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Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Abstract

Purpose of Review

Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala.

Recent Findings

This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD.

Summary

Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.

    Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol. 2004;44:525–57.

  2. 2.

    Feder A, Nestler EJ, Charney DS. Psychobiology and molecular genetics of resilience. Nat Rev Neurosci. 2009;10:446–57.

  3. 3.

    Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10:434–45.

  4. 4.

    Liu XD, Liu PC, Santoro N, Thiele DJ. Conservation of a stress response: human heat shock transcription factors functionally substitute for yeast HSF. EMBO J. 1997;16:6466–77.

  5. 5.

    Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710.

  6. 6.

    Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–60.

  7. 7.

    Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B. PTSD and gene variants: new pathways and new thinking. Neuropharmacology. 2012;62:628–37.

  8. 8.

    Hauger RL, Olivares-Reyes JA, Dautzenberg FM, Lohr JB, Braun S, Oakley RH. Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology. 2012;62:705–14.

  9. 9.

    Gillespie CF, Phifer J, Bradley B, Ressler KJ. Risk and resilience: genetic and environmental influences on development of the stress response. Depress Anxiety. 2009;26:984–92.

  10. 10.

    Bauer MS, Altshuler L, Evans DR, Beresford T, Williford WO, Hauger R, et al. Prevalence and distinct correlates of anxiety, substance, and combined comorbidity in a multi-site public sector sample with bipolar disorder. J Affect Disord. 2005;85:301–15.

  11. 11.

    •• Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology. 2017;42:254–270. This reviews the current findings and future studies for understanding the role of pro- and anti-inflammatory signaling in PTSD pathophysiology.

  12. 12.

    Rasmusson AM, Schnurr PP, Zukowska Z, Scioli E, Forman DE. Adaptation to extreme stress: post-traumatic stress disorder, neuropeptide Y and metabolic syndrome. Exp Biol Med. 4 ed. 2010;235:1150–62.

  13. 13.

    Ahmadi N, Hajsadeghi F, Mirshkarlo HB, Budoff M, Yehuda R, Ebrahimi R. Post-traumatic stress disorder, coronary atherosclerosis, and mortality. Am J Cardiol. 2011;108:29–33.

  14. 14.

    Vaccarino V, Goldberg J, Rooks C, Shah AJ, Veledar E, Faber TL, et al. Post-traumatic stress disorder and incidence of coronary heart disease: a twin study. J Am Coll Cardiol. 2013;62:970–8.

  15. 15.

    Wolf EJ, Morrison FG. Traumatic stress and accelerated cellular aging: from epigenetics to cardiometabolic disease. Curr Psychiatry Rep. In Press

  16. 16.

    Cacciaglia R, Nees F, Grimm O, Ridder S, Pohlack ST, Diener SJ, et al. Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: implications for psychopathology. Psychoneuroendocrinology. 2017;76:19–28.

  17. 17.

    McEwen BS, Gianaros PJ. Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2011;62:431–45.

  18. 18.

    Weiss SJ. Neurobiological alterations associated with traumatic stress. Perspect Psychiatr Care. 2007;43:114–22.

  19. 19.

    Yehuda R, Flory JD, Pratchett LC, Buxbaum J, Ising M, Holsboer F. Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. Psychopharmacology. 2010;212:405–17.

  20. 20.

    Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259–84.

  21. 21.

    Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, et al. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry. 1999;156:585–8.

  22. 22.

    Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997;154:624–9.

  23. 23.

    Keen-Rhinehart E, Michopoulos V, Toufexis DJ, Martin EI, Nair H, Ressler KJ, et al. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol Psychiatry. 2009;14:37–50.

  24. 24.

    Risbrough VB, Hauger RL, Roberts AL, Vale WW, Geyer MA. Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci. 2004;24:6545–52.

  25. 25.

    Hauger RL, Risbrough V, Brauns O, Dautzenberg FM. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets. 2006;5:453–79.

  26. 26.

    Krishnan V, Han M-H, Mazei-Robison M, Iñiguez SD, Ables JL, Vialou V, et al. AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli. Biol Psychiatry. 2008;64:691–700.

  27. 27.

    Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel J, et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch Gen Psychiatry. 2011;68:901–10.

  28. 28.

    Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34(Suppl 1):S186–95.

  29. 29.

    Bremner D, Vermetten E, Kelley ME. Cortisol, dehydroepiandrosterone, and estradiol measured over 24 hours in women with childhood sexual abuse-related posttraumatic stress disorder. J Nerv Ment Dis. 2007;195:919–27.

  30. 30.

    Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol Psychiatry. 2009;66:708–11.

  31. 31.

    Meewisse M-L, Reitsma JB, de Vries G-J, Gersons BPR, Olff M. Cortisol and post-traumatic stress disorder in adults: systematic review and meta-analysis. Br J Psychiatry. 2007;191:387–92.

  32. 32.

    Bachmann AW, Sedgley TL, Jackson RV, Gibson JN, Young RM, Torpy DJ. Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology. 2005;30:297–306.

  33. 33.

    Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci. 2000;20:6225–31.

  34. 34.

    Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature. 2002;420:70–4.

  35. 35.

    Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004;43:897–905.

  36. 36.

    Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry. 2007;62:446–54.

  37. 37.

    Wilensky AE, Schafe GE, Kristensen MP, LeDoux JE. Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J Neurosci. 2006;26:12387–96.

  38. 38.

    Ciocchi S, Herry C, Grenier F, Wolff SBE, Letzkus JJ, Vlachos I, et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature. 2010;468:277–82.

  39. 39.

    Haubensak W, Kunwar PS, Cai H, Ciocchi S, Wall NR, Ponnusamy R, et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature. 2010;468:270–6.

  40. 40.

    Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88.

  41. 41.

    Corcoran KA, Desmond TJ, Frey KA, Maren S. Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J Neurosci. 2005;25:8978–87.

  42. 42.

    Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007;12:656–70.

  43. 43.

    Stevens JS, Kim YJ, Galatzer-Levy IR, Reddy R, Ely TD, Nemeroff CB, et al. Amygdala reactivity and anterior cingulate habituation predict posttraumatic stress disorder symptom maintenance after acute civilian trauma. Biol Psychiatry. 2017;81:1023–9.

  44. 44.

    Stefanacci L, Amaral DG. Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study. J Comp Neurol. 2002;451:301–23.

  45. 45.

    Koenigs M, Grafman J. Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala. Neuroscientist. 2009;15:540–8.

  46. 46.

    LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron. 1998;20:937–45.

  47. 47.

    Cheng DT, Knight DC, Smith CN, Helmstetter FJ. Human amygdala activity during the expression of fear responses. Behav Neurosci. 2006;120:1187–95.

  48. 48.

    Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90.

  49. 49.

    Milad MR, Rauch SL, Pitman RK, Quirk GJ. Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol. 2006;73:61–71.

  50. 50.

    Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatry. 2006;60:376–82.

  51. 51.

    Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006;1071:67–79.

  52. 52.

    Bremner JD. Neuroimaging in posttraumatic stress disorder and other stress-related disorders. Neuroimaging Clin N Am. 2007;17:523–38–ix.

  53. 53.

    Koenigs M, Huey ED, Raymont V, Cheon B, Solomon J, Wassermann EM, et al. Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nat Neurosci. 2008;11:232–7.

  54. 54.

    Raymont V, Greathouse A, Reding K, Lipsky R, Salazar A, Grafman J. Demographic, structural and genetic predictors of late cognitive decline after penetrating head injury. Brain. 2008;131:543–58.

  55. 55.

    Laurent V, Westbrook RF. Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. Learn Mem. 2009;16:520–9.

  56. 56.

    Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology. 2011;36:529–38.

  57. 57.

    Li JZ, Vawter MP, Walsh DM, Tomita H, Evans SJ, Choudary PV, et al. Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Hum Mol Genet. 2004;13:609–16.

  58. 58.

    Friedman MJ, Huber BR, Brady CB, Ursano RJ, Benedek DM, Kowall NW, et al. VA’s National PTSD Brain Bank: A national Resource for Research. Curr Psychiatry Reports. In Press.

  59. 59.

    •• Zhang L, Li H, Su TP, Barker JL, Maric D, Fullerton CS, et al. p11 is up-regulated in the forebrain of stressed rats by glucocorticoid acting via two specific glucocorticoid response elements in the p11 promoter. Neuroscience. 2008;153:1126–34. This was the first study to examine gene expression changes in PTSD postmortem brain. They identified the cell cycle regulator p11 as upregulated in PTSD dorsolateral PFC.

  60. 60.

    Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, Yacoubi El M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80.

  61. 61.

    •• Licznerski P, Duric V, Banasr M, Alavian KN, Ota KT, Kang HJ, et al. Decreased SGK1 expression and function contributes to behavioral deficits induced by traumatic stress. Ressler K, editor. PLoS Biol. 2015;13:e1002282. This is the first multi-transcript study examining gene expression changes in PTSD dorsolateral prefrontal cortex.

  62. 62.

    Anacker C, Cattaneo A, Musaelyan K, Zunszain PA, Horowitz M, Molteni R, et al. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2013;110:8708–13.

  63. 63.

    Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, et al. Traumatic Stress Brain Study Group Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence PNAS 2017;114;(31):8390–8395.

  64. 64.

    Schulz B, Fendt M, Gasparini F, Lingenhöhl K, Kuhn R, Koch M. The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology. 2001;41:1–7.

  65. 65.

    Tronson NC, Guzman YF, Guedea AL, Huh KH, Gao C, Schwarz MK, et al. Metabotropic glutamate receptor 5/Homer interactions underlie stress effects on fear. Biol Psychiatry Elsevier Inc. 2010;68:1007–15.

  66. 66.

    Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, et al. Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children. Mol Psychiatry. 2005;10:1058–9.

  67. 67.

    Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291–305.

  68. 68.

    Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology. 2010;35:1684–92.

  69. 69.

    Watkins LE, Han S, Harpaz-Rotem I, Mota NP, Southwick SM, Krystal JH, et al. FKBP5 polymorphisms, childhood abuse, and PTSD symptoms: results from the National Health and Resilience in Veterans Study. Psychoneuroendocrinology. 2016;69:98–105.

  70. 70.

    Mohlenhoff BS, O'Donovan A, Weiner MW, Neylan TC. Inflammation, sleep, and dementia risk in posttraumatic stress disorder: a review. Curr Psychiatry Rep. In Press.

  71. 71.

    Pace TWW, Wingenfeld K, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim CM. Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder. Brain Behav Immun. 2012;26:13–7.

  72. 72.

    Zieker J, Zieker D, Jatzko A, Dietzsch J, Nieselt K, Schmitt A, et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol Psychiatry. 2007;12:116–8.

  73. 73.

    Neylan TC, Sun B, Rempel H, Ross J, Lenoci M, O'Donovan A, et al. Suppressed monocyte gene expression profile in men versus women with PTSD. Brain Behav Immun. 2011;25:524–31.

  74. 74.

    Sarapas C, Cai G, Bierer LM, Golier JA, Galea S, Ising M, et al. Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks. Dis Markers. 2011;30:101–10.

  75. 75.

    van Zuiden M, Geuze E, Willemen HLDM, Vermetten E, Maas M, Amarouchi K, et al. Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study. Biol Psychiatry. 2012;71:309–16.

  76. 76.

    Wingo AP, Almli LM, Stevens JS, Stevens JJ, Klengel T, Uddin M, et al. DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat Commun. 2015;6:10106.

  77. 77.

    •• Bharadwaj RA, Jaffe AE, Chen Q, Deep-Soboslay A, Goldman AL, Mighdoll MI, et al. Genetic risk mechanisms of posttraumatic stress disorder in the human brain. J Neurosci Res. 2016. https://doi.org/10.1002/jnr.23957 .This paper used RNA-seq to test for association of gene transcription in control dorsolateral PFC with several positive and candidate risk alleles for PTSD.

  78. 78.

    Seligman ME, Maier SF. Failure to escape traumatic shock. J Exp Psychol. 1967;74:1–9.

  79. 79.

    Armario A, Escorihuela RM, Nadal R. Long-term neuroendocrine and behavioural effects of a single exposure to stress in adult animals. Neurosci Biobehav Rev. 2008;32:1121–35.

  80. 80.

    •• Baratta MV, Christianson JP, Gomez DM, Zarza CM, Amat J, Masini CV, et al. Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear. Neuroscience. 2007;146:1495–503. This study comprehensively assess the role of stressor controllability and prefrontal cortex activity in development of aberrant fear behavior associated with PTSD.

  81. 81.

    Belda X, Márquez C, Armario A. Long-term effects of a single exposure to stress in adult rats on behavior and hypothalamic-pituitary-adrenal responsiveness: comparison of two outbred rat strains. Behav Brain Res. 2004;154:399–408.

  82. 82.

    Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8:365–71.

  83. 83.

    Amat J, Paul E, Zarza C, Watkins LR, Maier SF. Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci. 2006;26:13264–72.

  84. 84.

    Baratta MV, Zarza CM, Gomez DM, Campeau S, Watkins LR, Maier SF. Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress. Eur J Neurosci. 2009;30:1111–6.

  85. 85.

    Amat J, Dolzani SD, Tilden S, Christianson JP, Kubala KH, Bartholomay K, et al. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J Neurosci. 2016;36:153–61.

  86. 86.

    Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology. 1997;22:443–53.

  87. 87.

    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.

  88. 88.

    McFarlane AC, Barton CA, Yehuda R, Wittert G. Cortisol response to acute trauma and risk of posttraumatic stress disorder. Psychoneuroendocrinology. 2011;36:720–7.

  89. 89.

    Yehuda R, Boisoneau D, Lowy MT, Giller EL. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry. 1995;52:583–93.

  90. 90.

    Yehuda R, Golier JA, Halligan SL, Meaney M, Bierer LM. The ACTH response to dexamethasone in PTSD. Am J Psychiatry. 2004;161:1397–403.

  91. 91.

    Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab. 2006;291:E965–73.

  92. 92.

    Khan S, Liberzon I. Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology. 2004;172:225–9.

  93. 93.

    Yamamoto S, Morinobu S, Takei S, Fuchikami M, Matsuki A, Yamawaki S, et al. Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety. 2009;26:1110–7.

  94. 94.

    Takahashi T, Morinobu S, Iwamoto Y, Yamawaki S. Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psychopharmacology. 2006;189:165–73.

  95. 95.

    Yamamoto S, Morinobu S, Fuchikami M, Kurata A, Kozuru T, Yamawaki S. Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology. 2008;33:2108–16.

  96. 96.

    Perrine SA, Eagle AL, George SA, Mulo K, Kohler RJ, Gerard J, et al. Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress. Behav Brain Res. 2016;303:228–37.

  97. 97.

    Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, et al Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012;13:769–787.

  98. 98.

    Girgenti MJ, Ghosal S, Lopresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiol Dis. 2016;100:1–8.

  99. 99.

    Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of intravenous ketamine for treatment of chronic post-traumatic stress disorder: A randomized clinical trial. JAMA Psychiatry 2014;71:681.

  100. 100.

    Krystal JH, Abdallah CG, Averill LA, Kelmendi B, Harpaz-Rotem I, Sanacora G, et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Curr Psychiatry Rep. 2017;19:74.

  101. 101.

    Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18:1926–45.

  102. 102.

    Blanchard DC, Griebel G, Blanchard RJ. Conditioning and residual emotionality effects of predator stimuli: some reflections on stress and emotion. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27:1177–85.

  103. 103.

    Adamec R, Head D, Blundell J, Burton P, Berton O. Lasting anxiogenic effects of feline predator stress in mice: sex differences in vulnerability to stress and predicting severity of anxiogenic response from the stress experience. Physiol Behav. 2006;88:12–29.

  104. 104.

    Cohen H, Zohar J, Gidron Y, Matar MA, Belkind D, Loewenthal U, et al. Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats. Biol Psychiatry. 2006;59:1208–18.

  105. 105.

    Goswami S, Cascardi M, Rodríguez-Sierra OE, Duvarci S, Paré D. Impact of predatory threat on fear extinction in Lewis rats. Learn Mem. 2010;17:494–501.

  106. 106.

    Goswami S, Samuel S, Sierra OR, Cascardi M, Paré D. A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome. Front Behav Neurosci. 2012;6:26.

  107. 107.

    Yehuda R, McFarlane AC, Shalev AY. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol Psychiatry. 1998;44:1305–13.

  108. 108.

    Moore NLT, Gauchan S, Genovese RF. Differential severity of anxiogenic effects resulting from a brief swim or underwater trauma in adolescent male rats. Pharmacol Biochem Behav. 2012;102:264–8.

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Acknowledgements

Dr. Duman receives grant support from the National Institute of Mental Health, the VA National Center for PTSD, the VA National PTSD Brain Bank, and the Connecticut Mental Health Center. Dr. Girgenti receives grant support from the National Institute on Drug Abuse through the Yale Neuroproteomics Center.

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Correspondence to Ronald S. Duman.

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Matthew J. Girgenti, Brendan D. Hare, and Sriparna Ghosal declare that they have no conflict of interest.

Ronald S. Duman has consulted and/or received research support from Naurex, Lilly, Forest, Johnson & Johnson, Taisho, and Sunovion.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

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Girgenti, M.J., Hare, B.D., Ghosal, S. et al. Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD. Curr Psychiatry Rep 19, 85 (2017). https://doi.org/10.1007/s11920-017-0841-3

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Keywords

  • PTSD
  • Transcriptomics
  • Genomics
  • Glucocorticoid signaling
  • Prefrontal cortex
  • Animal models of PTSD