Abstract
To do translational research on illness, a suitable animal model is needed. Since the symptoms of post-traumatic stress disorder (PTSD) exist across a wide range of mental functions such as fear memory, negative operant conditioning, cognition, mood, and vigilance, it is difficult to completely reproduce the pathophysiology of PTSD with a single animal model. Here, we will explain the 3WFS model in rats, in which rats are subjected to aversive footshock during the third week of the postnatal period. 3WFS rats show an abnormality that delays the extinction of contextual fear conditioning, which is antagonized by the administration of D-cycloserine, which in turn is thought to promote the extinction of fear memory in humans. This indicates that the 3WFS model reproduces the pathophysiology of PTSD intrusion symptoms (recollection of morbid fear memory). Based on previous data, we speculated that the impaired fear extinction in 3WFS rats is due to abnormalities in the 5-HT neural system of the hippocampus. In this chapter, we will present how to create a 3WFS model and introduce our research on fear memory and the 5-HT neural system of the hippocampus.
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References
Javidi H, Yadollahie M (2012) Post-traumatic stress disorder. Int J Occup Environ Med 3(1):2–9
Careaga MBL, Girardi CEN, Suchecki D (2016) Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. Neurosci Biobehav Rev 71:48–57. https://doi.org/10.1016/j.neubiorev.2016.08.023
Liberzon I, Abelson JL (2016) Context processing and the neurobiology of post-traumatic stress disorder. Neuron 92(1):14–30. https://doi.org/10.1016/j.neuron.2016.09.039
Herman JL (1992) Complex PTSD: a syndrome in survivors of prolonged and repeated trauma. J Trauma Stress 5(3):377–391
Shin YJ, Kim SM, Hong JS, Han DH (2021) Correlations between cognitive functions and clinical symptoms in adolescents with complex post-traumatic stress disorder. Front Public Health 9:586389. https://doi.org/10.3389/fpubh.2021.586389
Whitaker AM, Gilpin NW, Edwards S (2014) Animal models of post-traumatic stress disorder and recent neurobiological insights. Behav Pharmacol 25(5–6):398–409. https://doi.org/10.1097/FBP.0000000000000069
Deslauriers J, Toth M, Der-Avakian A, Risbrough VB (2018) Current status of animal models of posttraumatic stress disorder: behavioral and biological phenotypes, and future challenges in improving translation. Biol Psychiatry 83(10):895–907. https://doi.org/10.1016/j.biopsych.2017.11.019
Richter-Levin G, Stork O, Schmidt MV (2019) Animal models of PTSD: a challenge to be met. Mol Psychiatry 24(8):1135–1156. https://doi.org/10.1038/s41380-018-0272-5
Matsumoto M, Togashi H, Konno K, Koseki H, Hirata R, Izumi T, Yamaguchi T, Yoshioka M (2008) Early postnatal stress alters the extinction of context-dependent conditioned fear in adult rats. Pharmacol Biochem Behav 89(3):247–252. https://doi.org/10.1016/j.pbb.2007.12.017
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, Amsterdam
Lyttle K, Ohmura Y, Konno K, Yoshida T, Izumi T, Watanabe M, Yoshioka M (2015) Repeated fluvoxamine treatment recovers juvenile stress-induced morphological changes and depressive-like behavior in rats. Brain Res 1616:88–100. https://doi.org/10.1016/j.brainres.2015.04.058
Matsuzaki H, Izumi T, Horinouchi T, Boku S, Inoue T, Yamaguchi T, Yoshida T, Matsumoto M, Togashi H, Miwa S, Koyama T, Yoshioka M (2011) Juvenile stress attenuates the dorsal hippocampal postsynaptic 5-HT1A receptor function in adult rats. Psychopharmacology 214(1):329–337. https://doi.org/10.1007/s00213-010-1987-4
Li X, Inoue T, Abekawa T, Weng S, Nakagawa S, Izumi T, Koyama T (2006) 5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala. Eur J Pharmacol 532(1–2):74–80. https://doi.org/10.1016/j.ejphar.2005.12.008
Parnas AS, Weber M, Richardson R (2005) Effects of multiple exposures to D-cycloserine on extinction of conditioned fear in rats. Neurobiol Learn Mem 83(3):224–231. https://doi.org/10.1016/j.nlm.2005.01.001
Attari A, Rajabi F, Maracy MR (2014) D-cycloserine for treatment of numbing and avoidance in chronic post traumatic stress disorder: a randomized, double blind, clinical trial. J Res Med Sci 19(7):592–598
Pedraza LK, Sierra RO, Giachero M, Nunes-Souza W, Lotz FN, de Oliveira AL (2019) Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction by remodeling hippocampal dendritic spines and slowing down systems consolidation. Transl Psychiatry 9(1):53. https://doi.org/10.1038/s41398-019-0371-3
Young MB, Norrholm SD, Khoury LM, Jovanovic T, Rauch SAM, Reiff CM, Dunlop BW, Rothbaum BO, Howell LL (2017) Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA). Psychopharmacology 234(19):2883–2895. https://doi.org/10.1007/s00213-017-4684-8
Steckler T, Risbrough V (2012) Pharmacological treatment of PTSD - established and new approaches. Neuropharmacology 62(2):617–627. https://doi.org/10.1016/j.neuropharm.2011.06.012
McGuire JF, Lewin AB, Storch EA (2014) Enhancing exposure therapy for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder. Expert Rev Neurother 14(8):893–910. https://doi.org/10.1586/14737175.2014.934677
Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149:150–190. https://doi.org/10.1016/j.pharmthera.2014.12.004
Hoskins MD, Sinnerton R, Nakamura A, Underwood JFG, Slater A, Lewis C, Roberts NP, Bisson JI, Lee M, Clarke L (2021) Pharmacological-assisted psychotherapy for post-traumatic stress disorder: a systematic review and meta-analysis. Eur J Psychotraumatol 12(1):1853379. https://doi.org/10.1080/20008198.2020.1853379
Acknowledgments
This work was supported by JSPS KAKENHI Grant Number JP21K07506. The authors are grateful to Dr. Hiroko Togashi (former professor, Health Sciences University of Hokkaido) and Dr. Machiko Matsumoto (former associate professor, Health Sciences University of Hokkaido) who founded and developed juvenile stress research. The authors also express our appreciation to everyone who has participated in juvenile stress research.
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Shikanai, H., Matsuzaki, H., Kasai, R., Kusaka, S., Shindo, T., Izumi, T. (2023). 5-HT Neural System Abnormalities in PTSD Model Rats. In: Pinna, G. (eds) Translational Methods for PTSD Research. Neuromethods, vol 198. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3218-5_10
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DOI: https://doi.org/10.1007/978-1-0716-3218-5_10
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