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Altered Slc25 Family Gene Expression As Markers of Mitochondrial Dysfunction in Brain Regions Under Experimental Mixed Anxiety/Depression‑Like Disorder Vladimir N

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Altered Slc25 Family Gene Expression As Markers of Mitochondrial Dysfunction in Brain Regions Under Experimental Mixed Anxiety/Depression‑Like Disorder Vladimir N Babenko et al. BMC Neurosci (2018) 19:79 https://doi.org/10.1186/s12868-018-0480-6 BMC Neuroscience RESEARCH ARTICLE Open Access Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression‑like disorder Vladimir N. Babenko1,2,3*, Dmitry A. Smagin1,2, Anna G. Galyamina1,2, Irina L. Kovalenko1,2 and Natalia N. Kudryavtseva1,2* Abstract Background: Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the diferentially expressed Slc25* family genes encoding mito- chondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica (http:// genoa​nalyt​ica.ru/, Moscow, Russia). Results: Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specifc. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifcally. Signifcant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. Conclusion: Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders. Keywords: RNA-Seq, Social defeat stress, Depression, Aggression, Slc25a* genes, Mrp* genes, Brain regions Background indicate that mitochondrial dysfunction may also be Mitochondrial dysfunction associated with mutations involved in the pathophysiology of schizophrenia, autism of one or more mitochondrial genes is thought to be and afective spectrum disorders and others [7–12]. involved in neurodegenerative disorders [1, 2] such as In spite of domination of the theory that a depletion in amyotrophic lateral sclerosis, Leigh’s syndrome, multiple the levels of monoamines, including serotonin, is a trig- sclerosis etc. It is suggested that mitochondrial dysfunc- ger of depression [13, 14], the publications of last years tion of several genes regulating mitochondrial function, strongly support the negative impact of mitochondrial morphology, and dynamics [3] plays an early and pre- dysfunction on synaptic plasticity and neurogenesis in ponderant role in the pathogenesis of Alzheimer’s dis- depression [11, 15–17]. Te concepts of mitochondrial ease [4, 5] and Parkinson’s disease [6]. Growing evidences dysfunction and monoamines are thought to be inter- related [9] and mitochondrial dysfunction is considered ubiquitous to many psychiatric disorders, including bipo- *Correspondence: [email protected]; [email protected] 1 Laboratory of Neuropathology Modeling, The Federal Research Center lar disorder and depression [18–23]. Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia In our study we use the model of depression induced by Full list of author information is available at the end of the article chronic social defeat stress [24], which has been widely © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Babenko et al. BMC Neurosci (2018) 19:79 Page 2 of 11 accepted in the original version and with modifcations September 22, 2010. Te study was approved by Scientifc [24–26]. Tis rodent model satisfes all criteria suggested Council No9 of the Institute of Cytology and Genetics SD for a relevant model of depression [27]: etiology, symp- RAS of March, 24, 2010, N 613 (Novosibirsk, http://spf. tomatology, sensitivity to antidepressants and anxiolytics bione t.nsc.ru/). treatments. Neurochemical changes in the brain are simi- lar to those in humans [28, 29]. It has also been shown Generation of alternative social behaviors under agonistic that the development of mixed anxiety/depression-like interactions in male mice states in repeatedly defeated mice are accompanied by Repeated positive and negative social experience, wins numerous molecular changes in the brain [25, 30–33]. and defeats, in male mice were induced by daily agonistic Analysis of brain genomic changes in depressive mice in interactions [24, 43]. Pairs of animals were each placed in comparison with the mice with alternative social experi- a cage (14 × 28 × 10 cm) bisected by a transparent per- ence, i.e. chronic aggression leading to the development forated partition allowing the animals to hear, see and of behavioral pathology similar to psychosis [34, 35], ena- smell each other, but preventing physical contact. Te bled us to reveal specifc and nonspecifc changes in the animals were left undisturbed for 2 days to adapt to new brain regions of afected mice. A 21-day period of ago- housing conditions and sensory contact before they were nistic interactions is accompanied by changes in sero- exposed to agonistic encounters. Every afternoon (14:00– tonin metabolism, serotonergic gene expression [28, 32, 17:00 p.m. local time) the cage cover was replaced by a 36, 37] and expression of mitochondrial Mrpl* and Mrps* transparent one, and 5 min later (the period necessary genes [33, 38] in diferent brain regions of mice, indica- for activation), the partition was removed for 10 min to tive of possible mitoribosomal biogenesis abnormalities. encourage agonistic interactions. Te superiority of one To confrm this observation, using the same RNA-Seq of the mice was established within two or three encoun- database we analyzed diferential expression of mtSlc25a* ters with the same opponent. Te superior mouse would genes encoding mitochondrial carriers from a superfam- be chasing, biting and attacking another, who would be ily of nucleus-encoded proteins that have been local- demonstrating only defensive behavior (upright or side- ized mostly at the inner mitochondrial membrane and ways postures, withdrawal etc.). Aggressive interactions serve as transporters of numerous metabolites, nucleo- between males are discontinued by lowering the partition tides, cofactors and inorganic anions [39] in the brain of if the strong attacking behavior has lasted 3 min (in some chronically defeated mice and aggressive mice. We also cases less) preventing the damage of defeated mice. Each studied correlations between FPKM levels of diferen- defeated mouse (loser, defeater) was exposed to the same tially expressed mitochondrial transporter family Slc25a* winner for 3 days, while afterwards each loser was placed, genes and mitoribosomal Mrpl* and Mrps* genes in dif- after the fght, in an unfamiliar cage with an unfamiliar ferent brain regions. winning partner behind the partition. Each aggressive Detailed description of mitochondrial proteins and mouse (winners), remained in its own cage. Tis proce- genes as well as their functions and dysfunctions is pre- dure was performed once a day for 20 days and yielded sented by Palmieri and co-authors [1, 40–42]. We assume an equal number of the losers and winners. that this study may be useful for understanding the Tree groups of animals were used: (1) Controls— mechanisms of mitochondrial dysfunction during devel- mice without a consecutive experience of agonistic opment of depression and for search of the ways of pos- interactions; (2) Losers—chronically defeated mice; (3) sible pharmacologic correction. Winners—chronically aggressive mice. Te losers and winners with the most expressed behavioral phenotypes Methods were selected for the transcriptome analysis. Te win- Animals ners demonstrated the biggest number and total attack- Adult C57BL/6 male mice were obtained from Ani- ing time and shortest latency of frst attack, as well as mal Breeding Facility, Branch of Institute of Bioorganic aggressive grooming, threats (tail rattling), hostility dur- Chemistry of the RAS (Pushchino, Moscow region). Ani- ing 20 day experiment. Te losers showed full submission mals were housed under standard conditions (at a con- (posture “on the back”), avoidance, or the biggest time of stant temperature of 22 ± 2 °C, 12:12 h light/dark regime passive defense (freezing, immobility) during the all time starting at 8:00 am, with food in pellets and water avail- of the agonistic interaction test. Te control animals and able ad libitum). Mice were weaned at 3 weeks of age the afected mice, 24 h after the last agonistic interac- and housed in groups of 8–10 in standard plastic cages. tion, were simultaneously decapitated. Te brain regions Experiments were performed with 10–12 week old ani- were dissected by the same experimenter according to mals. All procedures were in compliance with the Euro- the Allen Mouse Brain Atlas map [http://mouse .brain pean Communities Council Directive 210/63/EU on -map.org/stati c/atlas ]. All biological samples were placed
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