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

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dc.contributor.authorRodrigues, Rui S.
dc.contributor.authorMoreira, João B.
dc.contributor.authorMateus, Joana
dc.contributor.authorBarateiro, Andreia
dc.contributor.authorPaulo, Sara L
dc.contributor.authorVaz, Sandra H.
dc.contributor.authorLourenço, Diogo M.
dc.contributor.authorRibeiro, Filipa
dc.contributor.authorSoares, Rita
dc.contributor.authorLoureiro-Campos, E.
dc.contributor.authorBielefeld, P.
dc.contributor.authorSebastião, Ana M
dc.contributor.authorFernandes, Adelaide
dc.contributor.authorPinto, L.
dc.contributor.authorFitzsimons, C. P.
dc.contributor.authorXapelli, Sara
dc.date.accessioned2024-04-16T14:31:24Z
dc.date.available2024-04-16T14:31:24Z
dc.date.issued2024
dc.description© 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/.pt_PT
dc.description.abstractChronic 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationTransl Psychiatry. 2024 Mar 30;14(1):170pt_PT
dc.identifier.doi10.1038/s41398-024-02877-0pt_PT
dc.identifier.eissn2158-3188
dc.identifier.urihttp://hdl.handle.net/10451/64330
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationIF/01227/2015pt_PT
dc.relationUnderstanding the pathophysiology of depression by interrogating the role of adult astrogliogenesis in hippocampal connectivity
dc.relationInterplay between innate and acquired immune response at the basis for Multiple Sclerosis cognitive deficits
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationCB2ExStress: a neurogenic strategy to tackle mood disorders
dc.relationA designar
dc.relationA definir
dc.relationEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
dc.relation.publisherversionhttps://www.nature.com/tp/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleCannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stresspt_PT
dc.typejournal article
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oaire.awardTitleUnderstanding the pathophysiology of depression by interrogating the role of adult astrogliogenesis in hippocampal connectivity
oaire.awardTitleInterplay between innate and acquired immune response at the basis for Multiple Sclerosis cognitive deficits
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oaire.awardTitleCB2ExStress: a neurogenic strategy to tackle mood disorders
oaire.awardTitleA designar
oaire.awardTitleA definir
oaire.awardTitleEpileptogenesis and Epilepsy Network: from genes, synapses and circuits to pave the way for novel drugs and strategies
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oaire.citation.issue1pt_PT
oaire.citation.titleTranslational Psychiatrypt_PT
oaire.citation.volume14pt_PT
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