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Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus Following Chronic Social Defeat Stress in Male Mice As Revealed by RNA-Seq

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Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus Following Chronic Social Defeat Stress in Male Mice As Revealed by RNA-Seq Hindawi Publishing Corporation Neural Plasticity Volume 2016, Article ID 3289187, 6 pages http://dx.doi.org/10.1155/2016/3289187 Research Article Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq Dmitry A. Smagin,1 Irina L. Kovalenko,1 Anna G. Galyamina,1 Anatoly O. Bragin,2 Yuriy L. Orlov,2,3 and Natalia N. Kudryavtseva1 1 Modeling of Neuropathology Laboratory, Institute of Cytology and Genetics, Siberian Department of Russian Academy of Sciences, Novosibirsk 630090, Russia 2Laboratory of Behavioral Neuroinformatics, Institute of Cytology and Genetics, Siberian Department of Russian Academy of Sciences, Novosibirsk 630090, Russia 3Novosibirsk State University, Novosibirsk 630090, Russia Correspondence should be addressed to Natalia N. Kudryavtseva; [email protected] Received 9 August 2015; Accepted 29 September 2015 Academic Editor: Pablo R. Moya Copyright © 2016 Dmitry A. Smagin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs,andMprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach maybe used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with “ribosomopathies.” 1. Introduction responsible for translation, transcription, and proliferation and are involved in neural plasticity in healthy cells. Chronic social defeat stress (CSDS) can lead to the develop- Two groups of animals were analyzed: male mice in a ment of behavioral psychopathology, which is accompanied depression-like state following CSDS over a 21-day period by anxiety- and depression-like states in male mice [1–3] of agonistic interactions and control mice. Choice of the similar to those in humans. It has been shown that, under brain regions selected for testing was based on their func- CSDS, the adult brain undergoes numerous changes, includ- tions, localization of neurons of some neurotransmitter ing changes in gene expression in different brain regions systems, and differential involvement in the mechanisms of [3, 4], DNA methylation, histone acetylation, and chromatin a depression-like state in our experimental paradigm [1, 10]. remodeling[5,6]aswellasdecreasesinhippocampal These regions are as follows: the midbrain raphe nuclei, a neurogenesis [7–9]. multifunctional brain region, which contains the majority Analyzing the whole transcriptome using RNA-Seq in of serotonergic neuronal bodies; the ventral tegmental area five brain regions of depressive mice with chronic social (VTA), which contains the bodies of dopaminergic neurons, defeats experience, we observed changes in the expression is widely implicated in natural reward circuitry of the brain, of numerous genes. This report is concentrated on the and is important in cognition, motivation, drug addiction, analysis of genes encoding ribosomal and mitochondrial and emotions relating to several psychiatric disorders; the ribosomal proteins (Rps and Rpl, Mrpl and Mrps)whichare striatum, which is responsible for the regulation of motor 2 Neural Plasticity activity and stereotypical behaviors and is also potentially agonistic interaction and the control animals. The brain involved in a variety of cognitive processes; the hippocampus, regions from both experimental groups were dissected by one which belongs to the limbic system, is essential for memory experimenter according to the map presented in the Allen consolidation and storage, and plays important roles in the Mouse Brain Atlas (http://mouse.brain-map.org/static/atlas). neurogenesis and emotional mechanisms; and the hypotha- All of the biological samples were placed to the RNAlater ∘ lamus, which regulates the stress reaction and many other solution (Life Technologies, USA) and stored at −70 Cuntil physiological processes. sequencing. 2. Materials and Methods 2.3. RNA-Seq Method. The collected samples were sequenced at JSC Genoanalytica (http://genoanalytica.ru/, Moscow, 2.1. Animals. AdultmalemiceofC57BL/6Jwereobtained Russia), where the mRNA was extracted using the Dynabeads from Animal Breeding Center in Pushchino (Moscow region, mRNA Purification Kit (Ambion, USA). cDNA libraries were Russia). Animals were housed under standard conditions constructed using NEBNext mRNA Library PrepReagent (12:12 hr light/dark regime; switch-on at 8.00 a.m.: at tem- Set for Illumina (NEB, USA) following the manufacturer’s ∘ perature of 22 ± 1 C; and food (pellets) and water available protocol and were subjected to Illumina sequencing. More ad libitum). Experiments were performed on 10–12-week- than 20 million reads were obtained for each sample. The old animals. All procedures were in accordance with the resulting “fastq” format files were used to align all of the European Communities Council Directive of November 24, reads to the GRCm38.p3 reference genome using the TopHat 1986 (86/609/EEC). The study was approved by Scientific aligner [11]. The Cufflinks program was used to estimate the Council number 9 of the Institute of Cytology and Genetics gene expression levels in FPKM (fragments per kilobase of SB RAS of March, 24, 2010, N 613. transcript per million mapped reads) and then to detect the differentially expressed genes (DEGs) in the analyzed and control groups. Each brain region was considered separately 2.2. Chronic Social Defeat Stress. Prolongednegativesocial for 3 versus 3 animals. Only annotated gene sequences were experiences (defeats) in male mice were induced by daily used in the following analysis. Genes were considered to be agonistic interactions with an aggressive partner [1, 10]. Pairs differentially expressed at < 0.01. of weight-matched animals were placed in steel cages (14 × 28 × 10 cm) bisected by a perforated transparent partition, which allowed the animals to see, hear, and smell each 3. Results and Discussion otherbutpreventedphysicalcontact.Theanimalswereleft undisturbed for two days to allow for adaptation to the Gene expression levels were compared between mouse new housing conditions and sensory contact before they groups affected by social stress, depressive mice, and the were exposed to encounters. Every afternoon (14:00–17:00 control animals. Analysis of differentially expressed genes p.m. local time), a transparent cage lid was placed on the showed their dependence on the brain regions (Table 1): cage, and, 5 min later (the period necessary for individual in the hypothalamus, 3703 genes changed their expression activation), the partition was removed for 10 minutes to pattern under CSDS (ratio of up/down is 2244/1459, resp.); encourage agonistic interactions. The superiority of one in the striatum, 931 genes changed their expression pat- ofthemicewasfirmlyestablishedwithintwoorthree tern under CSDS (up/down, 770/161); in the hippocampus, encounters with the same opponent. The winning mouse 841 genes changed their expression pattern under CSDS would attack, bite, and chase the losing mouse, which would (up/down, 423/418); in the VTA, 549 genes changed their display only defensive behavior (sideways posture, upright expression pattern under CSDS (up/down, 229/320); and, posture, withdrawal, lying on the back, or freezing). As a rule, in the raphe nuclei, 453 genes changed their expression aggressive confrontations between males were discontinued pattern under CSDS (up/down, 104/349) at the chosen level by lowering the partition if the sustained attacks had lasted of statistical significance ( < 0.01). Thus, the largest number 3 min or less to prevent damage to the losers. Each defeated of differentially expressed genes in depressive mice was mouse (loser or defeater) was exposed to the same winner for observedinthehypothalamus,andapproximately4times three days; afterwards, each loser was placed, once a day after fewer genes were observed in the striatum and hippocampus the fight, in an unfamiliar cage with an unfamiliar winner and approximately 7 times fewer genes were observed in the behind the partition. Each winning mouse remained in its VTA and midbrain raphe nuclei. In the hypothalamus and original cage. This procedure was performed for 21 days and striatum, the number of upregulated genes was higher than yielded an equal number of winners and losers. Two groups number of downregulated genes. In the VTA and midbrain of animals were analyzed in this experiment: (1) depressive raphe nuclei area, most of the differentially expressed genes mice:groupsofchronicallydefeatedmiceon21stdaysof were downregulated. In the hippocampus, the numbers of agonistic interactions and (2) controls: the mice without any upregulated and downregulated genes were approximately consecutive experience of agonistic interactions. The detailed equal. We can assume that the number of differentially description of this behavioral method has been previously expressed
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