Skip to main content
SpringerLink
Log in

Tryptophan hydroxylase 2 and Bcl-xL in the rat raphe nucleus after acute and chronic forced swim stress

  • Published:
Russian Journal of Genetics: Applied Research

Abstract

Stressful events induce changes in the expression of numerous genes and their protein products in the brain. However, the mechanisms mediating these changes, as well as their significance for the development of stress-induced depression or for coping with stress, remain obscure. Evidence for the sensitivity of tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of the serotonin (5-HT) pathway, to stress is concisely reviewed, as well as the neuroprotective function of the antiapoptotic protein Bcl-xL in the brain. The goal of our experiments was to investigate the gene and protein expression of TPH2 and Bcl-xL in the dorsal (DRN) and median (MRN) raphe nuclei during repeated stress events. Gene (RT PCR) and protein (immunohistochemistry) expression was assessed 24 hours after the second and fourteenth forced swim sessions. The increase in TPH2 protein expression observed after the second swim stress exposure might reflect the protective action of Bcl-xL. During the subsequent stressful events, the stress-induced increase in Bcl-xL expression decreased. This effect was associated with the weakening of serotonergic neuron function evidenced by the compensatory activation of the TPH2 gene expression without TPH2 protein increase. Thus, shortand long-term forced swimming resulted in qualitatively different alterations in brain expression of TPH2 and Bcl-xL, suggesting their specific roles during acute and chronic stages in the development of stress-induced psychopathology. These changes may constitute a component of the mechanisms underlying elevated tph2 gene expression in depressed patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bach-Mizrachi, H., Underwood, M.D., Tin, A., Ellis, S.P., Mann, J.J., and Arango, V., Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides, Mol. Psychiatry, 2008, vol. 13, no. 5, pp. 507–513.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baumann, B., Bielau, H., Krell, D., Agelink, M.W., Diekmann, S., Wurthmann, C., Trubner, K., Bernstein, H.G., Danos, P., and Bogerts, B., Circumscribed numerical deficit of dorsal raphe neurons in mood disorders, Psychol. Med., 2002, vol. 32, no. 1, pp. 93–103.

    Article  CAS  PubMed  Google Scholar 

  • Bethea, C.L., Phu, K., Reddy, A.P., and Cameron, J.L., The effect of short-term stress on serotonin gene expression in high and low resilient macaques, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2013, vol. 44, pp. 143–153.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Boldrini, M., Underwood, M.D., Mann, J.J., and Arango, V., More tryptophan hydroxylase in the brainstem dorsal raphe nucleus in depressed suicides, Brain Res., 2005, vol. 1041, no. 1, pp. 19–28.

    Article  CAS  PubMed  Google Scholar 

  • Boyarskikh, U.A., Bondar, N.P., Filipenko, M.L., and Kudryavtseva, N.N., Downregulation of serotonergic gene expression in the raphe nuclei of the midbrain under chronic social defeat stress in male mice, Mol. Neurobiol., 2013, vol. 48, no. 1, pp. 13–21.

    Article  CAS  PubMed  Google Scholar 

  • Canli, T. and Lesch, K.P., Long story short: the serotonin transporter in emotion regulation and social cognition, Nat. Neurosci., 2007, vol. 10, no. 9, pp. 1103–1109.

    Article  CAS  PubMed  Google Scholar 

  • Celada, P., Bortolozzi, A., and Artigas, F., Serotonin 5HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research, CNS Drugs, 2013, vol. 27, no. 9, pp. 703–716.

    Article  CAS  PubMed  Google Scholar 

  • Chamas, F.M., Underwood, M.D., Arango, V., Serova, L., Kassir, S.A., Mann, J.J., and Sabban, E.L., Immobilization stress elevates tryptophan hydroxylase mRNA and protein in the rat raphe nuclei, Biol. Psychiatry, 2004, vol. 55, no. 3, pp. 278–283.

    Article  CAS  PubMed  Google Scholar 

  • Chen, G.L. and Miller, G.M., Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications, Am. J. Med. Genet., vol. Neuropsychiatr. Genet. 2012, vol. 159B, no. 2, pp. 152–171.

    Article  Google Scholar 

  • Chen, G.L. and Miller, G.M., Tryptophan hydroxylase-2: an emerging therapeutic target for stress disorders, Biochem. Pharmacol., 2013, vol. 85, no. 9, pp. 1227–1233.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cryan, J.F. and Mombereau, C., In search of a depressed mouse: utility of models for studying depressionrelated behavior in genetically modified mice, Mol. Psychiatry, 2004, vol. 9, no. 4, pp. 326–357.

    Article  CAS  PubMed  Google Scholar 

  • Drugan, R.C., Hibl, P.T., Kelly, K.J., Dady, K.F., Hale, M.W., and Lowry, C.A., Prior cold water swim stress alters immobility in the forced swim test and associated activation of serotonergic neurons in the rat dorsal raphe nucleus, Neuroscience, 2013, vol. 253, pp. 221–234.

    Article  CAS  PubMed  Google Scholar 

  • Fernandez, S.P. and Gaspar, P., Investigating anxiety and depressive-like phenotypes in genetic mouse models of serotonin depletion, Neuropharmacology, 2012, vol. 62, no. 1, pp. 144–154.

    Article  CAS  PubMed  Google Scholar 

  • Gardner, K.L., Hale, M.W., Oldfield, S., Lightman, S.L., Plotsky, P.M., and Lowry, C.A., Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus, Neuroscience, 2009, vol. 163, no. 4, pp. 991–1001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gonzalez, M.M. and Aston-Jones, G., Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats, Proc. Natl. Acad. Sci. USA, 2008, vol. 105, no. 12, pp. 4898–4903.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Goswami, D.B., May, W.L., Stockmeier, C.A., and Austin, M.C., Transcriptional expression of serotonergic regulators in laser-captured microdissected dorsal raphe neurons of subjects with major depressive disorder: sex-specific differences, J. Neurochem., 2010, vol. 112, no. 2, pp. 397–409.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hale, M.W., Shekhar, A., and Lowry, C.A., Development by environment interactions controlling tryptophan hydroxylase expression, J. Chem. Neuroanat., 2011, vol. 41, no. 4, pp. 219–226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heine, V.M., Maslam, S., Zareno, J., Joels, M., and Lucassen, P.J., Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible, Eur. J. Neurosci., 2004, vol. 19, no. 1, pp. 131–144.

    Article  PubMed  Google Scholar 

  • Kempermann, G. and Kronenberg, G., Depressed new neurons adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression, Biol. Psychiatry, 2003, vol. 54, no. 5, pp. 499–503.

    Article  PubMed  Google Scholar 

  • Kendler, K.S., Karkowski, L.M., and Prescott, C.A., Causal relationship between stressful life events and the onset of major depression, Am. J. Psychiatry, 1999, vol. 156, no. 6, pp. 837–841.

    Article  CAS  PubMed  Google Scholar 

  • Kessing, L.V., Agerbo, E., and Mortensen, P.B., Does the impact of major stressful life events on the risk of developing depression change throughout life?, Psychol. Med, 2003, vol. 33, no. 7, pp. 1177–1184.

    Article  CAS  PubMed  Google Scholar 

  • Klempin, F., Beis, D., Mosienko, V., Kempermann, G., Bader, M., and Alenina, N., Serotonin is required for exercise-induced adult hippocampal neurogenesis, J. Neurosci., 2013, vol. 33, no. 19, pp. 8270–8275.

    Article  CAS  PubMed  Google Scholar 

  • Krishnan, V. and Nestler, E.J., Animal models of depression: molecular perspectives, Curr. Top. Behav. Neurosci., 2011, vol. 7, pp. 121–147.

    Article  PubMed Central  PubMed  Google Scholar 

  • Mandelli, L., Antypa, N., Nearchou, F.A., Vaiopoulos, C., Stefanis, C.N., Serretti, A., and Stefanis, N.C., The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism, J. Affect. Disord., 2012, vol. 142, nos. 1–3, pp. 82–89.

    Article  CAS  PubMed  Google Scholar 

  • Mann, J.J., Currier, D., Murphy, L., Huang, Y.Y., Galfalvy, H., Brent, D., Greenhill, L., and Oquendo, M., No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover, J. Affect. Disord., 2008, vol. 106, nos. 1/2, pp. 117–121.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matthews, P.R. and Harrison, P.J., A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide, J. Affect. Disord., 2012, vol. 137, nos. 1/3, pp. 125–134.

    Article  PubMed Central  PubMed  Google Scholar 

  • Mezadri, T.J., Batista, G.M., Portes, A.C., Marino-Neto, J., and Lino-de-Oliveira, C., Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants, J. Neurosci. Methods, 2011, vol. 195, no. 2, pp. 200–205.

    Article  CAS  PubMed  Google Scholar 

  • Owens, M.J. and Nemeroff, C.B., Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter, Clin. Chem., 1994, vol. 40, no. 2, pp. 288–295.

    CAS  PubMed  Google Scholar 

  • Porsolt, R.D., Anton, G., Blavet, N., and Jalfre, M., Behavioural despair in rats: a new model sensitive to antidepressant treatments, Eur. J. Pharmacol., 1978, vol. 47, no. 4, pp. 379–391.

    Article  CAS  PubMed  Google Scholar 

  • Ripke, S., Wray, N.R., Lewis, C.M., et al., A mega-analysis of genome-wide association studies for major depressive disorder. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Mol. Psychiatry, 2013, vol. 18, no. 4, pp. 497–511.

    Article  CAS  PubMed  Google Scholar 

  • Shishkina, G.T., Kalinina, T.S., Berezova, I.V., Bulygina, V.V., and Dygalo, N.N., Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal bcl-xl expression, Behav. Brain Res., 2010, vol. 213, no. 2, pp. 218–224.

    Article  CAS  PubMed  Google Scholar 

  • Shishkina, G.T., Kalinina, T.S., Berezova, I.V., and Dygalo, N.N., Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressivelike behavior, Neuropharmacology, 2012, vol. 62, no. 1, pp. 177–183.

    Article  CAS  PubMed  Google Scholar 

  • Shishkina, G.T., Kalinina, T.S., and Dygalo, N.N., Upregulation of tryptophan hydroxylase-2 mRNA in the rat brain by chronic fluoxetine treatment correlates with its antidepressant effect, Neuroscience, 2007, vol. 150, no. 2, pp. 404–412.

    Article  CAS  PubMed  Google Scholar 

  • Shishkina, G.T., Bulygina, V.V., and Dygalo, N.N., Behavioral effects of glucocorticoids during the first exposures to the forced swim stress, Psychopharmacology (Berl.), 2014. [Epub ahead of print] DOI 10.1007/s00213-0143718-8

    Google Scholar 

  • Stepanichev, M., Dygalo, N.N., Grigoryan, G., Shishkina, G.T., and Gulyaeva, N., Rodent models of depression: neurotrophic and neuroinflammatory biomarkers, Biomed. Res. Int., 2014, vol. 2014, p. 932757.

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsai, S.J., Hong, C.J., Liou, Y.J., Yu, Y.W., Chen, T.J., Hou, S.J., and Yen, F.C., Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2009, vol. 33, no. 4, pp. 637–641.

    Article  CAS  PubMed  Google Scholar 

  • Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M., Fink, H., and Bader, M., Synthesis of serotonin by a second tryptophan hydroxylase isoform, Science, 2003, vol. 299, no. 5603, p. 76.

    Article  CAS  PubMed  Google Scholar 

  • Walther, D.J. and Bader, M., A unique central tryptophan hydroxylase isoform, Biochem. Pharmacol., 2003, vol. 66, no. 9, pp. 1673–1680.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, L. and Zheng, X., Integration of animal behaviors under stresses with different time courses, Neural Regen. Res., 2014, vol. 9, no. 15, pp. 1464–1473.

    Article  PubMed Central  PubMed  Google Scholar 

  • Zill, P., Baghai, T.C., Zwanzger, P., Schule, C., Eser, D., Rupprecht, R., Moller, H.J., Bondy, B., and Ackenheil, M., SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression, Mol. Psychiatry, 2004, vol. 9, no. 11, pp. 1030–1036.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    G. T. Shishkina, T. S. Kalinina, V. V. Bulygina, E. V. Babljuk & N. N. Dygalo

  2. Novosibirsk State University, Novosibirsk, Russia

    T. S. Kalinina & N. N. Dygalo

  3. All-Russia Research Institute for Agricultural Microbiology, St. Petersburg, 196608, Russia

    G. T. Shishkina, T. S. Kalinina, V. V. Bulygina, E. V. Babljuk & N. N. Dygalo

Authors
  1. G. T. Shishkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. S. Kalinina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. V. Bulygina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. V. Babljuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. N. Dygalo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. T. Shishkina.

Additional information

Original Russian Text © G.T. Shishkina, T.S. Kalinina, V.V. Bulygina, E.V. Babljuk, N.N. Dygalo, 2014, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2014, Vol. 18, No. 4/3, pp. 1117–1123.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shishkina, G.T., Kalinina, T.S., Bulygina, V.V. et al. Tryptophan hydroxylase 2 and Bcl-xL in the rat raphe nucleus after acute and chronic forced swim stress. Russ J Genet Appl Res 5, 577–581 (2015). https://doi.org/10.1134/S2079059715060167

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S2079059715060167

Keywords

Search

Navigation