Gαi2+ vomeronasal neurons govern the initial outcome of an acute social competition

Pheromone detection by the vomeronasal organ (VNO) mediates important social behaviors across different species, including aggression and sexual behavior. However, the relationship between vomeronasal function and social hierarchy has not been analyzed reliably. We evaluated the role of pheromone detection by receptors expressed in the apical layer of the VNO such as vomeronasal type 1 receptors (V1R) in dominance behavior by using a conditional knockout mouse for G protein subunit Gαi2, which is essential for V1R signaling. We used the tube test as a model to analyze the within-a-cage hierarchy in male mice, but also as a paradigm of novel territorial competition in animals from different cages. In absence of prior social experience, Gαi2 deletion promotes winning a novel social competition with an unfamiliar control mouse but had no effect on an established hierarchy in cages with mixed genotypes, both Gαi2−/− and controls. To further dissect social behavior of Gαi2−/− mice, we performed a 3-chamber sociability assay and found that mutants had a slightly altered social investigation. Finally, gene expression analysis in the medial prefrontal cortex (mPFC) for a subset of genes previously linked to social status revealed no differences between group-housed Gαi2−/− and controls. Our results reveal a direct influence of pheromone detection on territorial dominance, indicating that olfactory communication involving apical VNO receptors like V1R is important for the outcome of an initial social competition between two unfamiliar male mice, whereas final social status acquired within a cage remains unaffected. These results support the idea that previous social context is relevant for the development of social hierarchy of a group. Overall, our data identify two context-dependent forms of dominance, acute and chronic, and that pheromone signaling through V1R receptors is involved in the first stages of a social competition but in the long term is not predictive for high social ranks on a hierarchy.Fil: Pallé, Anna. Consejo Superior de Investigaciones Científicas; EspañaFil: Montero, Marta. Consejo Superior de Investigaciones Científicas; EspañaFil: Fernendez, Silvia. Consejo Superior de Investigaciones Científicas; EspañaFil: Tezanos, Patricia. Consejo Superior de Investigaciones Científicas; EspañaFil: De las Heras, Juan. Consejo Superior de Investigaciones Científicas; EspañaFil: Luskey, Valerie. Consejo Superior de Investigaciones Científicas; EspañaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Zufall, Frank. Universitat Saarland; AlemaniaFil: Chamero, Pablo. Centre National de la Recherche Scientifique; FranciaFil: Trejo, José Luis. Consejo Superior de Investigaciones Científicas; Españ

Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice

Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic-like behaviour and alleviated cognitive impairment in spatial memory in the cocaine-abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine-treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.This study was funded by the following grants: PSI2015-73,156-JIN to E.C-O. and PSI2017-82604R to L.J.S. (MINECO-AEI cofounded by FEDER), PID2020-114374RB-I00 (funded by MCIN/AEI/10.13039/501100011033) to E.C-O., PID2020-113806RB-I00 to L.J.S. (MICINN) and University of Malaga (B4: ‘Ayudas para Proyectos Puente’ to E. C–O). Authors M. C. M-P., P. T. and S. G-R. hold predoctoral grants from the Spanish Ministry of Science, Innovation and Universities (FPU17/00276 to M. C. M-P.; FPU18/00069 to P. T and FPU18/00941 to S. G-R.). The authors acknowledge the IBIMA's common research support structure of animal experimentation and behaviour (“Centro de Experimentación y Conducta Animal”; University of Malaga) and their staff for their valuable assistance during the behavioural experiments and maintenance of the mice and to Belén García and Carmen Hernández for their help with the confocal microscopy at the Cajal Institute // Funding for open access charge: Universidad de Málaga/CBUA

Controlled HIV-HCV Viremia and Immune-Reconstitution are Associated with Slow Progression of Liver Disease in Co-infected Hemophilic Patients After 30 Years of Follow-Up

Introduction and aim: Controversial results have been reported about the progressionof liver disease in HIV-HCV coinfected populations. The purpose of this study is to assesslong-term liver disease progression in a group of coinfected patients with hemophilia.1.2. Materials and Methods: From 1995 to 2015, liver disease was assessed through enzymelevels, platelet counts, Hepatitis C and HIV viral loads (VL), and CD4+T cell counts. Evolution of the APRI liver index was used to estimate hepatic disease (APRI > 1.0 indicatingsevere fibrosis).1.3. Results: 2005-2015 proportional liver-related mortality was below 17% while AIDSand other causes including hemorrhagic events reached 42% each. APRI index >1.0 wasfound in 3 of 32 (9%) patients alive, showing significant liver disease after more than 30years of infection. Analyzing the evolution of liver disease markers, liver enzymes increasedsignificantly only in those patients with detectable HIV and /or HCV VL (for AST and ALT,p<0.0001; for GGT, p=0.001). HIV suppression and reconstitution of CD4+T cell countswere required to achieve HCV eradication. Through multivariate logistic regression, pre ART(pre-antiretroviral therapy) HIV VL was associated with the development of liver fibrosis(OR=4.755; IC95: 1.057 21.387) and with altered liver enzyme values (OR=4.091; IC95:1.293 ? 12.947). No persistent increase in enzyme levels or APRI index was observed in thegroup controlling HIV and HCV replication and adequate immune recovery.1.4. Conclusions: The suppression of both viruses, HIV and HCV, together with adequateimmune recovery is associated with minimal or slow progression of liver disease.Fil: Badano, Maria Noel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Monzani, María Cecili. Academia Nacional de Medicina de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aloisi Zavala, Natalia Andrea. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Gualtieri, Ariel Félix. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Corti, Marcelo. Fundacion de la Hemofilia; ArgentinaFil: Parodi, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pinto, Tezanos. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Primiani, Laura. Fundacion de la Hemofilia; ArgentinaFil: Bracco, M. M. E. D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Chuit, Roberto. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Epidemiológicas; ArgentinaFil: Baré, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

A Multiple-Choice Maze-like Spatial Navigation Task for Humans Implemented in a Real-Space, Multipurpose Circular Arena

Spatial navigation is a key aspect of human behavior and it is still not completely understood. A number of experimental approaches exist, although most of the published data in the last decades have relied on virtual maze on-screen simulation or not-completely freely moving 3D devices. Some interesting recent developments, such as circular mazes, have contributed to analyze critical aspects of freely moving human spatial navigation in real space, although dedicated protocols only allow for simple approaches. Here, we have developed both specifically designed and home-assembled hardware equipment, and a customized protocol for spatial navigation evaluation in freely moving humans in a real space circular arena. The spatial navigation protocol poses an imitation of a real-space multiple-choice path maze with cul-de-sac and instances of non-linear movement. We have compared the results of this system to those of a number of validated, both virtual and real, spatial navigation tests in a group of participants. The system composed by hardware, the test protocol, and dedicated measure analysis designed in our laboratory allows us to evaluate human spatial navigation in a complex maze with a small and portable structure, yielding a highly flexible, adaptable, and versatile access to information about the subjects’ spatial navigation abilities

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio

Genistein early in life modifies the arcuate nucleus of the hypothalamus morphology differentially in male and female rats

In the present work we analyzed the effects of postnatal exposure to two doses of genistein (10 μg/g or 50 μg/g) from postnatal (P) day 6 to P13, on the morphology of the arcuate nucleus (Arc). The analyses of Arc coronal brain sections at 90 days showed that the ArcMP had higher values in volume, Nissl-stained neurons and GPER-ir neurons in males than in females and the treatment with genistein abolished these sex differences in most of the parameters studied. Moreover, in males, but not in females, the GPER-ir neurons decreased in the ArcMP but increased in the ArcL with both doses of genistein. In the ArcLP, GPER-ir population increased with the lowest doses and decreased with the highest one in males. Our results confirm that the Arc subdivisions have differential vulnerability to the effects of genistein during development, depending on which neuromorphological parameters, dose and sex are analyzed.The present work was supported by grants PSI 2017-86396-P, IMIENS and PID 2020-115829 GB-I00.S