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      Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury

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          Abstract

          The level of microRNA-9-5p (miRNA-9-5p) in brain tissues is significantly changed in the chronic phase after traumatic brain injury (TBI). However, the effect of miRNA-9-5p on brain function after TBI has not been elucidated. In this study, we used a controlled cortical impact (CCI) model to induce TBI in Sprague–Dawley rats. Brain microvascular endothelial cells (BMECs), astrocytes, and neurons were extracted from immature Sprague–Dawley rats and cocultured to reconstruct the neurovascular unit (NVU) in vitro. The results showed that downregulation of miRNA-9-5p in the chronic phase contributed to neurological function recovery by promoting astrocyte proliferation and increasing the release of astrocyte-derived neurotrophic factors around injured brain tissues after TBI. A dual-luciferase reporter assay validated that miRNA-9-5p was a post-transcriptional modulator of thrombospondin 2 (Thbs-2), and downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes. Furthermore, we verified that Thbs-2 can promote Notch pathway activation by directly binding to Jagged and Notch. Through in vitro experiments, we found that the expression of synaptic proteins and the number of synaptic bodies were increased in neurons in the NVU, which was constructed using astrocytes pretreated with miRNA-9-5p inhibitor. Moreover, we also found that downregulation of miRNA-9-5p promoted Thbs-2 expression in astrocytes, which activated the Notch/cylindromatosis/transforming growth factor-β-activated kinase 1 pathway in neurons and promoted the expression of synaptic proteins, including post-synaptic density protein 95 and synaptotagmin. Based on these results, miRNA-9-5p may be a new promising prognostic marker and treatment target for TBI.

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          Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.

          The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.
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            miR-9: a versatile regulator of neurogenesis

            Soon after its discovery, microRNA-9 (miR-9) attracted the attention of neurobiologists, since it is one of the most highly expressed microRNAs in the developing and adult vertebrate brain. Functional analyses in different vertebrate species have revealed a prominent role of this microRNA in balancing proliferation in embryonic neural progenitor populations. Key transcriptional regulators such as FoxG1, Hes1 or Tlx, were identified as direct targets of miR-9, placing it at the core of the gene network controlling the progenitor state. Recent data also suggest that this function could extend to adult neural stem cells. Other studies point to a role of miR-9 in differentiated neurons. Moreover miR-9 has been implicated in human brain pathologies, either displaying a protective role, such as in Progeria, or participating in disease progression in brain cancers. Altogether functional studies highlight a prominent feature of this highly conserved microRNA, its functional versatility, both along its evolutionary history and across cellular contexts.
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              Cerebral Vascular Injury in Traumatic Brain Injury.

              Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI.
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                Author and article information

                Contributors
                sunxch1445@qq.com
                zacharytaojiang@163.com
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                5 January 2021
                5 January 2021
                January 2021
                : 12
                : 1
                : 9
                Affiliations
                [1 ]GRID grid.452206.7, Department of Neurosurgery, , The First Affiliated Hospital of Chongqing Medical University, ; Chongqing, 400016 China
                [2 ]Department of Neurosurgery, General Hospital of The YangTze River Shipping, Wuhan Brain Hospital, Wuhan, Hubei 430014 China
                [3 ]GRID grid.203458.8, ISNI 0000 0000 8653 0555, College of Pharmacy, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, , Chongqing Medical University, ; Chongqing, Yuzhong 400016 China
                [4 ]GRID grid.413247.7, Department of Ultrasound, , Zhongnan Hospital of WuHan University, ; Wuhan, 430071 China
                [5 ]GRID grid.35030.35, ISNI 0000 0004 1792 6846, Dept of Computer Science, , City University of Hong Kong, ; 83 Tat Chee Ave, Kowloon Hong Kong, China
                [6 ]BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083 China
                [7 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Department of Neurosurgery, Beijing TianTan Hospital, , Capital Medical University, ; Beijing, 100050 China
                [8 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Beijing Neurosurgical Institute, , Capital Medical University, ; Beijing, 100050 China
                [9 ]GRID grid.411617.4, ISNI 0000 0004 0642 1244, China National Clinical Research Center for Neurological diseases, ; Beijing, China
                Author information
                http://orcid.org/0000-0002-1213-4888
                http://orcid.org/0000-0002-8529-4487
                Article
                3329
                10.1038/s41419-020-03329-5
                7790831
                33414448
                1f3e0a88-df53-4b68-b122-f3f0f5abf6c5
                © The Author(s) 2021

                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/.

                History
                : 26 May 2020
                : 3 December 2020
                : 7 December 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100010849, Health and Family Planning Commission of Wuhan Municipality;
                Award ID: WX19Q17
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100010846, Health and Family Planning Commission of Hubei Province (Hubei Provincial Health Department);
                Award ID: WJ2019H364
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 82071397
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100006739, Capital Foundation of Medical Development (Capital Foundation of Medical Development of China);
                Award ID: CFH2018-2-2042
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Cell biology
                synaptic plasticity,trauma
                Cell biology
                synaptic plasticity, trauma

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