Neurochemical Research

, Volume 41, Issue 9, pp 2223–2232 | Cite as

Histone Acetylation Regulation in Sleep Deprivation-Induced Spatial Memory Impairment

  • Ruifeng Duan
  • Xiaohua Liu
  • Tianhui Wang
  • Lei Wu
  • Xiujie Gao
  • Zhiqing ZhangEmail author
Original Paper


Sleep disorders negatively affect cognition and health. Recent evidence has indicated that chromatin remodeling via histone acetylation regulates cognitive function. This study aimed to investigate the possible roles of histone acetylation in sleep deprivation (SD)-induced cognitive impairment. Results of the Morris water maze test showed that 3 days of SD can cause spatial memory impairment in Wistar rats. SD can also decrease histone acetylation levels, increase histone deacetylase 2 (HDAC2) expression, and decrease histone acetyltransferase (CBP) expression. Furthermore, SD can reduce H3 and H4 acetylation levels in the promoters of the brain-derived neurotrophic factor (Bdnf) gene and thus significantly downregulate BDNF expression and impair the activity of key BDNF signaling pathways (pCaMKII, pErk2, and pCREB). However, treatment with the HDAC inhibitor trichostatin A attenuated all the negative effects induced by SD. Therefore, BDNF and its histone acetylation regulation may play important roles in SD-induced spatial memory impairment, whereas HDAC inhibition possibly confers protection against SD-induced impairment in spatial memory and hippocampal functions.


Sleep deprivation Spatial memory Histone acetylation Histone deacetylase Brain-derived neurotrophic factor 



This work was supported by grants from the National Natural Science Foundation of China (No. 81302415) and the Tianjin Natural Science Foundation (No. 12JCYBJC15800). The authors declare no conflicts of interest in this manuscript.

Author Contributions

Z.Z. conceived the study and designed the experiments. L.W. performed the cognition function detection and analysis. R.D. and X.L. performed the ChIP assay. T.W. and X.G. performed all other experiments. The manuscript was written by R.D. and Z.Z. and reviewed and approved by all authors.


  1. 1.
    Devnani P, Fernandes R (2015) Management of REM sleep behavior disorder: an evidence based review. Ann Indian Acad Neurol 18(1):1–5PubMedPubMedCentralGoogle Scholar
  2. 2.
    Luyster F, Strollo P, Zee P et al (2012) Sleep: a health imperative. Sleep 35(6):727–734CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Busch V, Haas J, Crönlein T et al (2012) Sleep deprivation in chronic somatoform pain—effects on mood and pain regulation. Psychiatry Res 195(3):134–143CrossRefPubMedGoogle Scholar
  4. 4.
    Motomura Y, Kitamura S, Oba K et al (2013) Sleep debt elicits negative emotional reaction through diminished amygdala-anterior cingulate functional connectivity. PLoS ONE 8(2):e56578CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Carskadon MA (2011) Sleep’s effects on cognition and learning in adolescence. Prog Brain Res 190:137–143CrossRefPubMedGoogle Scholar
  6. 6.
    Fullagar HH, Skorski S, Duffield R et al (2015) Sleep and athletic performance: the effects of sleep loss on exercise performance, and physiological and cognitive responses to exercise. Sports Med 45(2):161–186CrossRefPubMedGoogle Scholar
  7. 7.
    Tartar JL, Ward CP, McKenna JT et al (2006) Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation. Eur J Neurosci 23(10):2739–2748CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Vecsey CG, Baillie GS, Jaganath D et al (2009) Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461(7267):1122–1125CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Borragán G, Urbain C, Schmitz R et al (2015) Sleep and memory consolidation: motor performance and proactive interference effects in sequence learning. Brain Cognit 95:54–61CrossRefGoogle Scholar
  10. 10.
    Fernandes-Santos L, Patti CL, Zanin KA et al (2012) Sleep deprivation impairs emotional memory retrieval in mice: influence of sex. Prog Neurol Psychopharmacol Biol Psychiatry 38(2):216–222CrossRefGoogle Scholar
  11. 11.
    Hagewoud R, Havekes R, Novati A et al (2010) Sleep deprivation impairs spatial working memory and reduces hippocampal AMPA receptor phosphorylation. J Sleep Res 19(2):280–288CrossRefPubMedGoogle Scholar
  12. 12.
    Vollert C, Zagaar M, Hovatta I et al (2011) Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: potential role of oxidative stress mechanisms. Behav Brain Res 224(2):233–240CrossRefPubMedGoogle Scholar
  13. 13.
    Silva RH, Kameda SR, Carvalho RC et al (2004) Anxiogenic effect of sleep deprivation in the elevated plus-maze test in mice. Psychopharmacology (Berlin) 176(2):115–122CrossRefGoogle Scholar
  14. 14.
    Campbell I, Guinan M, Horowitz J (2002) Sleep deprivation impairs long-term potentiation in rat hippocampal slices. J Neurophysiol 88(2):1073–1076PubMedGoogle Scholar
  15. 15.
    Fu J, Li P, Ouyang X et al (2007) Rapid eye movement sleep deprivation selectively impairs recall of fear extinction in hippocampus-independent tasks in rats. Neuroscience 144(4):1186–1192CrossRefPubMedGoogle Scholar
  16. 16.
    Prince TM, Abel T (2013) The impact of sleep loss on hippocampal function. Learn Mem 20(10):558–569CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Levenson JM, Sweatt JD (2005) Epigenetic mechanisms in memory formation. Nat Rev Neurosci 6(2):108–118CrossRefPubMedGoogle Scholar
  18. 18.
    Jarome TJ, Lubin FD (2014) Epigenetic mechanisms of memory formation and reconsolidation. Neurobiol Learn Mem 115:116–127CrossRefPubMedGoogle Scholar
  19. 19.
    Frick KM (2013) Epigenetics, oestradiol and hippocampal memory consolidation. J Neuroendocrinol 25(11):1151–1162CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Schneider A, Chatterjee S, Bousiges O et al (2013) Acetyltransferases (HATs) as targets for neurological therapeutics. Neurotherapeutics 10(4):568–588CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Peserico A, Simone C (2011) Physical and functional HAT/HDAC interplay regulates protein acetylation balance. J Biomed Biotechnol 2011:371832CrossRefPubMedGoogle Scholar
  22. 22.
    Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13(4):539–550CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Guan JS, Haggarty SJ, Giacometti E et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459(7243):55–60CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Morris MJ, Mahgoub M, Na ES et al (2013) Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J Neurosci 33(15):6401–6411CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hanson JE, Deng L, Hackos DH et al (2013) Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons. J Neurosci 33(14):5924–5929CrossRefPubMedGoogle Scholar
  27. 27.
    McQuown SC, Barrett RM, Matheos DP et al (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31(2):764–774CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Stefanko DP, Barrett RM, Ly AR et al (2009) Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci USA 106(23):9447–9452CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Kim MS, Akhtar MW, Adachi M et al (2012) An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci 32(32):10879–10886CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Agis-Balboa RC, Pavelka Z, Kerimoglu C et al (2013) Loss of HDAC5 impairs memory function: implications for Alzheimer’s disease. J Alzheimers Dis 33(1):35–44PubMedGoogle Scholar
  31. 31.
    Govindarajan N, Rao P, Burkhardt S et al (2013) Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med 5(1):52–63CrossRefPubMedGoogle Scholar
  32. 32.
    Bahari-Javan S, Maddalena A, Kerimoglu C et al (2012) HDAC1 regulates fear extinction in mice. J Neurosci 32(15):5062–5073CrossRefPubMedGoogle Scholar
  33. 33.
    Goodman RH, Smolik S (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev 14(13):1553–1577PubMedGoogle Scholar
  34. 34.
    Saadati H, Esmaeili-Mahani S, Esmaeilpour K et al (2015) Exercise improves learning and memory impairments in sleep deprived female rats. Physiol Behav 138:285–291CrossRefPubMedGoogle Scholar
  35. 35.
    Salari M, Sheibani V, Saadati H et al (2015) The compensatory effect of regular exercise on long-term memory impairment in sleep deprived female rats. Behav Process 119:50–57CrossRefGoogle Scholar
  36. 36.
    Smith PK, Krohn RI, Hermanson GT et al (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150(1):76–85CrossRefPubMedGoogle Scholar
  37. 37.
    Martinowich K, Hattori D, Wu H et al (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302(5646):890–893CrossRefPubMedGoogle Scholar
  38. 38.
    Tsankova NM, Kumar A, Nestler EJ (2004) Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 24(24):5603–5610CrossRefPubMedGoogle Scholar
  39. 39.
    Tsankova NM, Berton O, Renthal W et al (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9(4):519–525CrossRefPubMedGoogle Scholar
  40. 40.
    Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10(12):850–860CrossRefPubMedGoogle Scholar
  41. 41.
    Zeng Y, Zhao D, Xie CW (2010) Neurotrophins enhance CaMKII activity and rescue amyloid-beta-induced deficits in hippocampal synaptic plasticity. J Alzheimers Dis 21(3):823–831PubMedPubMedCentralGoogle Scholar
  42. 42.
    Fischer A, Sananbenesi F, Wang X et al (2007) Recovery of learning and memory is associated with chromatin remodeling. Nature 447(7141):178–182CrossRefPubMedGoogle Scholar
  43. 43.
    Vecsey CG, Hawk JD, Lattal KM et al (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J Neurosci 27(23):6128–6140CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gräff J, Tsai LH (2013) The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 53:311–330CrossRefPubMedGoogle Scholar
  45. 45.
    Grønli J, Soulé J, Bramham CR (2014) Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress. Front Behav Neurosci 7:224CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Guzman-Marin R, Ying Z, Suntsova N et al (2006) Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats. J Physiol 575(Pt 3):807–819CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Timmusk T, Palm K, Metsis M et al (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10(3):475–489CrossRefPubMedGoogle Scholar
  48. 48.
    Metsis M, Timmusk T, Arenas E et al (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci USA 90(19):8802–8806CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Alhaider IA, Aleisa AM, Tran TT et al (2011) Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine. Mol Cell Neurosci 46(4):742–751CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ruifeng Duan
    • 1
  • Xiaohua Liu
    • 1
  • Tianhui Wang
    • 1
  • Lei Wu
    • 1
  • Xiujie Gao
    • 1
  • Zhiqing Zhang
    • 1
    Email author
  1. 1.Tianjin Institute of Health and Environmental MedicineTianjinChina

Personalised recommendations