Postoperative cognitive dysfunction (POCD) affects millions of patients each year in the USA and has been recognized as a significant complication after surgery. Epigenetic regulation of learning and memory has been shown. For example, an increase of histone deacetylases (HDACs), especially HDAC2, which epigenetically regulates gene expression, impairs learning and memory. However, the epigenetic contribution to the development of POCD is not known. Also, the effects of living situation on POCD have not been investigated. Here, we showed that mice that lived alone before the surgery and lived in a group after the surgery and mice that lived in a group before surgery and lived alone after surgery had impairment of learning and memory compared with the corresponding control mice without surgery. Surgery increased the activity of HDACs including HDAC2 but not HDAC1 and decreased brain-derived neurotrophic factor (BDNF), dendritic arborization, and spine density in the hippocampus. Suberanilohydroxamic acid (SAHA), a relatively specific inhibitor of HDAC2, attenuated these surgery effects. SAHA did not change BDNF expression, dendritic arborization, and spine density in mice without surgery. Surgery also reduced the activity of nuclear histone acetyltransferases (HATs). This effect was not affected by SAHA. Our results suggest that surgery activates HDACs, which then reduces BDNF and dendritic arborization to develop POCD. Thus, epigenetic change contributes to the occurrence of POCD.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, Mark DB, Reves JG et al (2001) Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 344:395–402 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11172175
Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, Gravenstein JS (2008) Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 108:18–30 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18156878
Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS (2009) Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110:548–555 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19225398
Fan D, Li J, Zheng B, Hua L, Zuo Z (2016) Enriched environment attenuates surgery-induced impairment of learning, memory, and neurogenesis possibly by preserving BDNF expression. Mol Neurobiol 53:344–354 http://www.ncbi.nlm.nih.gov/pubmed/25432890
Gui L, Lei X, Zuo Z (2017) Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats. J Mol Med (Berl) 95:369–379 https://www.ncbi.nlm.nih.gov/pubmed/28213636
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 459:55–60 http://www.ncbi.nlm.nih.gov/pubmed/19424149
Penney J, Tsai LH (2014) Histone deacetylases in memory and cognition. Sci Signal 7:re12 http://www.ncbi.nlm.nih.gov/pubmed/25492968
Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70:304–322 http://www.ncbi.nlm.nih.gov/pubmed/20186705
Matthews T, Danese A, Wertz J, Odgers CL, Ambler A, Moffitt TE, Arseneault L (2016) Social isolation, loneliness and depression in young adulthood: a behavioural genetic analysis. Soc Psychiatry Psychiatr Epidemiol 51:339–348 https://www.ncbi.nlm.nih.gov/pubmed/26843197
Kokare DM, Dandekar MP, Singru PS, Gupta GL, Subhedar NK (2010) Involvement of alpha-MSH in the social isolation induced anxiety- and depression-like behaviors in rat. Neuropharmacol 58:1009–1018 https://www.ncbi.nlm.nih.gov/pubmed/20080115
Lin D, Cao L, Wang Z, Li J, Washington JM, Zuo Z (2012) Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats. Behav Brain Res 228:319–327 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22192381
Zheng B, Lai R, Li J, Zuo Z (2017) Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery. Brain Behav Immun 61:365–374 https://www.ncbi.nlm.nih.gov/pubmed/28089560
Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256:675–677 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1585183
Seo SK, Hwang CS, Choe TB, Hong SI, Yi JY, Hwang SG, Lee HG, Oh ST et al (2015) Selective inhibition of histone deacetylase 2 induces p53-dependent survivin downregulation through MDM2 proteasomal degradation. Oncotarget 6:26528–26540 http://www.ncbi.nlm.nih.gov/pubmed/25605253
Thiemann M, Oertel S, Ehemann V, Weichert W, Stenzinger A, Bischof M, Weber KJ, Perez RL et al (2012) In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model. Radiat Oncol 7:52 http://www.ncbi.nlm.nih.gov/pubmed/22458853
Feng C, Zuo Z (2012) Regulatory factor X1-induced down-regulation of transforming growth factor beta2 transcription in human neuroblastoma cells. J Biol Chem 287:22730–22739 http://www.ncbi.nlm.nih.gov/pubmed/22582395
Shan W, Li J, Xu W, Li H, Zuo Z (2019) Critical role of UQCRC1 in embryo survival, brain ischemic tolerance and normal cognition in mice. Cell Mol Life Sci 76:1381–1396 https://www.ncbi.nlm.nih.gov/pubmed/30666338
Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406 http://www.ncbi.nlm.nih.gov/pubmed/13117757
Zhao T, Li Y, Wei W, Savage S, Zhou L, Ma D (2014) Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring. Neurobiol Dis 68:145–155 http://www.ncbi.nlm.nih.gov/pubmed/24780497
Caetano SC, Silva CM, Vettore MV (2013) Gender differences in the association of perceived social support and social network with self-rated health status among older adults: a population-based study in Brazil. BMC Geriatr 13:122 http://www.ncbi.nlm.nih.gov/pubmed/24229389
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840 http://www.ncbi.nlm.nih.gov/pubmed/19608861
Fisher A (2000) Therapeutic strategies in Alzheimer’s disease: M1 muscarinic agonists. Jpn J Pharmacol 84:101–112 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11128032
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749 http://www.ncbi.nlm.nih.gov/pubmed/12429021
Morris MJ, Mahgoub M, Na ES, Pranav H, Monteggia LM (2013) Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. JNS 33:6401–6411 http://www.ncbi.nlm.nih.gov/pubmed/23575838
Hanson JE, Deng L, Hackos DH, Lo SC, Lauffer BE, Steiner P, Zhou Q (2013) Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons. JNS : the official journal of the Society for Neuroscience 33:5924–5929 http://www.ncbi.nlm.nih.gov/pubmed/23554474
Knutson DC, Mitzey AM, Talton LE, Clagett-Dame M (2016) Mice null for NEDD9 (HEF1alpha) display extensive hippocampal dendritic spine loss and cognitive impairment. Brain Res 1632:141–155 http://www.ncbi.nlm.nih.gov/pubmed/26683084
Gillani RL, Tsai SY, Wallace DG, O'Brien TE, Arhebamen E, Tole M, Schwab ME, Kartje GL (2010) Cognitive recovery in the aged rat after stroke and anti-Nogo-A immunotherapy. Beh Brain Res 208:415–424 http://www.ncbi.nlm.nih.gov/pubmed/20035795
Graff 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 483:222–226 https://www.ncbi.nlm.nih.gov/pubmed/22388814
Yamakawa H, Cheng J, Penney J, Gao F, Rueda R, Wang J, Yamakawa S, Kritskiy O et al (2017) The transcription factor Sp3 cooperates with HDAC2 to regulate synaptic function and plasticity in neurons. Cell Rep 20:1319–1334 https://www.ncbi.nlm.nih.gov/pubmed/28793257
Litke C, Bading H, Mauceri D (2018) Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D. J Biol Chem 293:8196–8207 https://www.ncbi.nlm.nih.gov/pubmed/29632070
Zhu X, Wang S, Yu L, Jin J, Ye X, Liu Y, Xu Y (2017) HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease. Aging Cell 16:1073–1082 https://www.ncbi.nlm.nih.gov/pubmed/28771976
Vigers AJ, Amin DS, Talley-Farnham T, Gorski JA, Xu B, Jones KR (2012) Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior. Neurosci 212:1–18 http://www.ncbi.nlm.nih.gov/pubmed/22542678
Kaneko M, Xie Y, An JJ, Stryker MP, Xu B (2012) Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation. JNS 32:4790–4802 http://www.ncbi.nlm.nih.gov/pubmed/22492034
Sengupta N, Seto E (2004) Regulation of histone deacetylase activities. J Cell Biochem 93:57–67 http://www.ncbi.nlm.nih.gov/pubmed/15352162
This study was supported by grants (GM098308, HD089999, AG061047, NS099118, and AG056995 to Z Zuo) from the National Institutes of Health, Bethesda, MD, and the Robert M. Epstein Professorship endowment, University of Virginia, Charlottesville, VA.
Conflict of Interest
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Luo, F., Min, J., Wu, J. et al. Histone Deacetylases May Mediate Surgery-Induced Impairment of Learning, Memory, and Dendritic Development. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-020-01987-2
- Dendritic arborization
- Epigenetic regulation
- Histone deacetylase