The neuromolecular mechanisms forming behavioral pathology developing in male mice in response to repeated experience of aggression and mixed anxiety-depressive disorder due to chronic social stress were studied. These studies tested the suggestion that altered expression of genes of the Slc6a family, which encode monoamine, GABA, taurine, glycine, and other amino acid transporter proteins can be used as an indicator of changes in the operation of the neurotransmitter systems in five parts of the brain involved in the processes forming pathological forms of behavior. The transcriptomes of brain areas in control, aggressive, and depressive mice were sequenced at Genoanalytica (http://genoanalytica.ru/, Moscow, Russia). The analysis results (RNA-Seq) identified different changes in the expression of the transporter genes the Slc6a family depending on brain area, behavioral pathology, and the functions of the protein encoded by the corresponding genes. In particular, increases in the expression of most GABAergic Slc6a genes were seen in the hypothalamus, hippocampus, and striatum in depressive mice and in the hypothalamus of aggressive males. The midbrain raphe nuclei and ventral tegmental area showed specific and opposite changes in the expression of the monoaminergic genes. These data lead to the conclusion that the altered expression of the Slc6a genes, encoding the corresponding transporters, may serve as a marker for changes in the functions of the neurotransmitter systems in pathological states.
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Avgustinovich, D. F., Alekseenko, O. V., Bakshtanovskaya, I. V., et al., “Dynamic changes in serotoninergic and dopaminergic brain activity during the development of anxious depression: an experimental study,” Usp. Fiziol. Nauk., 35, No. 4, 19–40 (2004).
Avgustinovich, D. F., Kovalenko, I. L., and Kudryavtseva N. N., “A model of anxious depression: persistence of behavioral pathology,” Neurosci. Behav. Physiol., 35, No. 9, 917–924 (2005).
Bak, L. K., Schousboe, A., and Waagepetersen, H. S., “The glutamate/GABA glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer,” J. Neurochem., 98, 641–653 (2006).
Barker, D. J., Root, D. H., Zhang, S., and Morales, M., “Multiplexed neurochemical signaling by neurons of the ventral tegmental area,” J. Chem. Neuroanat., 73, 33–42 (2016).
Berton, O., McClung, C. A., Dileone, R. J., et al., “Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress,” Science, 311, No. 5762, 864–868 (2006).
Bondar, N. P., Boyarskikh, U. A., Kovalenko, I. L., et al., “Molecular implications of repeated aggression: Th, Dat1, Snca and Bdnf gene expression in the VTA of victorious male mice,” PLoS One, 4, No. 1, e4190 (2009).
Bourdy, R. and Barrot, M., “A new control center for dopaminergic systems: pulling the VTA by the tail,” Trends Neurosci., 35, No. 11, 681–690 (2012).
Boyarskikh, U. A., Bondar, N. P., Filipenko, M. L., and Kudryavtseva N. N., “Downregulation of serotonergic genes expression in the raphe nuclei of midbrain under chronic social defeat stress in male mice,” Mol. Neurobiol., 48, No. 1, 13–21 (2013).
Carkaci-Salli, N., Salli, U., Kuntz-Melcavage, K. L., et al., “TPH2 in the ventral tegmental area of the male rat brain,” Brain Res. Bull., 84, No. 6, 376–380 (2011).
Carrey, N. J., MacMaster, F. P., Gaudet, L., and Schmidt M. H., “Striatal creatine and glutamate/glutamine in attention-deficit/hyperactivity disorder,” J. Child Adolesc. Psychopharmacol., 17, No. 1, 11–17 (2007).
Chen, N. H., Reith, M. E., and Quick M. W., “Synaptic uptake and beyond: the sodium-and chloride-dependent neurotransmitter transporter family SLC6,” Pflügers Arch., 447, 519–531 (2004).
Devan, B. D., Hong, N. S., and McDonald R. J., “Parallel associative processing in the dorsal striatum: Segregation of stimulus-response and cognitive control subregions,” Neurobiol. Learn. Mem., 96, 95–120 (2011).
Fields, H. L., Hjelmstad, G. O., Margolis, E. B., and Nicola S. M., “Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement,” Annu. Rev. Neurosci., 30, 289–316 (2007).
Filipenko, M. L., Alekseyenko, O. V., Beilina, A. G., et al., “Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience,” Mol. Brain Res., 96, No. 1–2, 77–81 (2001).
Fowler, J. S., Volkow, N. D., Wang, G. J., et al., “PET and drug research and development,” J. Nucl. Med., 40, 1154–1163 (1999).
Fredriksson, R., Nordstrom, K. J., Stephansson, O., et al., “The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families,” FEBS Lett., 582, 3811–3816 (2008).
Galyamina, A. G., Kovalenko, I. L., Smagin, D. A., and Kudryavtseva N. N., “Changes in the expression of neurotransmitter system genes in the ventral tegmental area in depressive mice: RNA-Seq data,” Zh. Vyssh. Nerv. Deyat., 67, No. 1, 113–118 (2017).
Grace A. A., “Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia,” Neuroscience, 41, No. 1, 1–24 (1991).
He, L., Vasiliou, K., and Nebert D. W., “Analysis and update of the human solute carrier (SLC) gene superfamily,” Hum. Genomics, 3, 195–206 (2009).
Hediger, M. A., Romero, M. F., Peng, J. B., et al., “The ABCs of solute carriers: physiological, pathological, and therapeutic implications of human membrane transport proteins,” Pflügers Arch., 447, 465–468 (2004).
Herve, D., Pickel, V. M., Joh, T. H., and Beaudet, A., “Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons,” Brain Res., 435, No. 1–2, 71–83 (1987).
Houle, S., Ginovart, N., Hussey, D., et al., “Imaging the serotonin transporter with positron emission tomography: initial human studies with DAPP and DASB,” Eur. J. Nucl. Med., 27, 1719–1722 (2000).
Huang, Y., Hwang, D. R., Narendran, R., et al., “Comparative evaluation in nonhuman primates of five PET radiotracers for imaging the serotonin transporters: McN 5652, ADAM, DASB, DAPA, and AFM,” J. Cereb. Blood Flow Metab., 22, 1377–1398 (2002).
Kandel E. R., “The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB,” Mol. Brain, 5, 14 (2012).
Kovalenko, I. L., Smagin, D. A., Galyamina, A. G., et al., “Changes in the expression of dopaminergic genes in brain structures in male mice on exposure to chronic social stress: RNA-data,” Mol. Biol., 50, No. 1, 184–187 (2016).
Kristensen, A. S., Andersen, J., Jørgensen, T. N., et al., “SLC6 Neurotransmitter transporters: structure, function, and Regulation,” Pharmacol. Rev., 63, 585–640 (2011).
Kudryavtseva N. N., “The psychopathology of repeated aggression: a neurobiological aspect,” in: Perspectives on the Psychology of Aggression, J. P. Morgan (ed.), Nova Science Publishers, Inc., New York (2006), Chpt. 2, pp. 35–64.
Kudryavtseva N. N., “The sensory contact model for the study of aggressive and submissive behaviors in male mice,” Aggress. Behav., 17, No. 5, 285–291 (1991).
Kudryavtseva N. N., The Neurobiology of Aggression: Mice and Men: Monograph, Science Center Press, (2013).
Kudryavtseva, N. N. and Avgustinovich D. F., “Behavioral and physiological markers of experimental depression induced by social conflicts (DISC),” Aggress. Behav., 24, 271–286 (1998).
Kudryavtseva, N. N. and Bakshtanovskaya I. V., “Neurochemical control of aggression and submission,” Zh. Vyssh. Nerv. Deyat., 41, No. 5, 459–466 (1991).
Kudryavtseva, N. N., Bakshtanovskaya, I. V., and Koryakina, L. A., “Social model of depression in mice of C57BL/6J strain,” Pharmacol. Biochem. Behav., 38, No. 2, 315–320 (1991).
Kudryavtseva, N. N., Bondar, N. P., and Avgustinovich D. F., “Association between experience of aggression and anxiety in male mice,” Behav. Brain Res., 133, No. 1, 83–93 (2002).
Kudryavtseva, N. N., Smagin, D. A., Kovalenko, I. L., and Vishnivetskaya G. B., “Repeated positive fighting experience in male mice,” Nature Prot., 9, No. 11, 2705–2717 DOI: https://doi.org/10.1038/nprot.2014.156 (2014).
Kudryavtseva, N. N., Smagin, D. A., Kovalenko, I. L., et al., “Serotoninergic genes in the development of anxiety-depressive disorders and aggressive behavioral pathology in male mice: RNA-Seq data,” Mol. Biol., 51, No. 2, 288–300 (2017).
Laakso, A. and Hietala, J., “PET studies of brain monoamine transporters,” Curr. Pharm. Des., 6, 1611–1623 (2000).
Liljeholm, M. and O’Doherty J. P., “Contributions of the striatum to learning, motivation, and performance: an associative account,” Trends Cogn. Sci., 16, No. 9, 467–475 (2012).
Margolis, E. B., Lock, H., Hjelmstad, G. O., and Fields H. L., “The ventral tegmental area revisited: Is there an electrophysiological marker for dopaminergic neurons?” J. Physiol., 577, No. 3, 907–924 (2006).
Meyer J. H., “Imaging the serotonin transporter during major depressive disorder and antidepressant treatment,” J. Psychiatry Neurosci., 32, 86–102 (2007).
Nair-Roberts, R. G., Chatelain-Badie, S. D., Benson, E., et al., “Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat,” Neuroscience, 152, 1024–1031 (2008).
Polter, A. M. and Kauer J. A., “Stress and VTA synapses: implications for addiction and depression,” Eur. J. Neurosci., 39, No. 7, 1179–1188 (2014).
Rayman, J. B. and Kandel E. R., “Functional prions in the brain,” Cold Spring Harb. Perspect. Biol., 9, No. 1 (2017).
Russo, S. J. and Nestler E. J., “The brain reward circuitry in mood disorders,” Nat. Rev. Neurosci., 14, No. 9, 609–625 (2013).
Smagin, D. A., Boyarskikh, U. A., Bondar, N. P., et al., “Reduction of serotonergic gene expression in the midbrain raphe nuclei under positive fighting experience,” Adv. Biosci. Biotech., 4, No. 10B, 36–44 (2013).
Smagin, D. A., Galyamina, A. G., Kovalenko, I. L., et al., “Differentially expressed genes for neurotransmitter systems in the dorsal striatum of male mice with motor impairments,” Zh. Vyssh. Nerv. Deyat., 68, No. 2, 227–249 (2018).
Smagin, D. A., Galyamina, A. G., Kovalenko, I. L., et al., “Aberrant expression of collagen family genes in the brain regions developing under agonistic interactions in male mice: RNA-Seq data,” BioRxiv, DOI: https://doi.org/10.1101/276063 (2018b).
Smagin, D. A., Kovalenko, I. L., Galyamina, A. G., et al., “Dysfunction in ribosomal gene expression in the hypothalamus and hippocampus following chronic social defeat stress in male mice as revealed by RNA-Seq,” Neural Plast., 3289187 (2016).
Smagin, D. A., Kovalenko, I. L., Galyamina, A. G., et al., “Heterogeneity of brain ribosomal genes expression following repeated experience of aggression in male mice as revealed by RNA-Seq,” Mol. Neurobiol., 55, No. 1, 390–401 (2018a).
Tomasi, D. and Volkow N. D., “Functional connectivity of substantia nigra and ventral tegmental area: maturation during adolescence and effects of ADHD,” Cereb. Cortex, 24, No. 4, 935–944 (2014).
Trapnell, C., Pachter, L., and Salzberg S. L., “TopHat: discovering splice junctions with RNA-Seq,” Bioinformatics, 25, No. 9, 1105–1111 (2009).
Walsh, J. J. and Han M. H., “The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context,” Neuroscience, 282, 101–108 (2014).
Wilson, A. A., Ginovart, N., Schmidt, M., et al., “Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of 11C-labeled 2-(phenylthio)araalkylamines,” J. Med. Chem., 43, 3103–3110 (2000).
Winter, C., von Rumohr, A., Mundt, A., et al., “Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats,” Behav. Brain Res., 184, No. 2, 133–141 (2007).
Yager, L. M., Garcia, A. F., Wunsch, A. M., and Ferguson, S. M., “The ins and outs of the striatum: Role in drug addiction,” Neuroscience, 301, 529–541 (2015).
Yamaguchi, T., Sheen, W., and Morales, M., “Glutamatergic neurons are present in the rat ventral tegmental area,” Eur. J. Neurosci., 25, 106–118 (2007).
Zahniser, N. R. and Doolen, S., “Chronic and acute regulation of Na+/Cl–-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems,” Pharmacol. Ther., 92, 21–55 (2001).
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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 69, No. 1, pp. 98–112, January–February, 2019.
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Babenko, V.N., Smagin, D.A., Kovalenko, I.L. et al. Differentially Expressed Genes of the Slc6a Family as Markers of Altered Brain Neurotransmitter System Function in Pathological States in Mice. Neurosci Behav Physi 50, 199–209 (2020). https://doi.org/10.1007/s11055-019-00888-9
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DOI: https://doi.org/10.1007/s11055-019-00888-9