Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress

© The Author(s) 2024. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.This work was supported by ISN Career Development Grant, IBRO Early Career Award, ERASMUS+ Programme Strategic Partnerships (2023-1-PL01-KA220-HED-000160284), and FMUL/GAPIC project no. 20200008 granted to SX and by Fundação para a Ciência e a Tecnologia (FCT) IF/01227/2015 granted to SX, 2020.02855.CEECIND and 2022.02201. PTDC granted to LP and projects PTDC/MED-PAT/2582/2021, UIDB/04138/2020, UIDP/04138/2020 granted to AF as well as fellowships SFRH/BD/129710/2017 and COVID/BD/151880/2021 (RSR), IMM/CT/50-2023 (RS), PD/BD/141784/2018 (DML), PD/BD/150341/2019 (SLP), PD/BD/150343/2019 (JMM) and 2020.04492.BD (JBM). The authors would like to thank the European Union’s Horizon 2020 research and innovation programs H2020-WIDESPREAD-05-2020-Twinning (EpiEpinet, no. 952455) and ERA-NET-NEURON (EJTC 2016) granted to AMS and CPF, respectively.info:eu-repo/semantics/publishedVersio

Tolerance of genetically characterized Folsomia candida strains to phenmedipham exposure

Abstract Background, Aims, and Scope The springtail Folsomia candida is a commonly used model species in ecotoxicological soil testing. The species reproduces parthenogenetically and, thus, laboratories use different clonal lineages. In this study, we investigated if genetic divergence between F. candida strains impacts the reaction to chemical stress and may thus affect the outcome of toxicity tests. Methods In two exposure assays (life-cycle reproduction test and avoidance behaviour test), three laboratory strains of F. candida from Portugal (PTG), Spain (SPN) and Denmark (DNK) were exposed to different concentrations of the reference chemical phenmedipham. Genetic divergence among strains was estimated based on mitochondrial COI sequence data. Results No significant differences between tolerance towards phenmedipham exposure were observed in a reproduction test. In contrast, one strain (SPN) showed a decreased susceptibility to phenmedipham compared to the other strains (PTG and DNK) in the avoidance assay. Discussion A phylogenetic tree based on mitochondrial COI sequences revealed clear genetic differentiation between both ‘reaction types’. Thus, we found a potential lineage dependent stress reaction in avoidance behaviour towards the pesticide. Conclusions Our findings have implications for the comparability of test results among laboratories. Reproduction tests seem to be more robust towards interclonal genetic differentiation than avoidance tests. Recommendations and Perspectives We recommend the use of molecular tools for simple and cost effective genetic characterization of F. candida strains used in chemical avoidance tests. Closer investigations concerning the relation between genetic relatedness and chemical response will provide a more detailed and comprehensive picture on the role of intraspecific genetic differentiation in stress tolerance