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Molecular Neurobiology

, Volume 56, Issue 12, pp 8537–8556 | Cite as

Stress-Induced Epigenetic Changes in Hippocampal Mkp-1 Promote Persistent Depressive Behaviors

  • Jung-Eun Lee
  • Hye-Jin Kwon
  • Juli Choi
  • Pyung-Lim HanEmail author
Article

Abstract

Chronic stress induces persistent depressive behaviors. Stress-induced transcriptional alteration over the homeostatic range in stress hormone–sensitive brain regions is believed to underlie long-lasting depressive behaviors. However, the detailed mechanisms by which chronic stress causes those adaptive changes are not clearly understood. In the present study, we investigated whether epigenetic changes regulate stress-induced depressive behaviors. We found that chronic stress in mice downregulates the epigenetic factors HDAC2 and SUV39H1 in the hippocampus. A series of follow-up analyses including ChIP assay and siRNA-mediated functional analyses reveal that glucocorticoids released by stress cumulatively increase Mkp-1 expression in the hippocampus, and increased Mkp-1 then debilitates p-CREB and PPARγ, which in turn suppress the epigenetic factors HDAC2 and SUV39H1. Furthermore, HDAC2 and SUV39H1 normally suppress the transcription of the Mkp-1, and therefore the reduced expression of HDAC2 and SUV39H1 increases Mkp-1 expression. Accordingly, repeated stress progressively strengthens a vicious cycle of the Mkp-1 signaling cascade that facilitates depressive behaviors. These results suggest that the hippocampal stress adaptation system comprising HDAC2/SUV39H1-regulated Mkp-1 signaling network determines the vulnerability to chronic stress and the maintenance of depressive behaviors.

Keywords

Stress adaptation Epigenetic factors HDAC2 SUV39H1 Mkp-1 

Abbreviations

CaMKIIα

Ca2+/calmodulin-dependent protein kinase II alpha

Cbp

CREB-binding protein

ChIP

Chromatin immunoprecipitation

CREB

cAMP response element binding protein

ERK

Extracellular signal-regulated kinase

GC

Glucocorticoid

GR

Glucocorticoid receptor

GSH

Glutathione

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HDAC2

Histone deacetylase 2

JNK

c-Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

Mkp-1

Mitogen-activated protein kinase phosphatase-1

p38

p38 mitogen-activated protein kinase

PPARγ

Peroxisome proliferator-activated receptor gamma

RA

Rosmarinic acid

RT-PCR

Reverse transcription polymerase chain reaction

SUV39H1

Suppressor of variegation 3–9 homolog 1

VitC

Vitamin C

Notes

Funding Information

This research was supported by a grant (2018R1A2B2001535) from the Ministry of Science, ICT and Future Planning, Republic of Korea.

Compliance with Ethical Standards

Competing Interests

The authors declare no competing financial interests.

References

  1. 1.
    Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84CrossRefPubMedGoogle Scholar
  2. 2.
    Trapp T, Rupprecht R, Castrén M, Reul JM, Holsboer F (1994) Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS. Neuron 13:1457–1462CrossRefPubMedGoogle Scholar
  3. 3.
    McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873–904CrossRefPubMedGoogle Scholar
  4. 4.
    Covington HE 3rd, Vialou VF, LaPlant Q, Ohnishi YN, Nestler EJ (2011) Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition. Neurosci Lett 493:122–126CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Seo JS, Park JY, Choi J, Kim TK, Shin JH, Lee JK, Han PL (2012) NADPH oxidase mediates depressive behavior induced by chronic stress in mice. J Neurosci 32:9690–9699CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kim TK, Lee JE, Kim JE, Park JY, Choi J, Kim H, Lee EH, Han PL (2016) G9a-mediated regulation of OXT and AVP expression in the basolateral amygdala mediates stress-induced lasting behavioral depression and its reversal by exercise. Mol Neurobiol 53:2843–2856CrossRefPubMedGoogle Scholar
  7. 7.
    Vialou V, Feng J, Robison AJ, Nestler EJ (2013) Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol 53:59–87CrossRefPubMedGoogle Scholar
  8. 8.
    Nabeshima T, Kim HC (2013) Involvement of genetic and environmental factors in the onset of depression. Exp Neurobiol 22:235–243CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Shinkai Y, Tachibana M (2011) H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev 25:781–788CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhang TY, Labonté B, Wen XL, Turecki G, Meaney MJ (2013) Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology 38:111–123CrossRefPubMedGoogle Scholar
  11. 11.
    Bagot RC, Labonté B, Peña CJ, Nestler EJ (2014) Epigenetic signaling in psychiatric disorders: stress and depression. Dialogues Clin Neurosci 16:281–295PubMedPubMedCentralGoogle Scholar
  12. 12.
    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM et al (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hagelkruys A, Lagger S, Krahmer J, Leopoldi A, Artaker M, Pusch O, Zezula J, Weissmann S et al (2012) A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog. Development 141:604–616CrossRefGoogle Scholar
  15. 15.
    Aagaard L, Schmid M, Warburton P, Jenuwein T (2000) Mitotic phosphorylation of SUV39H1, a novel component of active centromeres, coincides with transient accumulation at mammalian centromeres. J Cell Sci 113:817–829PubMedGoogle Scholar
  16. 16.
    Sidler C, Woycicki R, Li D, Wang B, Kovalchuk I, Kovalchuk O (2014) A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts. Aging (Albany NY) 6:545–563CrossRefGoogle Scholar
  17. 17.
    Mozzetta C, Boyarchuk E, Pontis J, Ait-Si-Ali S (2015) Sound of silence: the properties and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol 16:499–513CrossRefPubMedGoogle Scholar
  18. 18.
    Mal AK (2006) Histone methyltransferase Suv39h1 represses MyoD-stimulated myogenic differentiation. EMBO J 25:3323–3334CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, Ulja D, Karuppagounder SS et al (2016) Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 5:e15092CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Han A, Sung YB, Chung SY, Kwon MS (2014) Possible additional antidepressant-like mechanism of sodium butyrate: targeting the hippocampus. Neuropharmacology 81:292–302CrossRefPubMedGoogle Scholar
  21. 21.
    Hutter D, Chen P, Barnes J, Liu Y (2000) Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase: critical role of the p38 C-terminal domain in its negative regulation. Biochem J 352:155–163CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kassel O, Sancono A, Krätzschmar J, Kreft B, Stassen M, Cato AC (2001) Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 20:7108–7116CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vandevyver S, Dejager L, Van Bogaert T, Kleyman A, Liu Y, Tuckermann J, Libert C (2012) Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. J Clin Invest 122:2130–2140CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, Duman RS (2010) A negative regulator of MAP kinase causes depressive behavior. Nat Med 16:1328–1332CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22:9754–9763CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kuipers SD, Bramham CR (2006) Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel 9:580–586PubMedGoogle Scholar
  27. 27.
    Taliaz D, Stall N, Dar DE, Zangen A. (2010). Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 15:80–92.Google Scholar
  28. 28.
    Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME (1997) CREB: a major mediator of neuronal neurotrophin responses. Neuron 19:1031–1047CrossRefPubMedGoogle Scholar
  29. 29.
    Duman RS, Malberg J, Nakagawa S. D'Sa C (2000). Neuronal plasticity and survival in mood disorders. Biol Psychiatry 48:732–739.CrossRefPubMedGoogle Scholar
  30. 30.
    Nosjean O, Boutin JA (2002) Natural ligands of PPARgamma: are prostaglandin J(2) derivatives really playing the part? Cell Signal 14:573–583CrossRefPubMedGoogle Scholar
  31. 31.
    Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771:1031–1045CrossRefPubMedGoogle Scholar
  32. 32.
    Grygiel-Górniak B (2014) Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications–a review. Nutr J 13:17CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kemp DE, Schinagle M, Gao K, Conroy C, Ganocy SJ, Ismail-Beigi F, Calabrese JR (2014) PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression. CNS Drugs 28:571–581CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Colle R, de Larminat D, Rotenberg S, Hozer F, Hardy P, Verstuyft C, Fève B, Corruble E (2017) PPAR-γ agonists for the treatment of major depression: a review. Pharmacopsychiatry 50:49–55PubMedGoogle Scholar
  35. 35.
    Kurhe Y, Mahesh R (2016) Pioglitazone, a PPARγ agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice. Neurobiol Stress 3:114–121CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Liao L, Zhang XD, Li J, Zhang ZW, Yang CC, Rao CL, Zhou CJ, Zeng L et al (2017) Pioglitazone attenuates lipopolysaccharide-induced depression-like behaviors, modulates NF-κB/IL-6/STAT3, CREB/BDNF pathways and central serotonergic neurotransmission in mice. Int Immunopharmacol 49:178–186CrossRefPubMedGoogle Scholar
  37. 37.
    Petersen M, Simmonds MS (2003) Rosmarinic acid. Phytochemistry 62:121–125CrossRefPubMedGoogle Scholar
  38. 38.
    Erkan N, Ayranci G, Ayranci E (2008) Antioxidant activities of rosemary (Rosmarinus Officinalis L.) extract, blackseed (Nigella sativa L.) essential oil, carnosic acid, rosmarinic acid and sesamol. Food Chem 110:76–82CrossRefPubMedGoogle Scholar
  39. 39.
    Andrade JM, Faustino C, Garcia C, Ladeiras D, Reis CP, Rijo P (2018) Rosmarinus officinalis L.: an update review of its phytochemistry and biological activity. Future Sci OA 4:FSO283CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Moore J, Yousef M, Tsiani E (2016) Anticancer effects of rosemary (Rosmarinus officinalis L.) extract and rosemary extract polyphenols. Nutrients pii: E731.Google Scholar
  41. 41.
    Seo JS, Choi J, Leem YH, Han PL (2015) Rosmarinic acid alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurobiol 24:341–350CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jin X, Liu P, Yang F, Zhang YH, Miao D (2013) Rosmarinic acid ameliorates depressive-like behaviors in a rat model of CUS and up-regulates BDNF levels in the hippocampus and hippocampal-derived astrocytes. Neurochem Res 38:1828–1837CrossRefPubMedGoogle Scholar
  43. 43.
    Park JY, Kim TK, Choi J, Lee JE, Kim H, Lee EH, Han PL (2014) Implementation of a two-dimensional behavior matrix to distinguish individuals with differential depression states in a rodent model of depression. Exp Neurobiol 23:215–223CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kim H, Kim TK, Kim JE, Park JY, Lee Y, Kang M, Kim KS, Han PL (2014) Adenylyl cyclase-5 in the dorsal striatum function as a molecular switch for the generation of behavioral preferences for cue-directed food choices. Mol Brain 7:77CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Im JY, Kim D, Paik SG, Han PL (2006) Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation. Free Radic Biol Med 41:960–972CrossRefPubMedGoogle Scholar
  46. 46.
    Choi J, Kim JE, Kim TK, Park JY, Lee JE, Kim H, Lee EH, Han PL (2015) TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors. Neuropharmacology 97:346–356CrossRefPubMedGoogle Scholar
  47. 47.
    Kim TK, Kim JE, Choi J, Park JY, Lee JE, Lee EH, Lee Y, Kim BY et al (2017) Local Interleukin-18 system in the basolateral amygdala regulates susceptibility to chronic stress. Mol Neurobiol 54:5347–5358CrossRefPubMedGoogle Scholar
  48. 48.
    Reuter S, Gupta SC, Park B, Goel A, Aggarwal BB (2011) Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr 6:93–108CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Yang MD, Chiang YM, Higashiyama R, Asahina K, Mann DA, Mann J, Wang CC, Tsukamoto H (2012) Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect. Hepatology 55:1271–1281CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Remely M (2015) Therapeutic perspectives of epigenetically active nutrients. Br J Pharmacol 172:2756–2768CrossRefPubMedGoogle Scholar
  51. 51.
    Sun P, Enslen H, Myung PS, Maurer RA (1994) Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev 8:2527–2539CrossRefPubMedGoogle Scholar
  52. 52.
    Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. SCIENCE 273:959–963CrossRefPubMedGoogle Scholar
  53. 53.
    Burns KA, Vanden Heuvel JP (2007) Modulation of PPAR activity via phosphorylation. Biochim Biophys Acta 1771:952–960CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kondoh K, Nishida E (2007) Rugulation of MAP kinase by MAP kinase phosphatases. Biochim Biophys Acta 1773:1227–1237CrossRefPubMedGoogle Scholar
  55. 55.
    Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837CrossRefPubMedGoogle Scholar
  56. 56.
    Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L (2012) H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genomics 13:424CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Vaute O, Nicolas E, Vandel L, Trouche D (2002) Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases. Nucleic Acids Res 30:475–481CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M (2003) Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J Biol Chem 278:24132–24138CrossRefPubMedGoogle Scholar
  59. 59.
    Beltman J, McCormick F, Cook SJ (1996) The selective protein kinase C inhibitor, Ro-31-8220, inhibits mitogen-activated protein kinase phosphatase-1 (MKP-1) expression, induces c-Jun expression, and activates Jun N-terminal kinase. J Biol Chem 271:27018–27024CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang J, Wang Q, Zhu N, Yu M, Shen B, Xiang J, Lin A (2008) Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIP(L) and MKP-1, thereby antagonizing UV-induced apoptosis. Cell Death Differ 15:1654–1662CrossRefPubMedGoogle Scholar
  61. 61.
    Jeong Y, Du R, Zhu X, Yin S, Wang J, Cui H, Cao W, Lowenstein CJ (2014) Histone 1deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1. J Leukoc Biol 95:651–659CrossRefPubMedGoogle Scholar
  62. 62.
    Delghandi MP, Johannessen M, Moens U (2005) The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells. Cell Signal 17:1343–1351CrossRefPubMedGoogle Scholar
  63. 63.
    Mao LM, Tang Q, Wang JQ (2007) Protein kinase C-regulated cAMP response element-binding protein phosphorylation in cultured rat striatal neurons. Brain Res Bull 72:302–308CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Turpeinen T, Nieminen R, Moilanen E, Korhonen R (2010) Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. J Pharmacol Exp Ther 333:310–318CrossRefPubMedGoogle Scholar
  65. 65.
    Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM, Chao MV (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13:1373–1379CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ferlemi AV, Katsikoudi A, Kontogianni VG, Kellici TF, Iatrou G, Lamari FN, Tzakos AG, Margarity M (2015) Rosemary tea consumption results to anxiolytic- and anti-depressant-like behavior of adult male mice and inhibits all cerebral area and liver cholinesterase activity; phytochemical investigation and in silico studies. Chem Biol Interact 237:47–57CrossRefPubMedGoogle Scholar
  67. 67.
    Ito N, Yabe T, Gamo Y, Nagai T, Oikawa T, Yamada H, Hanawa T (2008) Rosmarinic acid from Perillae Herba produces an antidepressant-like effect in mice through cell proliferation in the hippocampus. Biol Pharm Bull 31:1376–1380CrossRefPubMedGoogle Scholar
  68. 68.
    Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Brain and Cognitive SciencesEwha Womans UniversitySeoulRepublic of Korea
  2. 2.Department of Chemistry and Nano ScienceEwha Womans UniversitySeoulRepublic of Korea
  3. 3.Brain Disease Research InstituteEwha Womans UniversitySeoulRepublic of Korea

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