Beyond new neurons in the adult hippocampus: imipramine acts as a pro-astrogliogenic factor and rescues cognitive impairments induced by stress exposure

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants—fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field.ARMS: ELC, NDA, PP, AMP, JSC, MM, AJR, JFO, and L.P. received fellowships from the Portuguese Foundation for Science and Technology (FCT) (IF/00328/2015 to J.F.O.; 2020.02855.CEECIND to LP). This work was funded by FCT (IF/01079/2014, PTDC/MED-NEU/31417/2017 Grant to JFO), BIAL Foundation Grants (037/18 to J.F.O. and 427/14 to L.P.), “la Caixa” Foundation Health Research Grant (LCF/PR/HR21/52410024) and Nature Research Award for Driving Global Impact—2019 Brain Sciences (to L.P.). This was also co-funded by the Life and Health Sciences Research Institute (ICVS), and by FEDER, through the Competitiveness Internationalization Operational Program (POCI), and by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020. Moreover, this work has been funded by ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; “la Caixa” Foundation (ID 100010434 to A.J.R.), under the agreement LCF/PR/HR20/52400020; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 101003187 to A.J.R.)

Anatomy Teaching at the School of Health Sciences of University of Minho

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Metabolism and adult neurogenesis: Towards an understanding of the role of lipocalin-2 and iron-related oxidative stress

Accepted manuscriptThe process of generating new functional neurons in the adult mammalian brain occurs from the local neural stem and progenitor cells and requires tight control of the progenitor cell's activity. Several signaling pathways and intrinsic/extrinsic factors have been well studied over the last years, but recent attention has been given to the critical role of cellular metabolism in determining the functional properties of progenitor cells. Here, we review recent advances in the current understanding of when and how metabolism affects neural stem cell (NSC) behavior and subsequent neuronal differentiation and highlight the role of lipocalin-2 (LCN2), a protein involved in the control of oxidative stress, as a recently emerged regulator of NSC activity and neuronal differentiation.IF/00231/2013 of the Portuguese Foundation for Science and Technology (FCT, Portugal). This work was supported by the Foundation for Science and Technology (FCT) and COMPETE through the project EXPL/NEU-OSD/2196/2013. The work has been developed under the scope of the project NORTE-01-0145-FEDER-000013, which is supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement through the European Regional Development Fund (FEDER) and is funded by FEDER funds through the Competitiveness Factors Operational Programme (COMPETE) and by National funds through the Foundation for Science and Technology (FCT) under the scope of the project POCI-01-0145-FEDER-007038info:eu-repo/semantics/publishedVersio

Cell cycle regulation of hippocampal progenitor cells in experimental models of depression and after treatment with fluoxetine

Changes in adult hippocampal cell proliferation and genesis have been largely implicated in depression and antidepressant action, though surprisingly, the underlying cell cycle mechanisms are largely undisclosed. Using both an in vivo unpredictable chronic mild stress (uCMS) rat model of depression and in vitro rat hippocampal-derived neurosphere culture approaches, we aimed to unravel the cell cycle mechanisms regulating hippocampal cell proliferation and genesis in depression and after antidepressant treatment. We show that the hippocampal dentate gyrus (hDG) of uCMS animals have less proliferating cells and a decreased proportion of cells in the G2/M phase, suggesting a G1 phase arrest; this is accompanied by decreased levels of cyclin D1, E, and A expression. Chronic fluoxetine treatment reversed the G1 phase arrest and promoted an up-regulation of cyclin E. In vitro, dexamethasone (DEX) decreased cell proliferation, whereas the administration of serotonin (5-HT) reversed it. DEX also induced a G1-phase arrest and decreased cyclin D1 and D2 expression levels while increasing p27. Additionally, 5-HT treatment could partly reverse the G1-phase arrest and restored cyclin D1 expression. We suggest that the anti-proliferative actions of chronic stress in the hDG result from a glucocorticoid-mediated G1-phase arrest in the progenitor cells that is partly mediated by decreased cyclin D1 expression which may be overcome by antidepressant treatment.This research was funded by FCT (grant number IF/01079/2014 and 2020.02855.CEECIND to LP) and the Nature Research Award for Driving Global Impact-2019 Brain Sciences (to LP); the Life and Health Sciences Research Institute (ICVS); FEDER, through the Competitiveness Internationalization Operational Program (POCI); National funds through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020; the projects NORTE-01- 0145-FEDER-000013 and NORTE-01-0145-FEDER-000023.; the ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145- FEDER-022122); National funds through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020. Part of this work was also funded by “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400020; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 101003187)

The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: A meta-analysis

Schizophrenia is associated with patterns of aberrant neurobiological circuitry. The disease complexity is mirrored by multiple biological interactions known to contribute to the disease pathology. One potential contributor is the family of neurotrophins which are proteins involved in multiple functional processes in the nervous system, with crucial roles in neurodevelopment, synaptogenesis and neuroplasticity. With these roles in mind, abnormal neurotrophin profiles have been hypothesized to contribute to the pathology of schizophrenia.CS is supported by the Fundación Tatiana Pérez de Guzman el Bueno and Rede Galega de Investigación en DemenciasIN607C-2017/02, GAIN, Xunta de Galicia, JMO is supported by ISCIIIP16/00405, RCAB is funded by FEDER, a Ramón& Cajal grant (RYC-2014-15246) and the Galicia Innovation Agency - GAIN grant (IN607D-2016/003)info:eu-repo/semantics/publishedVersio