SpringerLink
Log in

Serotonergic genes in the development of anxiety/depression-like state and pathology of aggressive behavior in male mice: RNA-seq data

  • Genomics. Transcriptomics
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

In course of daily agonistic interactions, mice tend to stratify into those with chronic social defeats and those that repeatedly display aggression, which lead to the development of mixed anxiety/depression-like state and the pathology of aggressive behavior, respectively. Using the data of whole transcriptome analysis (RNA-seq), the changes in the expression of serotonergic genes involved in the synthesis, inactivation, and reception of serotonin, as well as of the Creb1 (transcription factor) gene and the Bdnf (brain-derived neurotrophic factor) gene were detected in the striatum (STR), ventral tegmental area (VTA), midbrain raphe nuclei (MRN), hypothalamus (HYP), and hippocampus (HIP) of defeated and aggressive male mice. In mice of both groups, the Tph2, Ddc, Slc6a4, Htr2a, Htr3a, Htr5b, Slc18a2, and Bdnf genes were downregulated in the MRN and the Tph2, Ddc, and Slc6a4 genes were upregulated in the VTA. These changes were more significant in defeated mice. The Htr5b gene has first been shown to be involved in mechanisms of depression and pathology of aggressive behavior. In the defeated mice, the expression levels of the Htr4 and Aldh1b1 genes were increased in the MRN, and expression levels of the Maob, Htr4, Htr1a, and Slc18a2 genes were increased in the VTA, while the expression level of the Htr3a gene was decreased. In the HYP of aggressive mice the Maoa, Htr2a, Htr2c, and Creb1 genes were downregulated and the Htr6 gene was upregulated. In the defeated mice, the Maoa and Creb1 genes were downregulated and the Htr6 and Aldh1b1 genes were upregulated in the HYP. In the STR, the Htr1a gene was downregulated and the Htr7 and Bdnf genes were upregulated. The Htr1b gene was upregulated in the HIP. The coexpression of dopaminergic and serotonergic genes in the MRN and VTA in the control of pathological behaviors is discussed. Thus, the complex pattern of differential expression of serotonergic genes in brain regions develo** under repeated agonistic interactions in mice in dependence on behavioral pathology have been observed

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Tph2 :

tryptophan hydroxylase 2 gene

Ddc :

DOPA-decarboxylase gene

Slc6a4 :

serotonin transporter gene

Slc18a2 :

serotonin and dopamine transporter gene

Maoa :

monoamine oxidase A gene

Maob :

monoamine oxidase B gene

Aldh1b1 :

aldehyde dehydrogenase 1b1 gene

Aldh3a1 :

aldehyde dehydrogenase 3a1 gene

Htr :

serotonin receptor genes, the indices in the names (1a, 1b, and others) match the type of receptor

Creb1 :

transcription factor (cAMP responsive element binding protein 1) gene

Bdnf :

a brain-derived neurotrophic factor gene

Real-time PCR:

real-time polymerase chain reaction

5-HT:

serotonin

TPH:

tryptophan hydroxylase

VTA:

ventral tegmental area

References

  1. American Psychiatric Association 2013. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). Arlington. VA: Am. Psychiatr. Assoc. Publ.

    Book  Google Scholar 

  2. Fakhoury M 2016. Revisiting the serotonin hypothesis: Implications for major depressive disorders. Mol. Neurobiol. 53(5), 2778–2786.

    Article  CAS  PubMed  Google Scholar 

  3. Jacobsen J.P., Medvedev I.O., Caron M.G 2012. The 5-HT deficiency theory of depression: Perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knocking mouse. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 367(1601), 2444–2459.

    Article  CAS  Google Scholar 

  4. Massart R., Mongeau R., Lanfumey L 2012. Beyond the monoaminergic hypothesis: Neuroplasticity and epigenetic changes in a transgenic mouse model of depression. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 367(1601), 2485–2494.

    Article  CAS  Google Scholar 

  5. Avgustinovich D.F., Alekseenko O.V., Bakshtanovskaya I.V., Koryakina L.A., Lipina T.V., Tenditnik M.V., Bondar’ N.P., Kovalenko I.L., Kudryavtseva N.N 2004. Dynamics changes in brain serotonergic and dopaminergic activity during the development of anxious depression: An experimental study. Usp. Fiziol. Nauk. 35(4), 19–40.

    CAS  PubMed  Google Scholar 

  6. Berton O., McClung C.A., Dileone R.J., Krishnan V., Renthal W., Russo S.J., Graham D., Tsankova N.M., Bolanos C.A., Rios M., Monteggia L.M., Self D.W., Nestler E.J 2006. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 311(5762), 864–868.

    Article  CAS  PubMed  Google Scholar 

  7. Kudryavtseva N.N., Bakshtanovskaya I.V., Koryakina L.A 1991. Social model of depression in mice of C57BL/6J strain. Pharmacol. Biochem. Behav. 38(2), 315–320.

    Article  CAS  PubMed  Google Scholar 

  8. Kudryavtseva N.N., Avgustinovich D.F 1998. Behavioral and physiological markers of experimental depression induced by social conflicts (DISC). Aggress. Behav. 24, 271–286.

    Article  Google Scholar 

  9. Hammels C., Pishva E., de Vry J., Van den Hove D.L.A., Prickaerts J., van Winkel R., Selten J.-P., Lesch K.-P., Daskalakis N., Steinbusch H.W.M., van Os J., Kenis G., Rutten B.P.F 2015. Defeat stress in rodents: From behavior to molecules, Neurosci. Biobehav. Rev. 59, 111–140.

    Article  CAS  Google Scholar 

  10. Bondar N.P., Kovalenko I.L., Avgustinovich D.F., Smagin D.A., Kudryavtseva N.N 2009. Anhedonia in the shadow of chronic social defeat stress, or when the experimental context matters. Open Behav. Sci. 3, 17–27.

    Article  Google Scholar 

  11. Kudryavtseva N.N., Amstislavskaya T.G., Avgustinovich D.F., Bakshtanovskaya I.V., Lipina T.V., Gorbach O.V., Koryakina L.A 1996. Effect of repeated experience of victory and defeat in social confrontations on the state of the mouse brain serotonergic system. Zh. Vyssh. Nervn. Deyat. 46(6), 1088–1096.

    Google Scholar 

  12. Amstislavskaya T.G., Kudryavtseva, N.N. (1997. Effect of repeated experience of victory and defeat in daily agonistic confrontations on brain tryptophan hydroxylase activity. FEBS Lett. 406 (1–2), 106–108.

    Article  CAS  PubMed  Google Scholar 

  13. Boyarskikh U.A., Bondar N.P., Filipenko M.L., Kudryavtseva N.N 2013. Downregulation of serotonergic genes expression in the raphe nuclei of midbrain under chronic social defeat stress in male mice. Mol. Neurobiol. 48(1), 13–21.

    Article  CAS  PubMed  Google Scholar 

  14. Kudryavtseva N.N., Avgustinovich D.F., Bondar N.P., Tenditnik M.V., Kovalenko I.L 2008. An experimental approach for the study of psychotropic drug effects under simulated clinical conditions. Curr. Drug Metab. 9(4), 352–360.

    Article  CAS  PubMed  Google Scholar 

  15. Coccaro E.F 1992. Impulsive aggression and central serotonergic system function in humans: An example of a dementional brain behavior relationship. Intern. Clin. Psychopharmacol. 7, 3–12.

    Article  CAS  Google Scholar 

  16. Linnoila V.M., Virkkunen M 1992. Aggression, suicidality, and serotonin J. Clin. Psychiatry. 53, 46–51.

    Google Scholar 

  17. Tuinier S., Verhoeven W.M.A., van Praag H.M 1995. Cerebrospinal fluid 5-hydroxyindolacetic acid and aggression: A critical reappraisal of the clinical data. Int. Clin. Psychopharmacol. 10, 147–156.

    Article  CAS  PubMed  Google Scholar 

  18. de Boer S.F., Koolhaas J.M. 2005. 5-HT1A and 5-HT1B receptor agonists and aggression: A pharmacological challenge of the serotonin deficiency hypothesis. Eur. J. Pharmacol. 526(1–3), 125–139.

  19. Miczek K.A., de Almeida R.M., Kravitz E.A., Rissman E.F., de Boer S.F., Raine A 2007. Neurobiology of escalated aggression and violence. J. Neurosci. 27(44), 11803–11806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Popova N.K 2008. From gene to aggressive behavior: The role of brain serotonin. Neurosci. Behav. Physiol. 38(5), 471–475.

    Article  CAS  PubMed  Google Scholar 

  21. Kudryavtseva N.N 2006. Psychopathology of repeated aggression: A neurobiological aspect. In: Perspectives on the Psychology of Aggression. Ed. Morgan J.P. New York: NOVA Sci., pp. 35–64.

    Google Scholar 

  22. Lane S.D., Kjome K.L., Moeller F.G 2011. Neuropsychiatry of aggression. Neurol. Clin. 29(1), 49–64.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Avgustinovich D.F., Alekseyenko O.V., Tenditnik M.V 2001. Fighting among C57BL/6J mice and its applications for [3H]-8-hydroxy-N,N-dipropyl-2-aminotetralin binding in various brain regions. Neurosci. Lett. 305(3), 189–192.

    Article  CAS  PubMed  Google Scholar 

  24. Bondar’ N.P., Kudryavtseva N.N 2003. Effect of buspirone on aggressive and axious behavior of male mice with different aggressive experience. Eksp. Klim. Farmakol. 66(4), 12–16.

    Google Scholar 

  25. Caramaschi D., de Boer S.F., Koolhaas J.M 2007. Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: An across-strain comparison. Physiol. Behav. 90(4), 590–601.

    Article  CAS  PubMed  Google Scholar 

  26. Smagin D.A., Boyarskikh U.A., Bondar N.P., Filipenko M.L., Kudryavtseva N.N 2013. Reduction of serotonergic gene expression in the midbrain raphe nuclei under positive fighting experience. Adv. Biosci. Biotech. 4 (10B), 36–44.

    Article  CAS  Google Scholar 

  27. Kudryavtseva N.N 2015. Serotonergic control of aggressive behavior: New approaches, new interpretations. Zh. Vyssh. Nervn. Deyat. 65(5), 546–563.

    CAS  Google Scholar 

  28. Kudryavtseva N.N 1991. The sensory contact model for the study of aggressive and submissive behaviors in male mice. Aggress. Behav. 17(5), 285–291.

    Article  Google Scholar 

  29. Kudryavtseva N.N., Smagin D.A., Kovalenko I.L., Vishnivetskaya G.B 2014. Repeated positive fighting experience in male inbred mice. Nat. Prot. 9(11), 2705–2717.

    Article  Google Scholar 

  30. Numakawa T., Suzuki S., Kumamaru E., Adachi N., Richards M., Kunugi H 2010. BDNF function and intracellular signaling in neurons. Histol. Histopathol. 25, 237–258.

    CAS  PubMed  Google Scholar 

  31. Martinowich K., Lu B 2008. Interaction between BDNF and serotonin: Role in mood disorders. Neuropsychopharmacology. 33, 73–83.

    Article  CAS  PubMed  Google Scholar 

  32. Trapnell C., Pachter L., Salzberg S.L. 2009. TopHat: Discovering splice junctions with RNA-Seq. Bioinformatics. 25(9), 1105–1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Törk I 1990. Anatomy of the serotonergic system. Ann. NY Acad. Sci. 600, 9–34.

    Article  PubMed  Google Scholar 

  34. Lesch K.-P., Araragi N., Waider J., Van den Hove D., Gutknecht L 2012. Targeting brain serotonin synthesis: Insights into neurodevelopmental disorders with longterm out comes related to negative emotionality, aggression and antisocial behavior. Phils. Trans. R. Soc. Lond. B. 367, 2426–2443.

    Article  CAS  Google Scholar 

  35. Angoa-Pérez M., Kane M.J., Briggs D.I., Sykes C.E., Shah M.M., Francescutti D.M., Rosenberg D.R., Thomas D.M., Kuhn D.M 2012. Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity. J. Neurochem. 121(6), 974–984.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Matthes H., Boschert U., Amlaiky N., Grailhe R., Plassat J.L., Muscatelli F., Mattei M.G., Hen R 1993. Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: Cloning, functional expression, and chromosomal localization. Mol. Pharmacol. 43(3), 313–319.

    CAS  PubMed  Google Scholar 

  37. Serrats J., Raurich A., Vilaró M.T., Mengod G., Cortés R. 2004. 5-ht5B receptor mRNA in the raphe nuclei: Coexpression with serotonin transporter. Synapse. 51(2), 102–111.

  38. Maekawa T., Kim S., Nakai D., Makino C., Takagi T., Ogura H., Yamada K., Chatton B., Ishii S 2010. Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene. EMBO J. 29(1), 196–208.

    Article  CAS  PubMed  Google Scholar 

  39. King M.V., Marsden C.A., Fone K.C 2008. A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol. Sci. 29(9), 482–492.

    Article  CAS  PubMed  Google Scholar 

  40. Lucas G 2009. Serotonin receptors, type 4: A new hope? Curr. Drug Targets. 10(11), 1085–1095.

    Article  CAS  Google Scholar 

  41. Bai M., Zhu X.Z., Zhang Y., Zhang S., Zhang L., Xue L., Zhong M., Zhang X 2014. Anhedonia was associated with the dysregulation of hippocampal HTR4 and microRNA Let-7a in rats. Physiol. Behav. 129, 135–141.

    Article  CAS  PubMed  Google Scholar 

  42. Mendez-David I., David D.J., Darcet F., Wu M.V., Kerdine-Römer S., Gardier A.M., Hen R 2014. Rapid anxiolytic effects of a 5-HT4 receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology. 39(6), 1366–1378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Samuels B.A., Mendez-David I., Faye C., David S.A., Pierz K.A., Gardier A.M., Hen R., David D.J 2014. Serotonin 1A and serotonin 4 receptors: Essential mediators of the neurogenic and behavioral actions of antidepressants. Neuroscientist. 22(1), 26–45. doi 10.1177/1073858414561303

    Article  PubMed  PubMed Central  Google Scholar 

  44. Vidal R., Castro E., Pilar-Cuéllar F., Pascual-Brazo J., Díaz A., Rojo M.L., Linge R., Martín A., Valdizán E.M., Pazos A 2014. Serotonin 5-HT4 receptors: A new strategy for develo** fast acting antidepressants? Curr. Pharm. Des. 20(23), 3751–3762.

    CAS  Google Scholar 

  45. Warner-Schmidt J.L., Flajolet M., Maller A., Chen E.Y., Qi H., Svenningsson P., Greengard P 2009. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation J. Neurosci. 29(6), 1937–1946.

    Article  CAS  Google Scholar 

  46. Herve D., Pickel V.M., Joh T.H., Beaudet A 1987. Serotonin axon terminals in the ventral tegmental area of the rat: Fine structure and synaptic input to dopaminergic neurons. Brain Res. 435 (1–2), 71–83.

    Article  CAS  PubMed  Google Scholar 

  47. Carkaci-Salli N., Salli U., Kuntz-Melcavage K.L., Pennock M.M., Ozgen H., Tekin I., Freeman W.M., Vrana K.E 2011. TPH2 in the ventral tegmental area of the male rat brain. Brain Res. Bull. 84(6), 376–380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kovalenko I.L., Smagin D.A., Galyamina A.G., Orlov Yu.L., Kudryavtseva N.N 2016. Changes in the expression of dopaminergic genes in brain structures of male mice exposed to chronic social defeat stress: An RNA-seq study. Mol. Biol. (Moscow). 50(1), 161–163.

    Article  CAS  Google Scholar 

  49. Tsuji M., Miyagawa K., Takeda H 2014. Epigenetic regulation of resistance to emotional stress: Possible involvement of 5-HT1A receptor-mediated histone acetylation. J. Pharmacol. Sci. 125(4), 347–54.

    Article  CAS  PubMed  Google Scholar 

  50. Kirilly E., Gonda X., Bagdy G 2015. Antidepressants, stressors and the serotonin 1A receptor. Neuropsychopharmacol. Hung. 17(2), 81–89.

    PubMed  Google Scholar 

  51. Bondar N.P., Boyarskikh U.A., Kovalenko I.L., Filipenko M.L., Kudryavtseva N.N 2009. Molecular implications of repeated aggression: Th, Dat1, Snca and Bdnf gene expression in the ventral tegmental area of victorious male mice. PLoS ONE. 4 (1), e4190.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Rilstone J.J., Alkhater R.A., Minassian B.A 2013. Brain dopamine-serotonin vesicular transport disease and its treatment. N. Engl. J. Med. 368(6), 543–550.

    Article  CAS  PubMed  Google Scholar 

  53. Dremencov E., Gispan-Herman I., Rosenstein M., Mendelman A., Overstreet D.H., Zohar J., Yadid G 2004. The serotonin-dopamine interaction is critical for fast-onset action of antidepressant treatment: in vivo studies in an animal model of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry. 28(1), 141–147.

    Article  CAS  PubMed  Google Scholar 

  54. Kudryavtseva N.N., Bondar N.P., Boyarskikh U.A., Filipenko M.L 2010. Snca and Bdnf gene expression in the VTA and raphe nuclei of midbrain in chronically victorious and defeated male mice. PLoS ONE. 5 (11), e14089.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Brennan T.J., Seeley W.W., Kilgard M., Schreiner C.E., Tecott L.H 1997. Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. Nat. Genet. 16(4), 387–390.

    Article  CAS  PubMed  Google Scholar 

  56. Guo Y., Zhang H., Gao J., Wei S., Song C., Sun P., Qiao M 2015. Study of genes associated with the ‘anger-in’ and ‘anger-out’ emotions of humans using a rat model. Exp. Ther. Med. 9(4), 1448–1454.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lassig J.P., Vachirasomtoon K., Hartzell K., Leventhal M. Courchesne E., Courchesne R., Lord C., Leventhal B.L., Cook E.H 1999. Physical map** of the serotonin 5-HT(7) receptor gene (HTR7) to chromosome 10 and pseudogene (HTR7P) to chromosome 12, and testing of linkage disequilibrium between HTR7 and autistic disorder. Am. J. Med. Genet. 88(5), 472–475.

    Article  CAS  PubMed  Google Scholar 

  58. Waters K.A., Stean T.O., Hammond B., Virley D.J., Upton N., Kew J.N., Hussain I 2012. Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition. Behav. Brain Res. 228(1), 211–218.

    Article  CAS  PubMed  Google Scholar 

  59. Di Pilato P., Niso M., Adriani W., Romano E., Travaglini D., Berardi F., Colabufo N.A., Perrone R., Laviola G., Lacivita E., Leopoldo M 2014. Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: An overview. Rev. Neurosci. 25(3), 401–415.

    Article  PubMed  Google Scholar 

  60. Renner U., Zeug A., Woehler A., Niebert M., Dityatev A., Dityateva G., Gorinski N., Guseva D., Abdel-Galil D., Fröhlich M., Döring F., Wischmeyer E., Richter D.W., Neher E., Ponimaskin E.G 2012. Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. J. Cell Sci. 125(10), 2486–2499. doi 10.1242/jcs.101337

    Article  CAS  PubMed  Google Scholar 

  61. Naumenko V.S., Popova N.K., Lacivita E., Leopoldo M., Ponimaskin E.G 2014. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci. Ther. 20(7), 582–590.

    Article  CAS  PubMed  Google Scholar 

  62. Tokarski K., Kusek M., Sowa J., Bobula B 2014. Possible involvement of 5-HT7 receptor in pathophysiology of affective disorders and action of antidepressant drugs. Postepy Hig. Med. Dosw. 68, 1104–1113.

    Article  Google Scholar 

  63. Rocha B.A., Scearce-Levie K., Lucas J.J., Hiroi N., Castanon N., Crabbe J.C., Nestler E.J., Hen R 1998. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature. 393(6681), 175–178.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, 630090, Russia

    N. N. Kudryavtseva, D. A. Smagin, I. L. Kovalenko, A. G. Galyamina, G. B. Vishnivetskaya, V. N. Babenko & Yu. L. Orlov

Authors
  1. N. N. Kudryavtseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. A. Smagin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. L. Kovalenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. G. Galyamina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. B. Vishnivetskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. N. Babenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu. L. Orlov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. N. Kudryavtseva.

Additional information

Original Russian Text © N.N. Kudryavtseva, D.A. Smagin, I.L. Kovalenko, A.G. Galyamina, G.B. Vishnivetskaya, V.N. Babenko, Yu.L. Orlov, 2017, published in Molekulyarnaya Biologiya, 2017, Vol. 51, No. 2, pp. 288–300.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kudryavtseva, N.N., Smagin, D.A., Kovalenko, I.L. et al. Serotonergic genes in the development of anxiety/depression-like state and pathology of aggressive behavior in male mice: RNA-seq data. Mol Biol 51, 251–262 (2017). https://doi.org/10.1134/S0026893317020133

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893317020133

Keywords

Search

Navigation