Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions. Is endogenous oxytocin implicated in emotion discrimination? Ferretti, Maltese et al. demonstrate that oxytocin signaling in the central amygdala plays a key role in the ability of mice to discriminate unfamiliar conspecifics based on their emotional state, both in physiological and genetically determined pathological conditions

Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist

In a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30?min and 24?h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.Acknowledgements: M.G.-S. was recipient of a contract from the Sistema Nacional de Garantía Juvenil co-funded by the European Social Fund. We also thank Novartis for the generous gift of NVP-AAM077. This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13/00038 and PI16/00217) that were co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

Maternal Weaning Modulates Emotional Behavior and Regulates the Gut-Brain Axis.

Evidence shows that nutritional and environmental stress stimuli during postnatal period influence brain development and interactions between gut and brain. In this study we show that in rats, prevention of weaning from maternal milk results in depressive-like behavior, which is accompanied by changes in the gut bacteria and host metabolism. Depressive-like behavior was studied using the forced-swim test on postnatal day (PND) 25 in rats either weaned on PND 21, or left with their mother until PND 25 (non-weaned). Non-weaned rats showed an increased immobility time consistent with a depressive phenotype. Fluorescence in situ hybridization showed non-weaned rats to harbor significantly lowered Clostridium histolyticum bacterial groups but exhibit marked stress-induced increases. Metabonomic analysis of urine from these animals revealed significant differences in the metabolic profiles, with biochemical phenotypes indicative of depression in the non-weaned animals. In addition, non-weaned rats showed resistance to stress-induced modulation of oxytocin receptors in amygdala nuclei, which is indicative of passive stress-coping mechanism. We conclude that delaying weaning results in alterations to the gut microbiota and global metabolic profiles which may contribute to a depressive phenotype and raise the issue that mood disorders at early developmental ages may reflect interplay between mammalian host and resident bacteria

Zidovudine plus Fosfomycin: synergistic effect against clinical isolates of multidrug-resistant Enterobacterales. In vitro and in vivo evidence.

In vitro synergistic activity between zidovudine (AZT) and fosfomycin against clinical isolates of MDR Enterobacteriaceae Background: Multidrug-resistant (MDR) Enterobacteriaceae are a priority health issue with few therapeutic options. “Old” antibiotics alongside with non-antibiotic molecules with antibacterial properties are being evaluated as alternative antimicrobial options in experimental studies. Fosfomycin inhibits bacterial wall synthesis with a unique mechanism of action and has been revalued as a carbapenem-sparing agent. Zidovudine (AZT), a thymidine analogue licensed for HIV infection, has also known antibacterial properties. We evaluated the in vitro antimicrobial activity of the combination AZT + fosfomycin against clinical strains of MDR Enterobacteriaceae collected in different Italian hospitals. Materials/methods: We performed checkerboard assays on 33 MDR Enterobacterales (E. coli, K. pneumoniae, E. aerogenes, E. cloacae). Resistance mechanisms included ESBL, porin loss, KPC, OXA-48, NDM, VIM, mcr-1. Time-kill assays (0h, 4h, 8h, 24h) to confirm the most significant results are ongoing. Results: Among 33 strains tested with checkerboard assays, a synergistic effect between AZT and fosfomycin (FIC index ≤ 0.5) was observed in 20 (61%). In the remaining strains the combination of the two drugs showed an additive effect (0.5 32 µg/ml). In 14 (77.8%) of them AZT, given in combination, was able to restore fosfomycin-susceptibility, lowering fosfomycin MIC to ≤32 µg/ml. As shown in the figure below, preliminary time-kill assays, performed on 3 isolates exhibiting high resistance level towards fosfomycin, confirmed the results found with checkerboard assays. Conclusions: We demonstrated the synergistic activity of the combination AZT + fosfomycin in 61% of tested MDR strains and an additive effect was however observed in the remaining strains. AZT breakpoints for bacterial infections are unknown. Literature data suggest that AZT concentrations currently tested can be reached in human serum/urine using the actual or slightly increased licensed dosage. The potential mild side effects of such drug combination and the observed synergism (with reversal fosfomycin susceptibility) make this combination worthy of in vivo studies

Impact of Covid-19 pandemic on injection-based practice: report from an Italian multicenter and multidisciplinary survey

Background. There are no papers exploring the impact of COVID-19 pandemic on the injection-based practice in patients affected by different rheumatic diseases, including osteoarthritis. The aim was to investigate the impact of COVID-19 pandemic on injection-based practice trough the Italian country. Study design. A survey-based retrospective cross-sectional study Methods. An Italian-language questionnaire was developed by a group of senior researchers and distributed by e-mail to some Rheumatology, Orthopedic and Rehabilitation Units from different geographic areas of Italy. The survey included information about the number of injections performed during COVID-19 pandemic (stratified by injected agents and injected joint), in comparison to the pre-pandemic period, and the possible reasons behind an eventual reduction. Responses were collected and descriptive analysis calculated. Results. Eleven centers of the National Health Service completed the survey. The activities of the injections services significantly decreased across the country with a percentage of reduction of 60% compared to the pre-pandemic period. A significant reduction of both intra-articular and peri-articular injections was registered. Among intra-articular. treatments, the most affected ones were the hyaluronic acid injections, when compared to corticosteroids. A significant decrease of the total amount of peri-articular injections was observed. The strict government restrictions and the fear of patients to become infected represented the most limiting factors. Conclusions. The reported decrease of the injection-based practice in our country during the COVID-19 pandemic highlights the detrimental effects of the COVID-19 pandemic on the management of chronic musculoskeletal diseases with possible negative consequences in terms of disability and quality of life