset of several symptoms and signs of HHL, along with infectious complications. Results: Results: Once the diagnosis of HHL was made, treatment with Etoposide and Dexamethasone was started, and with the diagnosis of T-cell lymphoma established, chemotherapy treatment with a CHOEP scheme was started, with a favorable initial evolution. Main conclusion: As HHL is a rare entity associated with high mortality, initial suspicion must be high when facing an acute onset of fever, cytopenia and splenomegaly. Nonetheless, diagnosing HHL is challenging and often appear superimposed on multiple infectious diseases. The early initiation of treatmbent is important given the high mortality of this pathology

Introducción: La linfohistiocitosis hemofagocítica (LHH) es un síndrome hiperinflamatorio severo causado por activación aberrante de macrófagos y células T citotóxicas que se manifiesta clínicamente como un cuadro febril asociado a citopenias, hiperferritininemia y esplenomegalia. Ante su diagnóstico en adultos se deben buscar causas secundarias como neoplasias hematológicas. El inicio precoz del tratamiento es importante debido a su elevada mortalidad. Métodos: Se presenta el caso de una paciente de 53 años de edad que se le realizó diagnóstico de LHH asociada a Linfoma de células T. La forma de presentación de dicho cuadro fue de manera abrupta con varios síntomas y signos de dicho síndrome, además de múltiples complicaciones infecciosas asociadas. Resultados: Ante el diagnóstico inicial de LHH se inició tratamiento con etopósido y dexametasona, y al obtener el diagnóstico de Linfoma de células T, se instauró tratamiento quimioterápico con esquema de CHOEP, con evolución inicial favorable. Conclusiones: La LHH es una entidad poco frecuente asociada a una elevada mortalidad, por lo que su índice de sospecha debe de ser elevado ante un cuadro clínico y analítico compatible. Sin embargo, su diagnóstico constituye un gran desafío clínico, pudiendo presentarse en algunas ocasiones superpuesto a cuadros infecciosos múltiples. El inicio precoz del tratamiento es importante debido a su alta mortalidad.

Effect of simple and complex enrichment added to standard-sized cages in behavioral, physiological, and neurological variables in female Swiss mice (Mus musculus).

Environmental enrichment (EE) has been a widely used tool to improve animal welfare, as well as to study brain plasticity. Traditional EE settings in the field of neuroscience employ highly complex cages with numerous objects and increased space, whereas more simple additions included for the control treatment are rarely considered in the experimental design. This leads to a lack of consistency of what neuroscientists designate as "standard housing," which might compromise the reproducibility of the results. Therefore, we employed standard-sized cages to study how different EE configurations can affect several biological markers of animal welfare. We first compared barren cages with cages containing nest material and a cardboard roll or cages having a complex set of elements. For this purpose, we studied anxiety-like behavior, corticosterone metabolites in feces, and cell survival in the hippocampus. Complex enrichment (CE) increased the concentration of corticosterone metabolites while also decreasing anxiety-like behavior. Interestingly, both simple and CEs were able to promote cell survival in the hippocampus, and this measure was positively correlated to corticosterone metabolites. Furthermore, in a second experiment, one of the elements of the CE was able to reduce anxiety-like behavior and blood glucose reactivity after exposure to a stressful situation. Altogether, this study calls attention about how sensitive experimental outcomes are to these simple EE elements. Even though EE is recommended by most guidelines for the care and use of laboratory animals, a detailed analysis of the EE protocol that is going to be implemented is highly encouraged. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Comparison of serological techniques for the diagnosis of equine infectious Anemia in an endemic area of Argentina.

Equine Infectious Anemia is a transmissible viral disease present worldwide, caused by an RNA virus. Viral transmission is mainly mechanical through blood or its products most frequently by blood-sucking arthropods and iatrogenesis as well. OIE recommends Coggins Test as the diagnostic method of choice. Some ELISA tests detect antibodies earlier than the Coggins test, but may produce false-positive results. Currently, new techniques for EIA diagnosis are being developed, such as fluorescence polarization assay which is a simple method for measuring antigen-antibody interaction. The aim of this study was to assess cELISA and Fluorescence Polarization Assay performance for the serological diagnosis of EIA by comparing their results with those of the Coggins test. Tests were performed on 91 workhorses from an endemic zone in the northeast region of Argentina. From the total samples analyzed, 42 tested negative and 49 tested positive in the Coggins test. Same results were obtained using FPA. Using the cELISA, 41 negative results and 50 positive results were obtained. The Receiver Operating Characteristic analysis showed that FPA performance was excellent. Therefore FPA is proposed as an outstanding EIA diagnostic test to be validated in the near future by its simplicity, speed, and objective interpretation of results.

Lithium in drinking water, altitude, and suicide rates in rural areas of Argentinean Andes.

The Lithium Triangle in the Andean plateau involves high altitude (>3,000 m asl) hydrological systems having high lithium graded waters. This research was carried-out in rural areas of north westernmost Argentinean Andes and was aimed: 1) to determine concentrations of lithium in drinking waters; 2) to calculate suicide mortality rates based on available official data (2003-2013); 3) to analyze bivariate differences between lithium concentrations in drinking water, mean rates of suicide mortality, altitude of sampling sites, and water sources; 4) to analyze bivariate correlations between lithium concentrations in drinking water, mean rates of suicide mortality, and altitude; 5) to test predictive models for mean rates of suicide mortality, when considering the predictors lithium concentrations in drinking water, altitude, and water sources. Lithium determinations in drinking waters were performed by Microwave Plasma-Atomic Emission Spectrometer. Nonparametric tests were applied to analyze differences and correlations. Generalized linear models (GLM) were used to fitting models for mean rates of suicide. Drinking waters contained up to 2.98 mg L-1 of lithium. Mean rates of suicide mortality (per 100,000 inhabitants) were high, ranging from 19.12 (± 19.83) to 30.22 (± 16.70). Lithium but not altitude was positively correlated with suicide mortality when analyzing bivariate correlations (Li: rho = 0.76, p-value < 0.001). However, when GLM were calculated, a significant interaction effect was found between lithium and altitude (p-value < 0.001). This interaction effect would act in some way restraining the suicide mortality rates.

The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood.

Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain. On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders. It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges. We tested the hypothesis that the 5-HT2B receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate. First, we observed that Htr2b-/- mice, knock-out for the 5-HT2B receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild-type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation. Second, to assess the specific contribution of the microglial 5-HT2B receptor, we investigated the response to LPS of conditional knock-out mice invalidated for Htr2b in microglia only. We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage. In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect. These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5-HT2B receptors is necessary to prevent microglia overreactivity in adulthood.

Genetic Characterization of Mangalarga Marchador Breed Horses Based on Microsatellite Molecular Markers.

The Mangalarga Marchador (MM) horse breed has expressive importance in the Brazilian economy. Thus, the aim of this study was to investigate diversity in the MM breed. A database with a total of 3,193 genotyped horses was used (MM, n = 2,829; Andalusian - AND, n = 67; Pure Blood Lusitano - LUS, n = 43; English Thoroughbred - THO, n = 54; Arabian - ARA, n = 99; Campolina - CAM, n = 61; and Mangalarga - MAN, n = 40) for 13 microsatellite. Diversity parameters were estimates, such as mean number of alleles (Nma) and the number of rare alleles (AR), expected heterozygosity (He), F statistics, genetic distances, Hardy-Weinberg equilibrium test (HWE), population structure, and others. The Nma was 10.85, the AR was prevalent in the MM, and the He was 0.7402. In MM, the values of Fis (-0.0195), Fit (0.0566), Fst (0.0748), and deviations of HWE were observed. The genetic distances of the ARA and THO breeds with the other breeds were greater than the distances between the Brazilian breeds and between these and the breeds in the Iberian Peninsula. The population structure indicated that MM was substructured, yet there were some more genetically defined breeding farms. The genetic diversity is satisfactory for MM conservation, but the population is substructure, and parameters indicate moderate gene flow and the existence, though few, of crosses with other horse breeds. Immediate implementation of a genetic breeding program is required, especially seeking to conserve the structure of the MM breed as a well-defined genetic entity.

Neurochemical, Behavioral, and Neurogenic Validation of a Hyposerotonergic Animal Model by Voluntary Oral Consumption of para-Chlorophenylalanine.

The inhibitor of tryptophan hydroxylase, para-chlorophenylalanine (PCPA), has been classically employed as a pharmacological tool to deplete serotonin (5-HT) in animal models and to evaluate whether this neurotransmitter is involved in the action of pharmacological compounds. PCPA is usually administrated by intraperitoneal (ip) injections, which are stressful and painful. To avoid ip injections, we designed and validated a protocol for PCPA oral administration. C57BL/6 elite male mice received PCPA during 7 days either ip or by giving the drug inside jelly cubes at an estimated dose of 500 mg/kg on days 1 and 2 and 250 mg/kg for the rest of the treatment. 5-HT levels decreased by 85% and 55% in the hippocampus of mice treated with oral or ip PCPA, respectively, whereas in the prefrontal cortex, 5-HT levels decreased by 65% (oral) and 50% (ip). Behavioral tests, like the forced swimming test (FST), the nestlet shredding test (NST), and the marble burying test (MBT), were performed. In the FST, mice received fluoxetine ip 30 min before the test. In mice with oral PCPA treatment, fluoxetine did not induce significant reductions of immobility, indicating that reduction of 5-HT levels was effective. No effect of ip or oral 5-HT depletion was observed in the NST nor in the MBT. In a second experiment, mice received oral PCPA for 8 weeks: again, serotonin levels were significantly decreased in both hippocampus and cortex, and effects on hippocampal neurogenesis replicated previous observations in hyposerotonergic mice. Therefore, neurochemical, behavioral, and neurogenic results allow us to validate this refined protocol for voluntary oral consumption of PCPA.

Reproductive hormones influence zinc homeostasis in the bovine cumulus-oocyte complex: Impact on intracellular zinc concentration and transporters gene expression.

Zinc (Zn) is a vital trace element for the body and its bioavailability influences numerous reproductive events. However, the mechanisms that regulate Zn homeostasis in the cumulus-oocyte complex (COC) are yet to be elucidated. The aim of this study was to investigate the role of estradiol 17-beta (E2), FSH and LH in Zn homeostasis regulation in bovine COC matured in vitro and Zn transporters gene expression. For this purpose, intracellular Zn levels in oocytes and cumulus cells (CC) were assessed using a Zn-specific fluorescent indicator. In addition, gene expression and sequencing of six Zn transporters (Slc39a6, Slc39a8, Slc39a14, Slc30a3, Slc30a7 and Slc30a9) were assessed. Our results demonstrated that the simultaneous presence of E2, FSH, and LH during oocyte maturation altered intracellular zinc levels and transporters expression in both oocytes and CC. Transporter's gene expression was different in oocytes and CC, possibly due to cell-specific changes in Zn levels during maturation. The interaction effects of Zn with hormonal treatments influenced the results. This study emphasizes that Slc39a6 is highly sensitive to hormone induction. Overall, the hormonal modulation of Zn homeostasis in the COC was evidenced. Also, a preponderant role of FSH as a modulator of Zn intracellular levels and transporter gene expression is suggested.

Conducting and reporting animal experimentation: Quo vadis?

Most scientific journals ask authors to include a statement in their articles that animal studies have been carried out in agreement with international regulations on the use and care of laboratory animals. This statement implies that all the experiments conducted on animals have been evaluated and accepted by an Ethical Committee and, that animal welfare has been put as a priority throughout the experimental protocol. Nevertheless, discrepancies are commonly found between the described procedures and the guidelines that are claimed to have been followed; this reveals a double dilemma. First, animal welfare is not always considered, implicating discomfort or even worse, suffering to animals involved. Secondly, revisions of manuscripts are sometimes done without taking into account ethical and regulatory aspects concerning the use of animals. Underestimation of pain or suffering, disregard for physiological parameters, and other examples recently reported in scientific journals by neuroscientists from all over the world are discussed in this article. In a period of great debate about the ethical use of animals, with society being involved and engaged in the discussion, this Neuro-Opinion intends to call the attention of researchers, ethical committee members, and journal editors about the need of strictly endorsing international regulations and placing animal welfare as the top priority.

Differential Hippocampal Expression of BDNF Isoforms and Their Receptors Under Diverse Configurations of the Serotonergic System in a Mice Model of Increased Neuronal Survival.

Neurotrophic factors are relevant regulators of the neurogenic process at different levels. In particular, the brain-derived neurotrophic factor, BDNF, is highly expressed in the hippocampus (HC) of rodents and participates in the control of neuronal proliferation, and survival in the dentate gyrus (DG). Likewise, serotonin is also involved in the regulation of neurogenesis, though its role is apparently more complex. Indeed, both enhancement of serotonin neurotransmission as well as serotonin depletion, paradoxically increase neuronal survival in the HC of mice. In this study, we analyzed the protein expression of the BDNF isoforms, i.e., pro- and mature-BDNF, and their respective receptors p75 and TrkB, in the HC of mice chronically treated with para-chloro-phenyl-alanine (PCPA), an inhibitor of serotonin synthesis. The same analysis was conducted in hyposerotonergic mice with concomitant administration of the 5-HT1 A receptor agonist, 8-Hydroxy-2-(di-n- propylamino) tetralin (8-OH-DPAT). Increased expression of p75 receptor with decreased expression of pro-BDNF was observed after chronic PCPA. Seven-day treatment with 8-OH-DPAT reestablished the expression of pro-BDNF modified by PCPA, and induced an increase in the expression of p75 receptor. It has been demonstrated that PCPA-treated mice have higher number of immature neurons in the HC. Given that immature neurons participate in the pattern separation process, the object pattern separation test was conducted. A better performance of hyposerotonergic mice was not confirmed in this assay. Altogether, our results show that molecules in the BDNF signaling pathway are differentially expressed under diverse configurations of the serotonergic system, allowing for fine-tuning of the neurogenic process.

Genomic structural diversity in Criollo Argentino horses: Analysis of copy number variations.

Copy number variation (CNV) has been proved to be widespread in human, animal and plant genomes. Together with single nucleotide polymorphisms (SNPs), CVNs play a key role in genetic diversity. In this study, genome-wide detection of CNVs was performed based on SNP data from 24 Criollo Argentino horses genotyped with the GGP Equine70k array. Overall, 165 CNVs meeting stringent quality control criteria were identified and then aggregated into 87 CNV regions (CNVRs), representing a horse genome coverage of 13.69 Mb. Functional analysis of CNVRs allowed the identification of 337 genes implicated in a wide range of biological functions such as signal transducer activity (olfactory receptors), receptor activities and binding. Furthermore, enrichment analysis showed that the most represented protein classes (over 25%) were immunoglobulin receptor subfamily, immunoglobulins and major histocompatibility complex antigen (beta-2-microglobulin). To the best of our knowledge, this is the first report of CNV in Criollo Argentino horses.

Non-aversive photographic measurement method for subcutaneous tumours in nude mice.

We have developed a new method for the measurement of subcutaneous tumour volume which consists in taking photographs of mice in their home cages, to refine the standard method of measurement with calipers. We consider this new method to be non-aversive, as it may be more compatible with mice behavioural preferences and, therefore, improve their welfare. Photographs are captured when mice voluntarily go into an acrylic tube containing graph paper that is later used as a scale. Tumour volumes measured with the caliper and the non-aversive photographic method were compared to those obtained by water displacement volume and weight. Behavioural and physiological changes were evaluated to assess animal welfare. Significant differences were found between measurements obtained with the caliper and the non-aversive photographic method, v. the reference volume acquired by water displacement (P < 0.001). Nevertheless, there was good consistency for these measurements when tumours were measured repeatedly, with all Intra-Class Correlation Coefficients above 0.95. Mice on which the non-aversive photographic method was employed were significantly less reluctant to establish contact with the experimenter (P < 0.001) and behaved less anxiously in a modified-Novelty Suppressed Feeding test. Particularly, statistically significant differences were found in connection with the latency to eat an almond piece (P < 0.05), the frequency of grooming (P < 0.001) and the frequency of defecation (P < 0.001). Corticosterone concentration in faeces and blood glucose were determined and no significant changes were found. Therefore, we propose the non-aversive photographic method to measure subcutaneous tumours as a way to refine methodologies in the field of experimental oncology.

Positive regulation of raphe serotonin neurons by serotonin 2B receptors.

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.

Estimación de riesgo carcinógeno por exposición crónica al arsénico a través del agua de consumo en la Puna, Jujuy / Estimation of Carcinogenic Risk due to Chronic Exposure to Arsenic via Water for Human Consumption in Puna, Jujuy

INTRODUCCIÓN: La ingesta crónica de arsénico (As) se asocia con cáncer. Se sabe que las cuencas hídricas de la Puna de Jujuy contienen As y que muchos hogares no tienen agua potable de red, pero aún no se había estimado el riesgo carcinógeno para los pobladores por ingerir el agua local. OBJETIVOS: Estimar el nivel de riesgo carcinógeno para los pobladores locales debido a exposición crónica al As a través del agua de bebida. MÉTODOS: Se determinaron las concentraciones de As en muestras de agua de consumo de poblados de Cochinoca, Susques y Tumbaya con espectroscopía de emisión atómica de plasma acoplado inductivamente. Se calculó el riesgo carcinógeno con modelos matemáticos de la United States Environmental Protection Agency. RESULTADOS: Se halló As en todas las muestras (rango 0,041-0,34 mg/l/As), y el 83% superó el máximo permitido para agua potable (0,05 mg/l/As). Según las concentraciones medias de As por departamento, el riesgo carcinógeno para los pobladores estuvo entre 2,44 x 10-3 y 5,89 x 10-3. El riesgo carcinógeno para quienes consumen agua potable de red fue de 2,36 x 10-3 y para quienes consumen agua de otras procedencias, de 4,76 x 10-3. Todos los valores hallados superaron el máximo de aceptabilidad del riesgo asociado a la exposición a un carcinógeno (10-5). CONCLUSIONES: Es necesario implementar programas de comunicación de riesgos y políticas en salud para disminuir riesgos debidos a ingesta de agua con contenidos arsenicales en esta región.

BDNF isoforms: a round trip ticket between neurogenesis and serotonin?

The brain-derived neurotrophic factor, BDNF, was discovered more than 30 years ago and, like other members of the neurotrophin family, this neuropeptide is synthetized as a proneurotrophin, the pro-BDNF, which is further cleaved to yield mature BDNF. The myriad of actions of these two BDNF isoforms in the central nervous system is constantly increasing and requires the development of sophisticated tools and animal models to refine our understanding. This review is focused on BDNF isoforms, their participation in the process of neurogenesis taking place in the hippocampus of adult mammals, and the modulation of their expression by serotonergic agents. Interestingly, around this triumvirate of BDNF, serotonin, and neurogenesis, a series of recent research has emerged with apparently counterintuitive results. This calls for an exhaustive analysis of the data published so far and encourages thorough work in the quest for new hypotheses in the field. BDNF is synthetized as a pre-proneurotrophin. After removal of the pre-region, proBDNF can be cleaved by intracellular or extracellular proteases. Mature BDNF can bind TrkB receptors, promoting their homodimerization and intracellular phosphorylation. Phosphorylated-TrkB can activate three different signaling pathways. Whereas G-protein-coupled receptors can transactivate TrkB receptors, truncated forms can inhibit mBDNF signaling. Pro-BDNF binds p75(NTR) by its mature domain, whereas the pro-region binds co-receptors.

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants.

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr(2B)(-/-)), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr(2B)(-/-) mice. We find, here, that Htr(2B)(-/-) mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr(2B)(+/+)) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr(2B)(-/-) mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr(2B)(-/-) mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed.