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Under a Creative Commons license Open access AbstractPost-traumatic stress disorder (PTSD) is a severe, long-term psychological disorder triggered by distressing events. The neural basis and underlying mechanisms of PTSD are not completely understood. Therefore, it is important to determine the pathology of PTSD using reliable animal models that mimic the symptoms of patients. However, the lack of evidence on the clinical relevance of PTSD animal models makes it difficult to interpret preclinical studies from a translational perspective. In this study, we performed a comprehensive screening of the behavioral, neuronal, glial, and electroencephalographic (EEG) profiles in the single prolonged stress and electric foot shock (SPS&S) mouse model. Based on the clinical features of PTSD, we observed fearful and excessive responses to trauma-related environments in the SPS&S mouse model that lasted longer than 14 days. The mice exhibited a defective and strong resistance to the extinction of fear memories caused by auditory cues and also showed enhanced innate fear induced by visual stimuli with concomitant phobias and anxiety. Furthermore, neurons, astrocytes, and microglia in PTSD-related brain regions were activated, supporting abnormal brain activation and neuroimmune changes. EEG assessment also revealed decreased power and impaired coupling strength between cortical regions. These results demonstrated that the SPS&S mouse model recapitulates the behavioral symptoms as well as neural and EEG profiles of PTSD patients, justifying the preclinical use of this mouse model. KeywordsPost-traumatic stress disorder Mouse model Mouse behavior Electroencephalography Data availabilityData will be made available on request. Cited by (0)© 2021 The Authors. Published by Elsevier Inc.
SummaryTranslational research on post-traumatic stress disorder (PTSD) has produced limited improvements in clinical practice. Fear conditioning (FC) is one of the dominant animal models of PTSD. In fact, FC is used in many different ways to model PTSD. The variety of FC-based models is ill defined, creating confusion and conceptual vagueness, which in turn impedes translation into the clinic. This article takes a historical and conceptual approach to provide a comprehensive picture of current research and help reorient the research focus. This work historically reviews the variety of models that have emerged from the initial association of PTSD with FC, highlighting conceptual pitfalls that have limited the translation of animal research into clinical advances. We then provide some guidance on how future translational research could benefit from conceptual and technological improvements to translate basic findings in patients. This objective will require transdisciplinary approaches and should involve physicians, engineers, philosophers, and neuroscientists. Cited by (0)© 2021 Elsevier Inc. Crocq MA, Crocq L. From shell shock and war neurosis to posttraumatic stress disorder: a history of psychotraumatology. Dialog Clin Neurosci. 2000;2:47–55. Article CAS Google Scholar Karam EG, Andrews G, Bromet E, Petukhova M, Ruscio AM, Salamoun M, et al. The role of Criterion A2 in the DSM-IV diagnosis of post-traumatic stress disorder. Biol Psychiatry. 2009;68:465–73. Article Google Scholar Steel Z, Chey T, Silove D, Marnane C, Bryant RA, van Ommeren M. Association of torture and other potentially traumatic events with mental health outcomes among populations exposed to mass conflict and displacement: a systematic review and meta-analysis. JAMA. 2009;302:537–49. Article CAS PubMed Google Scholar Brunello N, Davidson JR, Deahl M, Kessler RC, Mendlewicz J, Racagni G, et al. Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment. Neuropsychobiology. 2001;43:150–62. Article CAS PubMed Google Scholar Van der Kolk BA, Pelcovitz D, Roth S, Mandel FS, McFarlane A, Herman JL. Dissociation, somatization, and affect dysregulation: the complexity of adaptation to trauma. Am J Psychiatry. 1997;153:83–93. Google Scholar Guina J, Baker M, Stinson K, Maust J, Coles J, Broderick P. Should posttraumatic stress be a disorder or a specifier? Towards improved nosology within the DSM categorical classification system. Curr Psychiatry Rep. 2017;19:66. Article PubMed Google Scholar Stein JY, Wilmot DV, Solomon Z. Does one size fit all? Nosological, clinical, and scientific implications of variations in PTSD Criterion A. J Anxiety Disord. 2016;43:106–17. Article PubMed Google Scholar Mello PG, Silva GR, Donat JC, Kristensen CH. An update on the efficacy of cognitive-behavioral therapy, cognitive therapy, and exposure therapy for posttraumatic stress disorder. Int J Psychiatry Med. 2013;46:339–57. Article PubMed Google Scholar Kaczkurkin AN, Foa EB. Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence. Dialog Clin Neurosci. 2015;17:337–46. Article Google Scholar Kar N. Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review. Neuropsychiatr Dis Treat. 2011;7:167–81. Article PubMed PubMed Central Google Scholar Kozaric-Kovacic D. Psychopharmacotherapy of posttraumatic stress disorder. Croat Med J. 2008;49:459–75. Article CAS PubMed PubMed Central Google Scholar Ragen BJ, Seidel J, Chollak C, Pietrzak RH, Neumeister A. Investigational drugs under development for the treatment of PTSD. Expert Opin Investig Drugs. 2015;24:659–72. Article CAS PubMed Google Scholar Murrough JW, Charney DS. Is there anything really novel on the antidepressant horizon? Curr Psychiatry Rep. 2012;14:643–9. Article PubMed PubMed Central Google Scholar Hoskins M, Pearce J, Bethell A, Dankova L, Barbui C, Tol WA, et al. Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry. 2015;206:93–100. Article PubMed Google Scholar Papassotiropoulos A, de Quervain DJ. Failed drug discovery in psychiatry: time for human genome-guided solutions. Trends Cogn Sci. 2015;19:183–7. Article PubMed Google Scholar Insel TR. Next-generation treatments for mental disorders. Sci Transl Med. 2012;4:155ps19. Article PubMed CAS Google Scholar Abbott A. Novartis to shut brain research facility. Nature. 2011;480:161–2. Article CAS PubMed Google Scholar Shalev A, Liberzon I, Marmar C. Post-Traumatic Stress Disorder. N Engl J Med. 2017;376:2459–69. Article PubMed Google Scholar American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub, Arlington, VA, US, 2013. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51. Article PubMed Google Scholar Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialog Clin Neurosci. 2012;14:29–37. Article Google Scholar Schmidt U, Vermetten E. Integrating NIMH research domain criteria (RDoC) into PTSD research. In: Vermetten E, Baker D, Risbrough V, editors. Current topics in behavioral neurosciences. Berlin, Heidelberg: Springer; 2017. p. 1–23. Chapter Google Scholar Afifi TO, Asmundson GJG, Taylor S, Jang KL. The role of genes and environment on trauma exposure and posttraumatic stress disorder symptoms: a review of twin studies. Clin Psych Rev. 2010;30:101–12. Article Google Scholar Hyde CL, Nagle MW, Tian C, Chen X, Paciga SA, Wendland JR. et al.Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.Nat Gen. 2016;48:1031–6. Article CAS Google Scholar Almli LM, Fani N, Smith AK, Ressler KJ. Genetic approaches to understanding post-traumatic stress disorder. Int J Neuropsychopharmacol. 2014;17:355–70. Article PubMed Google Scholar Logue MW, Amstadter AB, Baker DG, Duncan L, Koenen KC, Liberzon I, et al. The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology. 2015;40:2287–97. Article PubMed PubMed Central Google Scholar Yehuda R, Golier JA, Halligan SL, Meaney M, Bierer LM. The ACTH response to dexamethasone in PTSD. Am J Psychiatry. 2004;161:1397–403. Article PubMed Google Scholar Daskalakis NP, Lehrner A, Yehuda R. Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment. Endocrinol Metab Clin North Am. 2013;42:503–13. Article PubMed Google Scholar Castro-Vale I, van Rossum EFC, Machado JC, Mota-Cardoso R, Carvalho D. Genetics of glucocorticoid regulation and posttraumatic stress disorder: What do we know? Neurosci Biobehav Rev. 2016;63:143–57. Article CAS PubMed Google Scholar Schmidt MV, Paez-Pereda M, Holsboer F, Hausch F. The prospect of FKBP51 as a drug target. ChemMedChem. 2012;7:1351–9. Article CAS PubMed Google Scholar Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33–41. Article CAS PubMed Google Scholar Klengel T, Binder EB. Epigenetics of stress-related psychiatric disorders and gene*environment interactions. Neuron. 2015;86:1343–57. Article CAS PubMed Google Scholar 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. Article CAS PubMed PubMed Central Google Scholar Boscarino JA, Erlich PM, Hoffman SN, Rukstalis M, Stewart WF. Association of FKBP5, COMT and CHRNA5 polymorphisms with PTSD among outpatients at risk for PTSD. Psychiatry Res. 2011;188:173–4. Article CAS PubMed PubMed Central Google Scholar 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. Article CAS PubMed Google Scholar 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. Article CAS PubMed PubMed Central Google Scholar Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol. 2015;11:33–37. Article CAS PubMed Google Scholar Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Rühter G, et al. Pharmacological inhibition of the psychiatric risk factor FKBP51 has anxiolytic properties. J Neurosci. 2015;35:9007–16. Article CAS PubMed PubMed Central Google Scholar Zhang L, Li XX, Hu XZ. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met. World J Psychiatry. 2016;206:1–6. Article Google Scholar Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25. Article CAS PubMed Google Scholar Grabe HJr, Spitzer C, Schwahn C, Marcinek A, Frahnow A, Barnow S, et al. Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population. Am J Psychiatry. 2009;166:926–33. Article PubMed Google Scholar Li L, Bao Y, He S, Wang G, Guan Y, Ma D, et al. The association between genetic variants in the dopaminergic system and posttraumatic stress disorder: a meta-analysis. Medicine (Baltimore). 2016;95:e3074. Article CAS Google Scholar Gressier F, Calati R, Balestri M, Marsano A, Alberti S, Antypa N. The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis. J Trauma Stress. 2013;26:645–53. Article PubMed Google Scholar 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;13:769–87. Article CAS PubMed PubMed Central Google Scholar Bennett MR, Hatton SN, Lagopoulos J. Stress, trauma and PTSD: translational insights into the core synaptic circuitry and its modulation. Brain Struct Funct. 2016;221:2401–26. Article PubMed Google Scholar Green CR, Corsi-Travali S, Neumeister A. The role of BDNF-TrkB signaling in the pathogenesis of PTSD. J Depress Anxiety. 2013;2013(S4):006. PubMed PubMed Central Google Scholar Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90. Article CAS PubMed PubMed Central Google Scholar Kozlovsky N, Matar MA, Kaplan Z, Kotler M, Zohar J, Cohen H. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int J Neuropsychopharmacol. 2007;10:741–58. Article CAS PubMed Google Scholar 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;45:460–8. Article PubMed Google Scholar Yu H, Wang Y, Pattwell S, Jing D, Liu T, Zhang Y, et al. Variant BDNF Val66Met polymorphism affects extinction of conditioned aversive memory. J Neurosci. 2009;29:4056–64. Article CAS PubMed PubMed Central Google Scholar Kazim SF, Iqbal K. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer’s disease. Mol Neurodegener. 2016;11:50. Article PubMed PubMed Central CAS Google Scholar Daskalakis NP, Cohen H, Cai G, Buxbaum JD, Yehuda R. Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes. Proc Natl Acad Sci USA. 2014;111:13529–34. Article CAS PubMed PubMed Central Google Scholar Sawamura T, Klengel T, Armario A, Jovanovic T, Norrholm SD, Ressler KJ, et al. Dexamethasone treatment leads to enhanced fear extinction and dynamic Fkbp5 regulation in amygdala. Neuropsychopharmacology. 2016;41:832–46. Article CAS PubMed Google Scholar Patel S, Hill MN, Cheer JF, Wotjak CT, Holmes A. The endocannabinoid system as a target for novel anxiolytic drugs. Neurosci Biobehav Rev. 2017;76:56–66. Article CAS PubMed PubMed Central Google Scholar Matar MA, Zohar J, Cohen H. Translationally relevant modeling of PTSD in rodents. Cell Tissue Res. 2013;354:127–39. Article CAS PubMed Google Scholar Daskalakis NP, Yehuda R, Diamond DM. Animal models in translational studies of PTSD. Psychoneuroendocrinology. 2013;38:1895–911. Article PubMed Google Scholar Borghans B, Homberg JR. Animal models for posttraumatic stress disorder: an overview of what is used in research. World J Psychiatry. 2015;5:387–96. Article PubMed PubMed Central Google Scholar Schöner J, Heinz A, Endres M, Gertz K, Kronenberg G. Post-traumatic stress disorder and beyond: an overview of rodent stress models. J Cell Mol Med. 2017;21:2248–56. Article PubMed PubMed Central Google Scholar Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. Article CAS PubMed PubMed Central Google Scholar Hyman SE. Psychiatric Drug Development: Diagnosing a Crisis. Cerebrum: The Dana Forum on Brain Science, 2013: 5. Brady KT. Posttraumatic stress disorder and comorbidity: recognizing the many faces of PTSD. J Clin Psychiatry. 1997;58 Suppl 9:12–5. PubMed Google Scholar Conway KP, Compton W, Stinson FS, Grant BF. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67:247–57. Article CAS PubMed Google Scholar Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialog Clin Neurosci. 2015;17:141–50. Article Google Scholar Willner P. The validity of animal models of depression. Psychopharmacology (Berlin). 1984;83:1–16. Article CAS Google Scholar Van der Staay FJ, Arndt SS, Nordquist RE. Evaluation of animal models of neurobehavioral disorders. Behav Brain Funct. 2009;5:11–33. Article PubMed PubMed Central Google Scholar Finsterwald C, Steinmetz AB, Travaglia A, Alberini CM. From memory impairment to posttraumatic stress disorder-like phenotypes: the critical role of an unpredictable second traumatic experience. J Neurosci. 2015;35:15903–15. Article CAS PubMed PubMed Central Google Scholar Desmedt A, Marighetto A, Piazza PV. Abnormal fear memory as a model for posttraumatic stress disorder. Biol Psychiatry. 2015;78:290–7. Article PubMed Google Scholar Deslauriers J, Toth M, Der-Avakian A, Risbrough VB. Current status of animal models of posttraumatic stress disorder: behavioral and biological phenotypes, and future challenges in improving translation. Biol Psychiatry. 2018;83:895–907. Article PubMed Google Scholar Hyman SE. Revolution stalled. Sci Transl Med. 2012;4:155cm11. Article PubMed Google Scholar Rothbaum BO, Foa EB, Riggs DS, Murdock T, Walsh W. A prospective examination of posttraumatic stress disorder in rape victims. J Trauma Stress. 1992;5:455–75. Article Google Scholar 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. Article CAS PubMed Google Scholar Bonanno GA, Mancini AD. The human capacity to thrive in the face of potential trauma. Pediatrics. 2008;121:369–75. Article PubMed Google Scholar Cohen H, Zohar J, Matar MA, Zeev K, Loewenthal U, Richter-Levin G. Setting apart the affected: the use of behavioral criteria in animal models of post-traumatic stress disorder. Neuropsychopharmacology. 2004;29:1962–70. Article PubMed Google Scholar Ardi Z, Ritov G, Lucas M, Richter-Levin G. The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus. Int J Neuropsychopharmacol. 2014;17:571–80. Article CAS PubMed Google Scholar Carmi L, Fostick L, Burshtein S, Cwikel-Hamzany S, Zohar J. PTSD treatment in light of DSM-5 and the “golden hours” concept. CNS Spectr. 2016;21:279–82. Article PubMed Google Scholar Ritov G, Boltyansky B, Richter-Levin G. A novel approach to PTSD modeling in rats reveals alternating patterns of limbic activity in different types of stress reaction. Mol Psychiatry. 2016;21:630–41. Article CAS PubMed Google Scholar Ardi Z, Albrecht A, Richter-Levin A, Saha R, Richter-Levin G. Behavioral profiling as a translational approach in an animal model of posttraumatic stress disorder. Neurobiol Dis. 2016;88:139–47. Article PubMed Google Scholar Ritov G, Richter-Levin G. Pre-trauma methylphenidate in rats reduces PTSD-like reactions one month later. Transl Psychiatry. 2017;7:e1000. Article CAS PubMed PubMed Central Google Scholar Wang W, Liu Y, Zheng H, Wang HN, Jin X, Chen YC, et al. A modified single-prolonged stress model for post-traumatic stress disorder. Neurosci Lett. 2008;441:237–41. Article CAS PubMed Google Scholar Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19–32. Article CAS PubMed Google Scholar Ledoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155–84. Article CAS PubMed Google Scholar Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. Neurosci Biobehav Rev. 2016;71:48–57. Article PubMed Google Scholar Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 2012;35:24–35. Article CAS PubMed Google Scholar Johansen JP, Cain CK, Ostroff LE, LeDoux JE. Molecular mechanisms of fear learning and memory. Cell. 2011;147:509–24. Article CAS PubMed PubMed Central Google Scholar Lamprecht R. The role of actin cytoskeleton in memory formation in amygdala. Front Mol Neurosci. 2016;9:23. Article PubMed PubMed Central CAS Google Scholar Kwapis JL, Wood MA. Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci. 2014;37:706–20. Article CAS PubMed PubMed Central Google Scholar Sweatt JD. Experience-dependent epigenetic modifications in the central nervous system. Biol Psychiatry. 2009;65:191–7. Article PubMed Google Scholar Goswami S, Rodríguez-Sierra O, Cascardi M, Paré D. Animal models of post-traumatic stress disorder: face validity. Front Neurosci. 2013;7:89. Article PubMed PubMed Central Google Scholar Koo JW, Duman RS. Interleukin-1 receptor null mutant mice show decreased anxiety-like behavior and enhanced fear memory. Neurosci Lett. 2009;456:39–43. Article CAS PubMed PubMed Central Google Scholar Raab A, Popp S, Lesch KP, Lohse MJ, Fischer M, Deckert J. et al. Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice. Genes Brain Behav. 2017;17:e12420 Article PubMed CAS Google Scholar Amstadter AB, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, et al. Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure. J Anxiety Disord. 2009;23:369–73. Article PubMed Google Scholar Hovhannisyan L, Stepanyan A, Arakelyan A. Genetic variability of interleukin-1 beta as prospective factor from developing post-traumatic stress disorder. Immunogenetics. 2017;69:703–8. Article CAS PubMed Google Scholar Nishiyama H, Knopfel T, Endo S, Itohara S. Glial protein S100B modulates long-term neuronal synaptic plasticity. Proc Natl Acad Sci USA. 2002;99:4037–42. Article CAS PubMed PubMed Central Google Scholar Diehl LA, Silveira PP, Leite MC, Crema LM, Portella AK, Billodre MN, et al. Long lasting sex-specific effects upon behavior and S100b levels after maternal separation and exposure to a model of post-traumatic stress disorder in rats. Brain Res. 2007;1144:107–16. Article CAS PubMed Google Scholar Jones ME, Lebonville CL, Paniccia JE, Balentine ME, Reissner KJ, Lysle DT. Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β. Brain Behav Immun. 2018;67:355–63. Article CAS PubMed Google Scholar Vogel S, Klumpers F, Kroes MC, Oplaat KT, Krugers HJ, Oitzl MS, et al. A stress-induced shift from trace to delay conditioning depends on the mineralocorticoid receptor. Biol Psychiatry. 2015;78:830–9. Article CAS PubMed Google Scholar Sananbenesi F, Fischer A, Schrick C, Spiess J, Radulovic J. Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory. J Neurosci. 2003;23:11436–43. Article CAS PubMed PubMed Central Google Scholar 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. 2010;68:1007–15. Article CAS PubMed PubMed Central Google Scholar Ishikawa S, Saito Y, Yanagawa Y, Otani S, Hiraide S, Shimamura K, et al. Early postnatal stress alters extracellular signal-regulated kinase signaling in the corticolimbic system modulating emotional circuitry in adult rats. Eur J Neurosci. 2012;35:135–45. Article PubMed Google Scholar Koseki H, Matsumoto M, Togashi H, Miura Y, Fukushima K, Yoshioka M. Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models. Synapse. 2009;63:805–13. Article CAS PubMed Google Scholar Müller I, Çalışkan G, Stork O. The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology. Genes Brain Behav. 2015;14:37–45. Article PubMed CAS Google Scholar Tsuda MC, Yeung HM, Kuo J, Usdin TB. Incubation of fear is regulated by TIP39 peptide signaling in the medial nucleus of the amygdala. J Neurosci. 2015;35:12152–61. Article CAS PubMed PubMed Central Google Scholar Xu W, Südhof TC. A neural circuit for memory specificity and generalization. Science. 2013;339:1290–5. Article CAS PubMed PubMed Central Google Scholar Zhou H, Xiong GJ, Jing L, Song NN, Pu DL, Tang X, et al. The interhemispheric CA1 circuit governs rapid generalisation but not fear memory. Nat Commun. 2017;8:2190. Article PubMed PubMed Central CAS Google Scholar Jasnow AM, Ehrlich DE, Choi DC, Dabrowska J, Bowers ME, McCullough KM, et al. Thy1-expressing neurons in the basolateral amygdala may mediate fear inhibition. J Neurosci. 2013;33:10396–404. Article CAS PubMed PubMed Central Google Scholar Yoshii T, Hosokawa H, Matsuo N. Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory. Neuropharmacology. 2017;113:1–9. Article CAS PubMed Google Scholar Heldt SA, Mou L, Ressler KJ. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice. Transl Psychiatry. 2012;2:e181. Article CAS PubMed PubMed Central Google Scholar Fitzgerald PJ, Pinard CR, Camp MC, Feyder M, Sah A, Bergstrom HC, et al. Durable fear memories require PSD-95. Mol Psychiatry. 2015;20:901–12. Article CAS PubMed Google Scholar Saha R, Knapp S, Chakraborty D, Horovitz O, Albrecht A, Kriebel M, et al. GABAergic synapses at the axon initial segment of basolateral amygdala projection neurons modulate fear extinction. Neuropsychopharmacology. 2017;42:473–84. Article CAS PubMed Google Scholar Raza SA, Albrecht A, Çalışkan G, Müller B, Demiray YE, Ludewig S, et al. HIPP neurons in the dentate gyrus mediate the cholinergic modulation of background context memory salience. Nat Commun. 2017;8:189. Article PubMed PubMed Central CAS Google Scholar Rau V, DeCola JP, Fanselow MS. Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev. 2005;29:1207–23. Article PubMed Google Scholar Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology. 1997;22:443–53. Article CAS PubMed Google Scholar 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. Article CAS PubMed Google Scholar Richter-Levin G. Acute and long-term behavioral correlates of underwater trauma--potential relevance to stress and post-stress syndromes. Psychiatry Res. 1998;79:73–83. Article CAS PubMed Google Scholar Adamec R, Toth M, Haller J, Halasz J, Blundell J. Activation patterns of cells in selected brain stem nuclei of more and less stress responsive rats in two animal models of PTSD - predator exposure and submersion stress. Neuropharmacology. 2012;62:725–36. Article CAS PubMed Google Scholar Cohen H, Benjamin J, Kaplan Z, Kotler M. Administration of high-dose ketoconazole, an inhibitor of steroid synthesis, prevents posttraumatic anxiety in an animal model. Eur Neuropsychopharmacol. 2000;10:429–35. Article CAS PubMed Google Scholar 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;11:259–81. Article PubMed PubMed Central Google Scholar 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;44:106–11. Article PubMed Google Scholar Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flügge G, Korte SM, et al. (2011) Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev. 2011;35:1291–301. Article CAS PubMed Google Scholar Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602. Article PubMed Google Scholar Olaya B, Alonso J, Atwoli L, Kessler RC, Vilagut G, Haro JM. Association between traumatic events and post-traumatic stress disorder: results from the ESEMeD-Spain study. Epidemiol Psychiatr Sci. 2015;24:172–83. Article CAS PubMed Google Scholar Bromet EJ, Atwoli L, Kawakami N, Navarro-Mateu F, Piotrowski P, King AJ. et al. Post-traumatic stress disorder associated with natural and human-made disasters in the World Mental Health Surveys. Psychol Med. 2017;47:227–41. Article CAS PubMed Google Scholar Geerse GJ, van Gurp LC, Wiegant VM, Stam R. Individual reactivity to the open-field predicts the expression of stress-induced behavioural and somatic pain sensitisation. Behav Brain Res. 2006;174:112–8. Article PubMed Google Scholar King JA, Abend S, Edwards E. Genetic predisposition and the development of posttraumatic stress disorder in an animal model. Biol Psychiatry. 2001;50:231–7. Article CAS PubMed Google Scholar Walker SE, Sandi C. Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual’s glucocorticoid responsiveness to stress. Stress. 2018;7:1–10. Google Scholar Herrero AI, Sandi C, Venero C. Individual differences in anxiety trait are related to spatial learning abilities and hippocampal expression of mineralocorticoid receptors. Neurobiol Learn Mem. 2006;86:150–9. Article CAS PubMed Google Scholar Sandi C, Richter-Levin G. From high anxiety trait to depression: a neurocognitive hypothesis. Trends Neurosci. 2009;32:312–20. Article CAS PubMed Google Scholar Zovkic IB, Sweatt JD. Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology. 2013;38:77–93. Article CAS PubMed Google Scholar Reul JM. Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Front Psychiatry. 2014;5:5. Article PubMed PubMed Central Google Scholar Zannas AS, Provençal N, Binder EB. Epigenetics of posttraumatic stress disorder: current evidence, challenges, and future directions. Biol Psychiatry. 2015;78:327–35. Article CAS PubMed Google Scholar Bohacek J, Mansuy IM. Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat Rev Genet. 2015;16:641–52. Article CAS PubMed Google Scholar Sheerin CM, Lind MJ, Bountress KE, Nugent NR, Amstadter AB. The genetics and epigenetics of PTSD: overview, recent advances, and future directions. Curr Opin Psychol. 2017;14:5–11. Article PubMed PubMed Central Google Scholar Hager T, Jansen RF, Pieneman AW, Manivannan SN, Golani I, van der Sluis S, et al. Display of individuality in avoidance behavior and risk assessment of inbred mice. Front Behav Neurosci. 2014;8:314. Article PubMed PubMed Central Google Scholar Heim C, Nemeroff CB. Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry. 2002;7:147–59. Article PubMed Google Scholar Molet J, Maras PM, Avishai-Eliner S, Baram TZ. Naturalistic rodent models of chronic early-life stress. Dev Psychobiol. 2014;56:1675–88. Article PubMed PubMed Central Google Scholar Avital A, Richter-Levin G. Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. Int J Neuropsychopharmacol. 2005;8:163–73. Article PubMed Google Scholar Horovitz O, Tsoory MM, Hall J, Jacobson-Pick S, Richter-Levin G. Post-weaning to pre-pubertal (‘juvenile’) stress: a model of induced predisposition to stress-related disorders. Neuroendocrinology. 2012;95:56–64. Article CAS PubMed Google Scholar Fuentes S, Carrasco J, Armario A, Nadal R. Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats. Horm Behav. 2014;66:475–86. Article CAS PubMed Google Scholar Albrecht A, Müller I, Ardi Z, Çalışkan G, Gruber D, Ivens S, et al. Neurobiological consequences of juvenile stress: a GABAergic perspective on risk and resilience. Neurosci Biobehav Rev. 2017;74(Pt A):21–43. Article CAS PubMed Google Scholar Li C, Liu Y, Yin S, Lu C, Liu D, Jiang H, et al. Long-term effects of early adolescent stress: dysregulation of hypothalamic-pituitary-adrenal axis and central corticotropin releasing factor receptor 1 expression in adult male rats. Behav Brain Res. 2015;288:39–49. Article CAS PubMed Google Scholar Dirven BCJ, Homberg JR, Kozicz T, Henckens MJAG.. Epigenetic programming of the neuroendocrine stress response by adult life stress. J Mol Endocrinol. 2017;59:R11–R31. Article CAS PubMed Google Scholar Schmidt MV, Abraham WC, Maroun M, Stork O, Richter-Levin G. Stress-induced metaplasticity: from synapses to behavior. Neuroscience. 2013;250:112–20. Article CAS PubMed Google Scholar Hermos JA, Young MM, Lawler EV, Rosenbloom D, Fiore LD. Long-term, high-dose benzodiazepine prescriptions in veteran patients with PTSD: influence of preexisting alcoholism and drug-abuse diagnoses. J Trauma Stress. 2007;20:909–14. Article PubMed Google Scholar Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted sleep: effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev. 2008;12:197–210. Article PubMed Google Scholar Horn SR, Charney DS, Feder A. Understanding resilience: new approaches for preventing and treating PTSD. Exp Neurol. 2016;284(Pt B):119–32. Article CAS PubMed Google Scholar Nederhof E, Schmidt MV. Mismatch or cumulative stress: toward an integrated hypothesis of programming effects. Physiol Behav. 2012;106:691–700. Article CAS PubMed Google Scholar Ellis BJ, Del Giudice M. Beyond allostatic load: rethinking the role of stress in regulating human development. Dev Psychopathol. 2014;26:1–20. Article PubMed Google Scholar Shapero BG, Hamilton JL, Stange JP, Liu RT, Abramson LY, Alloy LB. Moderate childhood stress buffers against depressive response to proximal stressors: a multi-wave prospective study of early adolescents. J Abnorm Child Psychol. 2015;43:1403–13. Article PubMed PubMed Central Google Scholar Hsiao YM, Tsai TC, Lin YT, Chen CC, Huang CC, Hsu KS. Early life stress dampens stress responsiveness in adolescence: evaluation of neuroendocrine reactivity and coping behavior. Psychoneuroendocrinology. 2016;67:86–99. Article PubMed Google Scholar Santarelli S, Lesuis SL, Wang XD, Wagner KV, Hartmann J, Labermaier C, et al. Evidence supporting the match/mismatch hypothesis of psychiatric disorders. E Neuropsychopharmacol. 2014;24:907–18. Article CAS Google Scholar Santarelli S, Zimmermann C, Kalideris G, Lesuis SL, Arloth J, Uribe A, et al. An adverse early life environment can enhance stress resilience in adulthood. Psychoneuroendocrinology. 2017;78:213–21. Article PubMed Google Scholar Cohen H, Zohar J, Matar M. The relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biol Psychiatry. 2003;53:463–73. Article PubMed Google Scholar Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol Psychiatry. 2008;64:708–17. Article CAS PubMed Google Scholar Bazak N, Kozlovsky N, Kaplan Z, Matar M, Golan H, Zohar J, et al. Pre-pubertal stress exposure affects adult behavioral response in association with changes in circulating corticosterone and brain-derived neurotrophic factor. Psychoneuroendocrinology. 2009;34:844–58. Article CAS PubMed Google Scholar Cohen H, Liu T, Kozlovsky N, Kaplan Z, Zohar J, Mathé AA. The neuropeptide Y (NPY)-ergic system is associated with behavioral resilience to stress exposure in an animal model of post-traumatic stress disorder. Neuropsychopharmacology. 2012;37:350–63. Article CAS PubMed Google Scholar Horovitz O, Tsoory MM, Yovell Y, Richter-Levin G. A rat model of pre-puberty (juvenile) stress-induced predisposition to stress-related disorders: sex similarities and sex differences in effects and symptoms. World J Biol Psychiatry. 2014;15:36–48. Article CAS PubMed Google Scholar Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54:1044–8. Article CAS PubMed Google Scholar 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. Article CAS PubMed Google Scholar Norris FH, Friedman MJ, Watson PJ, Byrne CM, Diaz E, Kaniasty K. 60,000 disaster victims speak: Part I. An empirical review of the empirical literature, 1981–2001. Psychiatry. 2002;65:207–39. Article PubMed Google Scholar Tolin DF, Foa EB. Sex differences in trauma and posttraumatic stress disorder: a quantitative review of 25 years of research. Psychol Bull. 2006;132:959–92. Article PubMed Google Scholar Stein MB, Walker J, Forde D. (2000). Gender differences in susceptibility to posttraumatic stress disorder. Behav Res Ther. 1995;38:619–28. Article Google Scholar Hu, J, Feng, B, Zhu, Y, Wang, W, Xie, J, Zheng, X Gender differences in PTSD: susceptibility and resilience. In: Gender differences in different contexts. InTech. (ed.) Aida Alvinius 21-42, Rijeka, Croatia 2017. Briscione MA, Michopoulos V, Jovanovic T, Norrholm SD. Neuroendocrine underpinnings of increased risk for posttraumatic stress disorder in women. Vitam Horm. 2017;103:53–83. Article CAS PubMed Google Scholar Maeng LY, Milad MR. Sex differences in anxiety disorders: interactions between fear, stress, and gonadal hormones. Horm Behav. 2015;76:106–17. Article CAS PubMed PubMed Central Google Scholar Fenchel D, Levkovitz Y, Vainer E, Kaplan Z, Zohar J, Cohen H. Beyond the HPA-axis: the role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD. Eur Neuropsychopharmacol. 2015;25:944–57. Article CAS PubMed Google Scholar Scharfman HE, MacLusky NJ. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats. Neuropharmacology. 2014;76(Pt C):696–708. Article CAS PubMed Google Scholar Lilly MM, Pole N, Best SR, Metzler T, Marmar CR. Gender and PTSD: what can we learn from female police officers? J Anxiety Disord. 2009;23:767–74. Article PubMed PubMed Central Google Scholar Haskell SG, Gordon KS, Mattocks K, Duggal M, Erdos J, Justice A, et al. Gender differences in rates of depression, PTSD, pain, obesity, and military sexual trauma among Connecticut War Veterans of Iraq and Afghanistan. J Women’s Health (Larchmt). 2010;19:267–71. Article Google Scholar Crum-Cianflone NF, Jacobson I. Gender differences of postdeployment post-traumatic stress disorder among service members and veterans of the Iraq and Afghanistan conflicts. Epidemiol Rev. 2014;36:5–18. Article PubMed Google Scholar Cohen H, Yehuda R. Gender differences in animal models of posttraumatic stress disorder. Dis Markers. 2011;30:141–50. Article PubMed PubMed Central Google Scholar Peters L, Issakidis C, Slade T, Andrews G. Gender differences in the prevalence of DSM-IV and ICD-10 PTSD. Psychol Med. 2006;36:81–9. Article PubMed Google Scholar Hourani L, Williams J, Bray R, Kandel D. Gender differences in the expression of PTSD symptoms among active duty military personnel. J Anxiety Disord. 2015;29:101–8. Article PubMed Google Scholar Pineles SL, Arditte Hall KA, Rasmusson AM. Gender and PTSD: different pathways to a similar phenotype. Curr Opin Psychol. 2017;14:44–48. Article PubMed Google Scholar Gradus JL, Leatherman S, Curreri A, Myers LG, Ferguson R, Miller M. Gender differences in substance abuse, PTSD and intentional self-harm among veterans health administration patients. Drug Alcohol Depend. 2017;171:66–69. Article PubMed Google Scholar Shors TJ. Opposite effects of stressful experience on memory formation in males versus females. Dialog Clin Neurosci. 2002;4:139–47. Article Google Scholar Shors TJ, Mathew J, Sisti HM, Edgecomb C, Beckoff S, Dalla C. Neurogenesis and helplessness are mediated by controllability in males but not in females. Biol Psychiatry. 2007;62:487–95. Article PubMed PubMed Central Google Scholar Brydges NM, Wood ER, Holmes MC, Hall J. Prepubertal stress and hippocampal function: sex-specific effects. Hippocampus. 2014;24:684–92. Article PubMed Google Scholar Zitman FM, Richter-Levin G. Age and sex-dependent differences in activity, plasticity and response to stress in the dentate gyrus. Neuroscience. 2013;249:21–30. Article CAS PubMed Google Scholar Jacobson-Pick S, Richter-Levin G. Differential impact of juvenile stress and corticosterone in juvenility and in adulthood, in male and female rats. Behav Brain Res. 2010;214:268–76. Article CAS PubMed Google Scholar Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the U.S. National Comorbidity Survey. Br J Psychiatry. 1996;168:17–30. Article Google Scholar Kaufman J, Charney D. Comorbidity of mood and anxiety disorders. Depress Anxiety. 2000;12 Suppl:69–76. Article PubMed Google Scholar Alexander JL, Dennerstein L, Kotz K, Richardson G. Women, anxiety and mood: a review of nomenclature, comorbidity and epidemiology. Expert Rev Neurother. 2007;7 11 Suppl:S45–58. Article PubMed Google Scholar Lai HM, Cleary M, Sitharthan T, Hunt GE. Prevalence of comorbid substance use, anxiety and mood disorders in epidemiological surveys, 1990-2014: a systematic review and meta-analysis. Drug Alcohol Depend. 2015;154:1–13. Article PubMed Google Scholar Rytwinski NK, Scur MD, Feeny NC, Youngstrom EA. The co-occurrence of major depressive disorder among individuals with posttraumatic stress disorder: a meta-analysis. J Trauma Stress. 2013;26:299–309. Article PubMed Google Scholar Sher L. New scientific evidence supports the concept of post-traumatic mood disorder and an association of post-traumatic mood disorder with completed suicide. Med Hypotheses. 2010;75:271–2. Article PubMed Google Scholar Auxéméry Y. Clinical forms of post-traumatic depression. Encephale. 2015;41:346–54. Article PubMed Google Scholar Lawrence-Wood E, Van Hooff M, Baur J, McFarlane AC. Re-experiencing phenomena following a disaster: the long-term predictive role of intrusion symptoms in the development of post-trauma depression and anxiety. J Affect Disord. 2016;190:278–81. Article PubMed Google Scholar American Psychiatric Association. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington, DC: American Psichiatric Association; 1994. Google Scholar Tsoory M, Richter-Levin G. Learning under stress in the adult rat is differentially affected by ‘juvenile’ or ‘adolescent’ stress. Int J Neuropsychopharmacol. 2006;9:713–28. Article PubMed Google Scholar Tsoory M, Cohen H, Richter-Levin G. Juvenile stress induces a predisposition to either anxiety or depressive-like symptoms following stress in adulthood. Eur Neuropsychopharmacol. 2007;17:245–56. Article CAS PubMed Google Scholar Patki G, Li L, Allam F, Solanki N, Dao AT, Alkadhi K, et al. Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav. 2014;130:47–53. Article CAS PubMed PubMed Central Google Scholar Ji LL, Tong L, Xu BK, Fu CH, Shu W, Peng JB, et al. Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder. Behav Brain Funct. 2014;10:28. Article PubMed PubMed Central CAS Google Scholar Serova LI, Laukova M, Alaluf LG, Pucillo L, Sabban EL. Intranasal neuropeptide Y reverses anxiety and depressive-like behavior impaired by single prolonged stress PTSD model. Eur Neuropsychopharmacol. 2014;24:142–7. Article CAS PubMed Google Scholar Lin CC, Tung CS, Liu YP. Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory. Psychopharmacology (Berlin). 2016;233:1135–46. Article CAS Google Scholar Cuthbert B, Insel T. The data of diagnosis: new approaches to psychiatric classification. Psychiatry. 2010;73:311–4. Article PubMed Google Scholar Kapur S, Phillips AG, Insel TR. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry. 2012;17:1174–9. Article CAS PubMed Google Scholar Macedo T, Wilheim L, Gonçalves R, Coutinho ES, Vilete L, Figueira I, et al. Building resilience for future adversity: a systematic review of interventions in non-clinical samples of adults. BMC Psychiatry. 2014;14:227. Article PubMed PubMed Central Google Scholar 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. Article CAS PubMed Google Scholar Neylan TC, Schadt EE, Yehuda R. Biomarkers for combat-related PTSD: focus on molecular networks from high-dimensional data. Eur J Psychotraumatol. 2014;5:23938. Article Google Scholar Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M. Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder. Mol Brain. 2015;8:14. Article PubMed PubMed Central CAS Google Scholar Logue MW, Smith AK, Baldwin C, Wolf EJ, Guffanti G, Ratanatharathorn A, et al. An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress. Psychoneuroendocrinology. 2015;57:1–13. Article CAS PubMed PubMed Central Google Scholar Febbraro F, Svenningsen K, Tran TP, Wiborg O. Neuronal substrates underlying stress resilience and susceptibility in rats. PLoS One. 2017;12:e0179434. Article PubMed PubMed Central CAS Google Scholar Southwick SM, Charney DS. The science of resilience: implications for the prevention and treatment of depression. Science. 2012;338:79–82. Article CAS PubMed Google Scholar Wu G, Feder A, Cohen H, Kim JJ, Calderon S, Charney DS. et al. Understanding resilience. Front Behav Neurosci. 2013;7:10 PubMed PubMed Central Google Scholar Tischer D, Weiner OD. Illuminating cell signalling with optogenetic tools. Nat Rev Mol Cell Biol. 2014;15:551–8. Article CAS PubMed PubMed Central Google Scholar Motta-Mena LB, Reade A, Mallory MJ, Glantz S, Weiner OD, Lynch KW, et al. An optogenetic gene expression system with rapid activation and deactivation kinetics. Nat Chem Biol. 2014;10:196–202. Article CAS PubMed PubMed Central Google Scholar Singh P, Schimenti JC, Bolcun-Filas E. A mouse geneticist’s practical guide to CRISPR applications. Genetics. 2015;199:1–15. Article CAS PubMed Google Scholar Walters BJ, Azam AB, Gillon CJ, Josselyn SA, Zovkic IB. Advanced In vivo use of CRISPR/Cas9 and anti-sense DNA inhibition for gene manipulation in the brain. Front Genet. 2016;6:362. Article PubMed PubMed Central CAS Google Scholar Wang P, Zhao D, Lachman HM, Zheng D. Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons. Transl Psychiatry. 2018;8:13. Article PubMed PubMed Central CAS Google Scholar Reznikov R, Bambico FR, Diwan M, Raymond RJ, Nashed MG, Nobrega JN, et al. Prefrontal cortex deep brain stimulation improves fear and anxiety-like behavior and reduces basolateral amygdala activity in a preclinical model of posttraumatic stress disorder. Neuropsychopharmacology. 2018;43:1099–106. Article PubMed Google Scholar 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. Article CAS PubMed Google Scholar Yehuda R, Pratchett LC, Elmes MW, Lehrner A, Daskalakis NP, Koch E, et al. Glucocorticoid-related predictors and correlates of post-traumatic stress disorder treatment response in combat veterans. Interface Focus. 2014;4:20140048. Article PubMed PubMed Central Google Scholar Wen L, Han F, Shi Y. Changes in the glucocorticoid receptor and Ca²+/calreticulin-dependent signalling pathway in the medial prefrontal cortex of rats with post-traumatic stress disorder. J Mol Neurosci. 2015;56:24–34. Article CAS PubMed Google Scholar Kohda K, Harada K, Kato K, Hoshino A, Motohashi J, Yamaji T, et al. Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience. 2007;148:22–33. Article CAS PubMed Google Scholar 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. Article PubMed PubMed Central Google Scholar 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. Article CAS PubMed PubMed Central Google Scholar Sabbagh JJ, O’Leary JC 3rd, Blair LJ, Klengel T, Nordhues BA, Fontaine SN, et al. Age-associated epigenetic upregulation of the FKBP5 gene selectively impairs stress resiliency. PLoS One. 2014;9:e107241. Article PubMed PubMed Central CAS Google Scholar Criado-Marrero M, Morales Silva RJ, Velazquez B, Hernández A, Colon M, Cruz E, et al. Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear. Learn Mem. 2017;24:145–52. Article CAS PubMed PubMed Central Google Scholar van der Doelen RH, Calabrese F, Guidotti G, Geenen B, Riva MA, Kozicz T, et al. Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain. Front Behav Neurosci. 2014;8:355. PubMed PubMed Central Google Scholar Xu J, Wang R, Liu Y, Liu D, Jiang H, Pan F. FKBP5 and specific microRNAs via glucocorticoid receptor in the basolateral amygdala involved in the susceptibility to depressive disorder in early adolescent stressed rats. J Psychiatr Res. 2017;95:102–13. Article PubMed Google Scholar Amstadter AB, Nugent NR, Yang BZ, Miller A, Siburian R, Moorjani P, et al. Corticotrophin-releasing hormone type 1 receptor gene (CRHR1) variants predict posttraumatic stress disorder onset and course in pediatric injury patients. Dis Markers. 2011;30:89–99. Article CAS PubMed PubMed Central Google Scholar White S, Acierno R, Ruggiero KJ, Koenen KC, Kilpatrick DG, Galea S, et al. Association of CRHR1 variants and posttraumatic stress symptoms in hurricane exposed adults. J Anxiety Disord. 2013;27:678–83. Article PubMed PubMed Central Google Scholar Wolf EJ, Mitchell KS, Logue MW, Baldwin CT, Reardon AF, Humphries DE, et al. Corticotropin releasing hormone receptor 2 (CRHR-2) gene is associated with decreased risk and severity of posttraumatic stress disorder in women. Depress Anxiety. 2013;30:1161–9. Article CAS PubMed Google Scholar Thoeringer CK, Henes K, Eder M, Dahlhoff M, Wurst W, Holsboer F, et al. Consolidation of remote fear memories involves corticotropin-releasing hormone (CRH) receptor type 1-mediated enhancement of AMPA receptor GluR1 signaling in the dentate gyrus. Neuropsychopharmacology. 2012;37:787–96. Article CAS PubMed Google Scholar Lebow M, Neufeld-Cohen A, Kuperman Y, Tsoory M, Gil S, Chen A. Susceptibility to PTSD-like behavior is mediated by corticotropin-releasing factor receptor type 2 levels in the bed nucleus of the stria terminalis. J Neurosci. 2012;32:6906–16. Article CAS PubMed PubMed Central Google Scholar Elharrar E, Warhaftig G, Issler O, Sztainberg Y, Dikshtein Y, Zahut R, et al. Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear. Biol Psychiatry. 2013;74:827–36. Article CAS PubMed Google Scholar Tyrka AR, Price LH, Gelernter J, Schepker C, Anderson GM, Carpenter LL. Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: effects on hypothalamic-pituitary-adrenal axis reactivity. Biol Psychiatry. 2009;66:681–5. Article CAS PubMed PubMed Central Google Scholar Toth M, Flandreau EI, Deslauriers J, Geyer MA, Mansuy IM, Merlo Pich E, et al. Overexpression of forebrain CRH during early life increases trauma susceptibility in adulthood. Neuropsychopharmacology. 2016;41:1681–90. Article CAS PubMed Google Scholar van der Doelen RH, Arnoldussen IA, Ghareh H, van Och L, Homberg JR, Kozicz T. Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain. Dev Psychopathol. 2015;27:123–35. Article PubMed Google Scholar Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011;470:492–7. Article CAS PubMed PubMed Central Google Scholar Otto C, Martin M, Wolfer DP, Lipp HP, Maldonado R, Schütz G. Altered emotional behavior in PACAP-type-I-receptor-deficient mice. Brain Res Mol Brain Res. 2001;92:78–84. Article CAS PubMed Google Scholar Farkas J, Kovács LÁ, Gáspár L, Nafz A, Gaszner T, Ujvári B, et al. Construct and face validity of a new model for the three-hit theory of depression using PACAP mutant mice on CD1 background. Neuroscience. 2017;354:11–29. Article CAS PubMed Google Scholar Lee HJ, Lee MS, Kang RH, Kim H, Kim SD, Kee BS, et al. Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety. 2005;21:135–9. Article CAS PubMed Google Scholar Wang Z, Baker DG, Harrer J, Hamner M, Price M, Amstadter A. The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism. Depress Anxiety. 2011;28:1067–73. Article CAS PubMed PubMed Central Google Scholar Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Brady K, et al. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry. 2009;66:1201–9. Article PubMed PubMed Central Google Scholar Mushtaq D, Ali A, Margoob MA, Murtaza I, Andrade C. Association between serotonin transporter gene promoter-region polymorphism and 4- and 12-week treatment response to sertraline in posttraumatic stress disorder. J Affect Disord. 2012;136:955–62. Article CAS PubMed Google Scholar Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, et al. Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci. 2007;27:684–91. Article CAS PubMed PubMed Central Google Scholar Malikowska N, Fijałkowski Ł, Nowaczyk A, Popik P, Sałat K. Antidepressant-like activity of venlafaxine and clonidine in mice exposed to single prolonged stress - a model of post-traumatic stress disorder. Pharmacodynamic and molecular docking studies. Brain Res. 2017;1673:1–10. Article CAS PubMed Google Scholar Everaerd D, Gerritsen L, Rijpkema M, Frodl T, van Oostrom I, Franke B, et al. Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. Neuropsychopharmacology. 2012;37:1848–55. Article CAS PubMed PubMed Central Google Scholar Belay H, Burton CL, Lovic V, Meaney MJ, Sokolowski M, Fleming AS. Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats. Behav Neurosci. 2011;125:150–60. Article CAS PubMed Google Scholar van der Doelen RH, Deschamps W, D’Annibale C, Peeters D, Wevers RA, Zelena D, et al. Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis. Transl Psychiatry. 2014;4:e409. Article PubMed PubMed Central CAS Google Scholar Sullivan GM, Ogden RT, Huang YY, Oquendo MA, Mann JJ, Parsey RV. Higher in vivo serotonin-1a binding in posttraumatic stress disorder: a PET study with [11C]WAY-100635. Depress Anxiety. 2013;30:197–206. Article CAS PubMed Google Scholar Klemenhagen KC, Gordon JA, David DJ, Hen R, Gross CT. Increased fear response to contextual cues in mice lacking the 5-HT1A receptor. Neuropsychopharmacology. 2006;31:101–11. Article CAS PubMed Google Scholar Luo FF, Han F, Shi YX. Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder. Mol Med Rep. 2011;4:843–7. CAS PubMed Google Scholar Gruber D, Gilling KE, Albrecht A, Bartsch JC, Çalışkan G, Richter-Levin G, et al. 5-HT receptor-mediated modulation of granule cell inhibition after juvenile stress recovers after a second exposure to adult stress. Neuroscience. 2015;293:67–79. Article CAS PubMed Google Scholar Hemmings SM, Martin LI, Klopper M, van der Merwe L, Aitken L, de Wit E, et al. BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. Prog Neuropsychopharmacol Biol Psychiatry. 2013;40:273–80. Article CAS PubMed Google Scholar Said N, Lakehayli S, El Khachibi M, El Ouahli M, Nadifi S, Hakkou F, et al. Prenatal stress induces vulnerability to nicotine addiction and alters D2 receptors’ expression in the nucleus accumbens in adult rats. Neuroscience. 2015;304:279–85. Article CAS PubMed Google Scholar Azzinnari D, Sigrist H, Staehli S, Palme R, Hildebrandt T, Leparc G, et al. Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function. Neuropharmacology. 2014;85:328–41. Article CAS PubMed Google Scholar Hettema JM, Chen X, Sun C, Brown TA. Direct, indirect and pleiotropic effects of candidate genes on internalizing disorder psychopathology. Psychol Med. 2015;45:2227–36. Article CAS PubMed PubMed Central Google Scholar Walder DJ, Trotman HD, Cubells JF, Brasfield J, Tang YL, Walker EF. Catechol-O-methyltransferase modulation of cortisol secretion in psychiatrically at-risk and healthy adolescents. Psychiatr Genet. 2010;20:166–70. Article PubMed PubMed Central Google Scholar O’Tuathaigh CM, Clarke G, Walsh J, Desbonnet L, Petit E, O’Leary C, et al. Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. Int J Neuropsychopharmacol. 2012;15:1331–42. Article PubMed CAS Google Scholar Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, et al. Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proc Natl Acad Sci USA. 2017;114:8390–5. Article CAS PubMed PubMed Central Google Scholar Bountress K, Sheerin C, Amstadter AB, Mandel H, Voltin J, Wang Z. The relation between GAD1 and PTSD symptoms: shared risk for depressive symptoms. Psychiatry Res. 2017;258:607–8. Article PubMed PubMed Central Google Scholar Bergado-Acosta JR, Sangha S, Narayanan RT, Obata K, Pape HC, Stork O. Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory. Learn Mem. 2008;15:163–71. Article CAS PubMed PubMed Central Google Scholar Sangha S, Narayanan RT, Bergado-Acosta JR, Stork O, Seidenbecher T, Pape HC. Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory. J Neurosci. 2009;29:15713–20. Article CAS PubMed PubMed Central Google Scholar Müller I, Obata K, Richter-Levin G, Stork O. GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology. Front Behav Neurosci. 2014;8:265. PubMed PubMed Central Google Scholar Miao YL, Guo WZ, Shi WZ, Fang WW, Liu Y, Liu J, et al. Midazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PLoS One. 2014;9:e101450. Article PubMed PubMed Central CAS Google Scholar Nelson EC, Agrawal A, Pergadia ML, Lynskey MT, Todorov AA, Wang JC, et al. Association of childhood trauma exposure and GABRA2 polymorphisms with risk of posttraumatic stress disorder in adults. Mol Psychiatry. 2009;14:234–5. Article CAS PubMed PubMed Central Google Scholar Jacobson-Pick S, Elkobi A, Vander S, Rosenblum K, Richter-Levin G. Juvenile stress-induced alteration of maturation of the GABAA receptor alpha subunit in the rat. Int J Neuropsychopharmacol. 2008;11:891–903. Article CAS PubMed Google Scholar Pibiri F, Nelson M, Guidotti A, Costa E, Pinna G. Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder. Proc Natl Acad Sci USA. 2008;105:5567–72. Article CAS PubMed PubMed Central Google Scholar Pinna G, Rasmusson AM. Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci. 2014;8:256. Article PubMed PubMed Central Google Scholar Shaban H, Humeau Y, Herry C, Cassasus G, Shigemoto R, Ciocchi S, et al. Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nat Neurosci. 2006;9:1028–35. Article CAS PubMed Google Scholar Lynch JF, Winiecki P, Gilman TL, Adkins JM, Jasnow AM. Hippocampal GABA(B(1a)) receptors constrain generalized contextual fear. Neuropsychopharmacology. 2017;42:914–24. Article CAS PubMed Google Scholar Heaney CF, Bolton MM, Murtishaw AS, Sabbagh JJ, Magcalas CM, Kinney JW. Baclofen administration alters fear extinction and GABAergic protein levels. Neurobiol Learn Mem. 2012;98:261–71. Article CAS PubMed PubMed Central Google Scholar Fride E, Suris R, Weidenfeld J, Mechoulam R. Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice. Behav Pharmacol. 2005;16:431–40. Article CAS PubMed Google Scholar Chhatwal JP, Davis M, Maguschak KA, Ressler KJ. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology. 2005;30:516–24. Article CAS PubMed Google Scholar Matchynski-Franks JJ, Susick LL, Schneider BL, Perrine SA, Conti AC. Impaired ethanol-induced sensitization and decreased cannabinoid receptor-1 in a model of posttraumatic stress disorder. PLoS One. 2016;11:e0155759. Article PubMed PubMed Central CAS Google Scholar Mota N, Sumner JA, Lowe SR, Neumeister A, Uddin M, Aiello AE, et al. The rs1049353 polymorphism in the CNR1 gene interacts with childhood abuse to predict posttraumatic threat symptoms. J Clin Psychiatry. 2015;76:e1622–3. Article PubMed PubMed Central Google Scholar Lee TT, Hill MN, Hillard CJ, Gorzalka BB. Disruption of peri-adolescent endocannabinoid signaling modulates adult neuroendocrine and behavioral responses to stress in male rats. Neuropharmacology. 2015;99:89–97. Article CAS PubMed Google Scholar Watkins LE, Han S, Krystal JH, Southwick SM, Gelernter J, Pietrzak RH. Association between functional polymorphism in neuropeptide Y gene promoter rs16147 and resilience to traumatic stress in US military veterans. J Clin Psychiatry. 2017;78:e1058–e9. Article PubMed Google Scholar Schmeltzer SN, Vollmer LL, Rush JE, Weinert M, Dolgas CM, Sah R. History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats. Stress. 2015;18:244–53. Article CAS PubMed Google Scholar Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, et al. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med. 2013;5:188ra73. Article PubMed PubMed Central CAS Google Scholar Zhang Y, Simpson-Durand CD, Standifer KM. Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. Br J Pharmacol. 2015;172:571–82. Article CAS PubMed Google Scholar Andero R, Dias BG, Ressler KJ. A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation. Neuron. 2014;83:444–54. Article CAS PubMed PubMed Central Google Scholar Pivac N, Kozaric-Kovacic D, Grubisic-Ilic M, Nedic G, Rakos I, Nikolac M, et al. The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder. World J Biol Psychiatry. 2012;13:306–11. Article PubMed Google Scholar Felmingham KL, Dobson-Stone C, Schofield PR, Quirk GJ, Bryant RA. The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biol Psychiatry. 2013;73:1059–63. Article CAS PubMed PubMed Central Google Scholar Dai W, Kaminga AC, Wu X, Wen SW, Tan H, Yan J, et al. Brain-derived neurotropic factor Val66Met polymorphism and posttraumatic stress disorder among survivors of the 1998 Dongting Lake Flood in China. Biomed Res Int. 2017;2017:4569698. PubMed PubMed Central Google Scholar Felmingham KL, Zuj DV, Hsu KCM, Nicholson E, Palmer MA, Stuart K, et al. The BDNF Val66Met polymorphism moderates the relationship between posttraumatic stress disorder and fear extinction learning. Psychoneuroendocrinology. 2018;91:142–8. Article CAS PubMed Google Scholar Hill JL, Hardy NF, Jimenez DV, Maynard KR, Kardian AS, Pollock CJ, et al. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation. Transl Psychiatry. 2016;6:e873. Article CAS PubMed PubMed Central Google Scholar 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;45:919–26. Article PubMed PubMed Central Google Scholar Gorski JA, Balogh SA, Wehner JM, Jones KR. Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice. Neuroscience. 2003;121:341–54. Article CAS PubMed Google Scholar 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. Article CAS PubMed PubMed Central Google Scholar Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327:863–6. Article CAS PubMed PubMed Central Google Scholar Young DA, Neylan TC, O’Donovan A, Metzler T, Richards A, Ross JA, et al. The interaction of BDNF Val66Met, PTSD, and child abuse on psychophysiological reactivity and HPA axis function in a sample of Gulf War Veterans. J Affect Disord. 2018;235:52–60. Article CAS PubMed PubMed Central Google Scholar Dincheva I, Pattwell SS, Tessarollo L, Bath KG, Lee FS. BDNF modulates contextual fear learning during adolescence. Dev Neurosci. 2014;36:269–76. Article CAS PubMed Google Scholar Sippel LM, Han S, Watkins LE, Harpaz-Rotem I, Southwick SM, Krystal JH, et al. Oxytocin receptor gene polymorphisms, attachment, and PTSD: results from the National Health and Resilience in Veterans Study. J Psychiatr Res. 2017;94:139–47. Article PubMed PubMed Central Google Scholar Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR. Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav. 2000;37:145–55. Article CAS PubMed Google Scholar Amico JA, Mantella RC, Vollmer RR, Li X. Anxiety and stress responses in female oxytocin deficient mice. J Neuroendocrinol. 2004;16:319–24. Article CAS PubMed Google Scholar Myers AJ, Williams L, Gatt JM, McAuley-Clark EZ, Dobson-Stone C, Schofield PR, et al. Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress. J Psychiatr Res. 2014;59:93–100. Article PubMed PubMed Central Google Scholar Kim TY, Chung HG, Shin HS, Kim SJ, Choi JH, Chung MY, et al. Apolipoprotein E gene polymorphism, alcohol use, and their interactions in combat-related posttraumatic stress disorder. Depress Anxiety. 2013;30:1194–201. Article CAS PubMed Google Scholar Johnson LA, Zuloaga DG, Bidiman E, Marzulla T, Weber S, Wahbeh H, et al. ApoE2 exaggerates PTSD-related behavioral, cognitive, and neuroendocrine alterations. Neuropsychopharmacology. 2015;40:2443–53. Article CAS PubMed PubMed Central Google Scholar Olsen RH, Agam M, Davis MJ, Raber J. ApoE isoform-dependent deficits in extinction of contextual fear conditioning. Genes Brain Behav. 2012;11:806–12. Article CAS PubMed PubMed Central Google Scholar Krzyzewska IM, Ensink JBM, Nawijn L, Mul AN, Koch SB, Venema A, et al. Genetic variant in CACNA1C is associated with PTSD in traumatized police officers. Eur J Hum Genet. 2018;26:247–57. Article CAS PubMed PubMed Central Google Scholar Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, et al. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci USA. 2011;108:15432–7. Article CAS PubMed PubMed Central Google Scholar Logue MW, Baldwin C, Guffanti G, Melista E, Wolf EJ, Reardon AF, et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol Psychiatry. 2013;18:937–42. Article CAS PubMed Google Scholar Frédéric F, Chianale C, Oliver C, Mariani J. Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice. J Neurosci Res. 2006;83:1525–32. Article PubMed CAS Google Scholar Lowe SR, Meyers JL, Galea S, Aiello AE, Uddin M, Wildman DE, et al. RORA and posttraumatic stress trajectories: main effects and interactions with childhood physical abuse history. Brain Behav. 2015;5:e00323. Article PubMed PubMed Central Google Scholar Boku S, Toda H, Nakagawa S, Kato A, Inoue T, Koyama T, et al. Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biol Psychiatry. 2015;77:335–44. Article CAS PubMed Google Scholar Van Dijken HH, Van der Heyden JA, Mos J, Tilders FJ. Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats. Physiol Behav. 1992;51:787–94. Article PubMed Google Scholar McGuire J, Herman JP, Horn PS, Sallee FR, Sah R. Enhanced fear recall and emotional arousal in rats recovering from chronic variable stress. Physiol Behav. 2010;101:474–82. Article CAS PubMed PubMed Central Google Scholar What does the self animal model of PTSD show?The SEFL model of PTSD simulates non-associative sensitization of fear that occurs prior to the actual test event. Consequently, this is a useful model for examining how prior exposure to traumatic events mediates learned fear in rodents.
What is the PTSD model?The cognitive model suggests a person will develop PTSD if the person processes a traumatic event in a way that leads to a feeling of a present and severe threat.
What is the biopsychosocial model of PTSD?He proposed the biopsychosocial model which asserts that the interactions between biological, psychological, and social factors determine the cause, manifestation, and outcome of disease. The biopsychosocial model is commonly discussed in relation to mental health.
What coping strategies work best for PTSD?Positive ways of coping with PTSD:. Learn about trauma and PTSD.. Join a PTSD support group.. Practice relaxation techniques.. Pursue outdoor activities.. Confide in a person you trust.. Spend time with positive people.. Avoid alcohol and drugs.. Enjoy the peace of nature.. |
