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microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

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      Abstract

      Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

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      Most cited references 62

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      miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades

      microRNAs (miRNAs) are a large class of small non-coding RNAs which post-transcriptionally regulate the expression of a large fraction of all animal genes and are important in a wide range of biological processes. Recent advances in high-throughput sequencing allow miRNA detection at unprecedented sensitivity, but the computational task of accurately identifying the miRNAs in the background of sequenced RNAs remains challenging. For this purpose, we have designed miRDeep2, a substantially improved algorithm which identifies canonical and non-canonical miRNAs such as those derived from transposable elements and informs on high-confidence candidates that are detected in multiple independent samples. Analyzing data from seven animal species representing the major animal clades, miRDeep2 identified miRNAs with an accuracy of 98.6–99.9% and reported hundreds of novel miRNAs. To test the accuracy of miRDeep2, we knocked down the miRNA biogenesis pathway in a human cell line and sequenced small RNAs before and after. The vast majority of the >100 novel miRNAs expressed in this cell line were indeed specifically downregulated, validating most miRDeep2 predictions. Last, a new miRNA expression profiling routine, low time and memory usage and user-friendly interactive graphic output can make miRDeep2 useful to a wide range of researchers.
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        Stress, depression, and neuroplasticity: a convergence of mechanisms.

        Increasing evidence demonstrates that neuroplasticity, a fundamental mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. Here we provide an overview of the evidence that chronic stress, which can precipitate or exacerbate depression, disrupts neuroplasticity, while antidepressant treatment produces opposing effects and can enhance neuroplasticity. We discuss neuroplasticity at different levels: structural plasticity (such as plastic changes in spine and dendrite morphology as well as adult neurogenesis), functional synaptic plasticity, and the molecular and cellular mechanisms accompanying such changes. Together, these studies elucidate mechanisms that may contribute to the pathophysiology of depression. Greater appreciation of the convergence of mechanisms between stress, depression, and neuroplasticity is likely to lead to the identification of novel targets for more efficacious treatments.
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          Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex.

          Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation-selection hypothesis of striatal functional organization.
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            Author and article information

            Affiliations
            [ 1 ] Department of Pharmacology Qingdao University School of Pharmacy Qingdao, Shandong 266021 China
            [ 2 ] College of Life Science, University of Chinese Academy of Sciences Beijing 100049 China
            [ 3 ] Institute of Biophysics, Chinese Academy of Sciences Beijing 100101 China
            Author notes
            [* ] Correspondence

            Jin‐Hui Wang, Institute of Biophysics, University of Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China. mails: jhw@ 123456ibp.ac.cn ; wangjinhui@ 123456ucas.ac.cn and Zhenhua Song, School of Pharmacy, Qingdao University, 38 Dengzhou, Qingdao, Shandong, 266021, China.

            Email: songzh@ 123456qdu.edu.cn

            [†]

            These authors contribute this work equally

            Contributors
            ORCID: http://orcid.org/0000-0002-3503-2788, songzh@qdu.edu.cn
            jhw@ibp.ac.cn , wangjinhui@ucas.ac.cn
            Journal
            Am J Med Genet B Neuropsychiatr Genet
            Am. J. Med. Genet. B Neuropsychiatr. Genet
            10.1002/(ISSN)1552-485X
            AJMG
            American Journal of Medical Genetics
            John Wiley & Sons, Inc. (Hoboken, USA )
            1552-4841
            1552-485X
            14 August 2018
            September 2018
            : 177
            : 6 ( doiID: 10.1002/ajmg.b.v177.6 )
            : 563-579
            30105773 6175222 10.1002/ajmg.b.32651 AJMGB32651
            © 2018 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc

            This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

            Counts
            Figures: 8, Tables: 3, Pages: 16, Words: 10745
            Product
            Funding
            Funded by: National Key R&D Program of China
            Award ID: 2016YFC1307101
            Funded by: National Natural Science Foundation of China
            Award ID: 81671071
            Award ID: 81471123
            Categories
            Research Article
            Research Articles
            Custom metadata
            2.0
            ajmgb32651
            September 2018
            Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0 mode:remove_FC converted:08.10.2018

            Genetics

            synapse, resilience, nucleus accumbens, neuron, depression

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