Download PDF
CC BY 4.0 · Glob Med Genet 2022; 09(01): 007-013
DOI: 10.1055/s-0041-1736633
Review Article

Epigenetic Approach to PTSD: In the Aspects of Rat Models

Asli Aykac
1   Department of Biophysics, Faculty of Medicine, Near East University, Nicosia, Cyprus
,
Rasime Kalkan
2   Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Near East University, Nicosia, Cyprus
3   Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus
› Author Affiliations Funding None.
› Further Information
   Permissions and Reprints

Abstract

Posttraumatic stress disorder (PTSD) is a stress-related mental disorder and develops after exposure to life-threatening traumatic experiences. The risk factors of PTSD included genetic factors; alterations in hypothalamic–pituitary–adrenal (HPA) axis; neurotrophic, serotonergic, dopaminergic, and catecholaminergic systems; and a variety of environmental factors, such as war, accident, natural disaster, pandemic, physical, or sexual abuse, that cause stress or trauma in individuals. To be able to understand the molecular background of PTSD, rodent animal models are widely used by researchers. When looking for a solution for PTSD, it is important to consider preexisting genetic risk factors and physiological, molecular, and biochemical processes caused by trauma that may cause susceptibility to this disorder. In studies, it is reported that epigenetic mechanisms play important roles in the biological response affected by environmental factors, as well as the task of programming cell identity. In this article, we provided an overview of the role of epigenetic modifications in understanding the biology of PTSD. We also summarized the data from animal studies and their importance during the investigation of PTSD. This study shed light on the epigenetic background of stress and PTSD.

Keywords

PTSD - epigenetics - methylation - rat studies


Publication History

Received: 11 August 2021

Accepted: 18 September 2021

Article published online:
11 November 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Gradus JL, Qin P, Lincoln AK. et al. Posttraumatic stress disorder and completed suicide. Am J Epidemiol 2010; 171 (06) 721-727
    CrossrefPubMedGoogle Scholar
  • 2 Forte G, Favieri F, Tambelli R, Casagrande M. COVID-19 pandemic in the Italian population: validation of a post-traumatic stress disorder questionnaire and prevalence of PTSD symptomatology. Int J Environ Res Public Health 2020; 17 (11) 4151-4164
    CrossrefPubMedGoogle Scholar
  • 3 Hossack MR, Reid MW, Aden JK, Gibbons T, Noe JC, Willis AM. Adverse childhood experience, genes, and PTSD risk in soldiers: a methylation study. Mil Med 2020; 185 (3-4): 377-384
    CrossrefPubMedGoogle Scholar
  • 4 Zoladz PR, Diamond DM. Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis. Exp Neurol 2016; 284 (pt. B): 211-219
    CrossrefPubMedGoogle Scholar
  • 5 Voisey J, Young RM, Lawford BR, Morris CP. Progress towards understanding the genetics of posttraumatic stress disorder. J Anxiety Disord 2014; 28 (08) 873-883
    CrossrefPubMedGoogle Scholar
  • 6 Solomon Z, Mikulincer M. Trajectories of PTSD: a 20-year longitudinal study. Am J Psychiatry 2006; 163 (04) 659-666
    CrossrefPubMedGoogle Scholar
  • 7 Borghans B, Homberg JR. Animal models for posttraumatic stress disorder: An overview of what is used in research. World J Psychiatry 2015; 5 (04) 387-396
    CrossrefPubMedGoogle Scholar
  • 8 Warren BL, Vialou VF, Iñiguez SD. et al. Neurobiological sequelae of witnessing stressful events in adult mice. Biol Psychiatry 2013; 73 (01) 7-14
    CrossrefPubMedGoogle Scholar
  • 9 Antelman SM. Time-dependent sensitization as the cornerstone for a new approach to pharmacotherapy - drugs as foreign stressful stimuli. Drug Dev Res 1988; 14: 1-30
    CrossrefGoogle Scholar
  • 10 Louvart H, Maccari S, Ducrocq F, Thomas P, Darnaudéry M. Long-term behavioural alterations in female rats after a single intense footshock followed by situational reminders. Psychoneuroendocrinology 2005; 30 (04) 316-324
    CrossrefPubMedGoogle Scholar
  • 11 Pawlyk AC, Jha SK, Brennan FX, Morrison AR, Ross RJ. A rodent model of sleep disturbances in posttraumatic stress disorder: the role of context after fear conditioning. Biol Psychiatry 2005; 57 (03) 268-277
    CrossrefPubMedGoogle Scholar
  • 12 Rau V, Fanselow MS. Exposure to a stressor produces a long lasting enhancement of fear learning in rats. Stress 2009; 12 (02) 125-133
    CrossrefPubMedGoogle Scholar
  • 13 Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 1997; 22 (06) 443-453
    CrossrefPubMedGoogle Scholar
  • 14 Balkaya M, Prinz V, Custodis F. et al. Stress worsens endothelial function and ischemic stroke via glucocorticoids. Stroke 2011; 42 (11) 3258-3264
    CrossrefPubMedGoogle Scholar
  • 15 Zoladz PR, Conrad CD, Fleshner M, Diamond DM. Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress 2008; 11 (04) 259-281
    CrossrefPubMedGoogle Scholar
  • 16 Kim HG, Harrison PA, Godecker AL, Muzyka CN. Posttraumatic stress disorder among women receiving prenatal care at three federally qualified health care centers. Matern Child Health J 2014; 18 (05) 1056-1065
    CrossrefPubMedGoogle Scholar
  • 17 Zoladz PR, Fleshner M, Diamond DM. Psychosocial animal model of PTSD produces a long-lasting traumatic memory, an increase in general anxiety and PTSD-like glucocorticoid abnormalities. Psychoneuroendocrinology 2012; 37 (09) 1531-1545
    CrossrefPubMedGoogle Scholar
  • 18 Blanchard RJ, Blanchard DC, Rodgers J, Weiss SM. The characterization and modelling of antipredator defensive behavior. Neurosci Biobehav Rev 1990; 14 (04) 463-472
    CrossrefPubMedGoogle Scholar
  • 19 Apfelbach R, Blanchard CD, Blanchard RJ, Hayes RA, McGregor IS. The effects of predator odors in mammalian prey species: a review of field and laboratory studies. Neurosci Biobehav Rev 2005; 29 (08) 1123-1144
    CrossrefPubMedGoogle Scholar
  • 20 Cohen H, Geva AB, Matar MA, Zohar J, Kaplan Z. Post-traumatic stress behavioural responses in inbred mouse strains: can genetic predisposition explain phenotypic vulnerability?. Int J Neuropsychopharmacol 2008; 11 (03) 331-349
    CrossrefPubMedGoogle Scholar
  • 21 Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. Neurosci Biobehav Rev 2016; 71: 48-57
    CrossrefPubMedGoogle Scholar
  • 22 Zovkic IB, Sweatt JD. Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 2013; 38 (01) 77-93
    CrossrefPubMedGoogle Scholar
  • 23 Kwapis JL, Wood MA. Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci 2014; 37 (12) 706-720
    CrossrefPubMedGoogle Scholar
  • 24 Saavedra-Rodríguez L, Feig LA. Chronic social instability induces anxiety and defective social interactions across generations. Biol Psychiatry 2013; 73 (01) 44-53
    CrossrefPubMedGoogle Scholar
  • 25 Imanaka A, Morinobu S, Toki S, Yamawaki S. Importance of early environment in the development of post-traumatic stress disorder-like behaviors. Behav Brain Res 2006; 173 (01) 129-137
    CrossrefPubMedGoogle Scholar
  • 26 Cloitre M, Stolbach BC, Herman JL. et al. A developmental approach to complex PTSD: childhood and adult cumulative trauma as predictors of symptom complexity. J Trauma Stress 2009; 22 (05) 399-408
    CrossrefPubMedGoogle Scholar
  • 27 Pulliam JV, Dawaghreh AM, Alema-Mensah E, Plotsky PM. Social defeat stress produces prolonged alterations in acoustic startle and body weight gain in male Long Evans rats. J Psychiatr Res 2010; 44 (02) 106-111
    CrossrefPubMedGoogle Scholar
  • 28 Yang R, Daigle Jr. BJ, Muhie SY. et al. Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder. BMC Syst Biol 2013; 7: 80
    CrossrefPubMedGoogle Scholar
  • 29 Ursano RJ, Li H, Zhang L. et al. Models of PTSD and traumatic stress: the importance of research “from bedside to bench to bedside”. Prog Brain Res 2008; 167: 203-215
    CrossrefPubMedGoogle Scholar
  • 30 Yehuda R, Hoge CW, McFarlane AC. et al. Post-traumatic stress disorder. Nat Rev Dis Primers 2015; 1: 15057
    CrossrefPubMedGoogle Scholar
  • 31 Frielingsdorf H, Bath KG, Soliman F, Difede J, Casey BJ, Lee FS. Variant brain-derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder. Ann N Y Acad Sci 2010; 1208: 150-157
    CrossrefPubMedGoogle Scholar
  • 32 Matsuoka Y, Nishi D, Noguchi H, Kim Y, Hashimoto K. Longitudinal changes in serum brain-derived neurotrophic factor in accident survivors with posttraumatic stress disorder. Neuropsychobiology 2013; 68 (01) 44-50
    CrossrefPubMedGoogle Scholar
  • 33 Maddox SA, Watts CS, Doyère V, Schafe GE. A naturally-occurring histone acetyltransferase inhibitor derived from Garcinia indica impairs newly acquired and reactivated fear memories. PLoS One 2013; 8 (01) e54463
    CrossrefPubMedGoogle Scholar
  • 34 Sartor CE, McCutcheon VV, Pommer NE. et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychol Med 2012; 41 (07) 1497-1505
    CrossrefPubMedGoogle Scholar
  • 35 Leen-Feldner EW, Feldner MT, Knapp A, Bunaciu L, Blumenthal H, Amstadter AB. Offspring psychological and biological correlates of parental posttraumatic stress: review of the literature and research agenda. Clin Psychol Rev 2013; 33 (08) 1106-1133
    CrossrefPubMedGoogle Scholar
  • 36 Lambert JE, Holzer J, Hasbun A. Association between parents' PTSD severity and children's psychological distress: a meta-analysis. J Trauma Stress 2014; 27 (01) 9-17
    CrossrefPubMedGoogle Scholar
  • 37 Basavarajappa BS, Subbanna S. Histone methylation regulation in neurodegenerative disorders. Int J Mol Sci 2021; 22 (09) 4654-4681.
    CrossrefPubMedGoogle Scholar
  • 38 Lubin FD, Sweatt JD. The IkappaB kinase regulates chromatin structure during reconsolidation of conditioned fear memories. Neuron 2007; 55 (06) 942-957
    CrossrefPubMedGoogle Scholar
  • 39 Maddox SA, Schafe GE. Epigenetic alterations in the lateral amygdala are required for reconsolidation of a Pavlovian fear memory. Learn Mem 2011; 18 (09) 579-593
    CrossrefPubMedGoogle Scholar
  • 40 Maddox SA, Watts CS, Schafe GE. p300/CBP histone acetyltransferase activity is required for newly acquired and reactivated fear memories in the lateral amygdala. Learn Mem 2013; 20 (02) 109-119
    CrossrefPubMedGoogle Scholar
  • 41 Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM. Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 2012; 72 (01) 25-33
    CrossrefPubMedGoogle Scholar
  • 42 Webb WM, Sanchez RG, Perez G. et al. Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory. Neurobiol Learn Mem 2017; 142 (pt. A): 66-78
    CrossrefPubMedGoogle Scholar
  • 43 Takei S, Morinobu S, Yamamoto S, Fuchikami M, Matsumoto T, Yamawaki S. Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder. J Psychiatr Res 2011; 45 (04) 460-468
    CrossrefPubMedGoogle Scholar
  • 44 Lee JB, Wei J, Liu W, Cheng J, Feng J, Yan Z. Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex. J Physiol 2012; 590 (07) 1535-1546
    CrossrefPubMedGoogle Scholar
  • 45 Blouin AM, Sillivan SE, Joseph NF, Miller CA. The potential of epigenetics in stress-enhanced fear learning models of PTSD. Learn Mem 2016; 23 (10) 576-586
    CrossrefPubMedGoogle Scholar
  • 46 Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy?. Genes Cancer 2011; 2 (06) 607-617
    CrossrefPubMedGoogle Scholar
  • 47 Khare T, Pai S, Koncevicius K. et al. 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nat Struct Mol Biol 2012; 19 (10) 1037-1043
    CrossrefPubMedGoogle Scholar
  • 48 Mehta D, Bruenig D, Carrillo-Roa T. et al. Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD. Acta Psychiatr Scand 2017; 136 (05) 493-505
    CrossrefPubMedGoogle Scholar
  • 49 Logue MW, Amstadter AB, Baker DG. et al. The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology 2015; 40 (10) 2287-2297
    CrossrefPubMedGoogle Scholar
  • 50 Almli LM, Stevens JS, Smith AK. et al. A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am J Med Genet B Neuropsychiatr Genet 2015; 8: 327-336
    CrossrefPubMedGoogle Scholar
  • 51 Xie P, Kranzler HR, Yang C, Zhao H, Farrer LA, Gelernter J. Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder. Biol Psychiatry 2013; 74 (09) 656-663
    CrossrefPubMedGoogle Scholar
  • 52 Duncan LE, Ratanatharathorn A, Aiello AE. et al. Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry 2018; 23 (03) 666-673
    CrossrefPubMedGoogle Scholar
  • 53 Ashley-Koch AE, Garrett ME, Gibson J. et al; Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup. Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans. J Affect Disord 2015; 184 (184) 225-234
    CrossrefPubMedGoogle Scholar
  • 54 Kilaru V, Iyer SV, Almli LM. et al. Genome-wide gene-based analysis suggests an association between neuroligin 1 (NLGN1) and post-traumatic stress disorder. Transl Psychiatry 2016; 6 (05) e820
    CrossrefPubMedGoogle Scholar
  • 55 Gelernter J, Sun N, Polimanti R. et al; Department of Veterans Affairs Cooperative Studies Program (#575B) and Million Veteran Program. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat Neurosci 2019; 22 (09) 1394-1401
    CrossrefPubMedGoogle Scholar
  • 56 Rutten BPF, Vermetten E, Vinkers CH. et al. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol Psychiatry 2018; 23 (05) 1145-1156
    CrossrefPubMedGoogle Scholar
  • 57 Hammamieh R, Chakraborty N, Gautam A. et al. Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans. Transl Psychiatry 2017; 7 (07) e1169
    CrossrefPubMedGoogle Scholar
  • 58 van Dongen J, Slagboom PE, Draisma HHM, Martin NG, Boomsma DI. The continuing value of twin studies in the omics era. Nat Rev Genet 2012; 13 (09) 640-653
    CrossrefPubMedGoogle Scholar
  • 59 Zhang TY, Labonté B, Wen XL, Turecki G, Meaney MJ. Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology 2013; 38 (01) 111-123
    CrossrefPubMedGoogle Scholar
  • 60 Klengel T, Mehta D, Anacker C. et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 2013; 16 (01) 33-41
    CrossrefPubMedGoogle Scholar
  • 61 Li X, Wei W, Zhao QY. et al. Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc Natl Acad Sci U S A 2014; 111 (19) 7120-7125
    CrossrefPubMedGoogle Scholar
  • 62 Kim GS, Smith AK, Nievergelt CM, Uddin M. Neuroepigenetics of Post-Traumatic Stress Disorder. Prog Mol Biol Transl Sci 2018; 158: 227-253
    CrossrefPubMedGoogle Scholar
  • 63 Roth TL, Zoladz PR, Sweatt JD, Diamond DM. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J Psychiatr Res 2011; 45 (07) 919-926
    CrossrefPubMedGoogle Scholar
  • 64 Gillespie CF, Bradley B, Mercer K. et al. Trauma exposure and stress-related disorders in inner city primary care patients. Gen Hosp Psychiatry 2009; 31 (06) 505-514
    CrossrefPubMedGoogle Scholar
  • 65 de Quervain DJ, Aerni A, Schelling G, Roozendaal B. Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol 2009; 30 (03) 358-370
    CrossrefPubMedGoogle Scholar
  • 66 Yehuda R, Daskalakis NP, Desarnaud F. et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry 2013; 4: 118
    CrossrefPubMedGoogle Scholar
  • 67 Collins LJ, Schönfeld B, Chen XS. The epigenetics of non-coding RNA. In: Tollefsbol T. ed. Handbook of Epigenetics. San Diego, CA: Academic Press; 2011: 49-61
    CrossrefGoogle Scholar
  • 68 Qureshi IA, Mehler MF. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci 2012; 13 (08) 528-541
    CrossrefPubMedGoogle Scholar
  • 69 Daskalakis NP, Rijal CM, King C, Huckins LM, Ressler KJ. Recent genetics and epigenetics approaches to PTSD. Curr Psychiatry Rep 2018; 20 (05) 30
    CrossrefPubMedGoogle Scholar
  • 70 Ambeskovic M, Babenko O, Ilnytskyy Y, Kovalchuk I, Kolb B, Metz GAS. Ancestral stress alters lifetime mental health trajectories and cortical neuromorphology via epigenetic regulation. Sci Rep 2019; 9 (01) 6389
    CrossrefPubMedGoogle Scholar
  • 71 Maurel OM, Torrisi SA, Barbagallo C. et al. Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p is associated with modulation of BDNF and FKBP5 in brain areas of PTSD-related susceptible and resilient mice. Int J Mol Sci 2021; 22 (10) 5157-5177
    CrossrefPubMedGoogle Scholar
  • 72 Li C, Liu Y, Liu D, Jiang H, Pan F. Dynamic alterations of miR-34c expression in the hypothalamus of male rats after early adolescent traumatic stress. Neural Plast 2016; 2016: 5249893
    PubMedGoogle Scholar
  • 73 Kang JI, Kim TY, Choi JH, So HS, Kim SJ. Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder. Psychoneuroendocrinology 2019; 103: 1-7
    CrossrefPubMedGoogle Scholar