Interventions on Fear Memory for the Prevention of Post-Traumatic Stress Disorder

Öz

The classical fear conditioning is extensively used in preclinical studies as an animal model for post traumatic stress disorder (PTSD). During the reconsolidation process, when memories are retrieved, the memory becomes susceptible to change and amenable to intervention. Interventions applied during the reconsolidation process triggered by exposure to a conditioned stimulus (CS) primarily lead to a decrease in fear responses triggered only by the exposed CS, without generalizing to other fear-related cues. However, in real-life scenarios, multiple CS’s can be linked to fear-inducing events. Therefore, recent studies have focused on the reactivation procedure with an unconditioned stimulus (US), which is believed to result in the reconsolidation of the entire fear memory. Interventions applied during the reconsolidation process that are triggered by US-based retrieval are considered more effective. Grounding on the fear memory studies activated by either CS or US, this review study discussed how acquired fear can be extinguished through behavioral and pharmacological interventions. Additionally, the brain regions involved in fear memory and the impact of gender differences on fear memory were also addressed. The aim of this review was to contribute to the field by exploring more effective treatment approaches for fear disorders.

Anahtar Kelimeler

• beta-adrenergic receptors
• fear conditioning
• NMDA receptors
• extinction
• Reconsolidation

Travma Sonrası Stres Bozukluğunun Önlenmesine Yönelik Korku Belleği Üzerine Yapılan Müdahaleler

Öz

Klasik korku koşullaması, klinik öncesi çalışmalarda travma sonrası stres bozukluğunu (TSSB) modellemede kullanılmaktadır. Yeniden-bütünleştirme sürecinde anılar belleğe geri çağrıldığında, bellek değişime açık bir hale gelir ve müdahale edilmeye uygundur. Koşullu uyarana (KU’lu uyaran) maruz bırakma ile tetiklenen yeniden-bütünleştirme sürecindeki müdahalelerin sadece maruz bırakılan KU’lu uyaranın tetiklediği korku tepkisinde azalmaya neden olduğu, korku ile ilişkili diğer ipuçlarına genellenmediği gözlenmiştir. Ancak günlük yaşamda, birden çok KU, korku uyandıran olayla ilişkilendirilebilir. Bu nedenle, son çalışmalarda tüm korku belleğinin yenidenbütünleştirme sürecine girmesine yol açtığı düşünülen, koşulsuz uyaran (KU’suz uyaran) ile geri çağırma prosedürüne odaklanılmıştır. KU’suz uyaran ile geri-çağırma ile tetiklenen yeniden-bütünleştirme sürecinde uygulanan müdahalelerin daha etkili olduğu düşünülmektedir. Bu derleme çalışmasında, KU’lu uyaran veya KU’suz uyaran ile aktive edilmiş korku belleği çalışmalara atıfta bulunularak, edinilmiş korkunun davranışsal ve farmakolojik müdahalelerle nasıl söndürülebileceğinden bahsedilmektedir. Ayrıca, korku belleğinde rol oynayan beyin bölgeleri ve cinsiyet farklılıklarının etkisi de ele alınmıştır. Bu derlemenin amacı, korku bozukluklarının daha etkili tedavi yaklaşımlarıyla nasıl çözülebileceğine yönelik alana katkıda bulunmaktır.

Anahtar Kelimeler

• beta-adrenergic reseptörler
• korku koşullaması
• NMDA reseptörleri
• sönme
• Yeniden-bütünleştirme

Kaynakça

1. Agren, T., Engman, J., Frick, A., Björkstrand, J., Larsson, E. M., Furmark, T. ve Fredrikson, M. (2012). Disruption of reconsolidation erases a fear memory trace in the human amygdala. Science, 337(6101), 1550–1552. https://doi.org/10.1126/science.1223006
2. Amaral, O. B., Luft, T., Cammarota, M., Izquierdo, I.ve Roesler, R. (2007). Temporary inactivation of the dorsal hippocampus induces a transient impairment in retrieval of aversive memory. Behavioural Brain Research, 180(2), 113–118. https://doi.org/10.1016/j.bbr.2007.02.031
3. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Publishing, Inc.
4. An, B., Kim, J., Park, K., Lee, S., Song, S. ve Choi, S. (2017). Amount of fear extinction changes its underlying mechanisms. eLife, 6, e25224. https://doi.org/10.7554/eLife.25224
5. Armstrong, T., Federman, S., Hampson, K., Crabtree, O. ve Olatunji, B. O. (2021). Fear Learning in Veterans with Combat-Related PTSD Is Linked to Anxiety Sensitivity: Evidence From Self-Report and Pupillometry. Behavior Therapy, 52(1), 149–161. https://doi.org/10.1016/j.beth.2020.03.006
6. Bechara, A., Tranel, D., Damasio, H., Adolphs, R., Rockland, C.ve Damasio, A. R. (1995). Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science, 269(5227), 1115–1118. https://doi.org/10.1126/science.7652558
7. Björkstrand, J., Agren, T., Åhs, F., Frick, A., Larsson, E. M., Hjorth, O., Furmark, T. ve Fredrikson, M. (2016). Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior. Current Biology: CB, 26(19), 2690–2695. https://doi.org/10.1016/j.cub.2016.08.022
8. Bouton, M. E. (2002). Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biological Psychiatry, 52(10), 976–986. https://doi.org/10.1016/s0006-3223(02)01546-9

9. Bouton, M. E. (2004). Context and behavioral processes in extinction. Learning & Memory, 11(5), 485-494. https://doi.org/10.1101/lm.78804
10. Bouton, M. E. ve Bolles, R. C. (1979). Contextual control of the extinction of conditioned fear. Learning and Motivation, 10(4), 445–466. https://doi.org/10.1016/0023-9690(79)90057-2
11. Bouton, M. E. ve Ricker, S. T. (1994). Renewal of extinguished responding in a second context. Animal Learning & Behavior, 22, 317-324. https://doi.org/10.3758/BF03209840
12. Briscione, M. A., Michopoulos, V., Jovanovic, T. ve Norrholm, S. D. (2017). Neuroendocrine Underpinnings of Increased Risk for Posttraumatic Stress Disorder in Women. In Vitamins and Hormones, 103, 53–83. https://doi.org/10.1016/bs.vh.2016.08.003
13. Brunet, A., Orr, S. P., Tremblay, J., Robertson, K., Nader, K. ve Pitman, R. K. (2008). Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. Journal of Psychiatric Research, 42(6), 503–506. https://doi.org/10.1016/j.jpsychires.2007.05.006
14. Brunet, A., Saumier, D., Liu, A., Streiner, D. L., Tremblay, J.ve Pitman, R. K. (2018). Reduction of PTSD symptoms with Pre-reactivation propranolol therapy: A randomized controlled trial. The American Journal of Psychiatry, 175(5), 427–433. https://doi.org/10.1176/appi.ajp.2017.17050481
15. Cahill, L., Prins, B., Weber, M. ve McGaugh, J. L. (1994). Beta-adrenergic activation and memory for emotional events. Nature, 371(6499), 702–704. https://doi.org/10.1038/371702a0
16. Chen, L., Huang, S., Yang, C., Wu, F., Zheng, Q., Yan, H., Yan, J., Luo, Y. ve Galaj, E. (2021). Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking. Frontiers In Pharmacology, 12, 686845. https://doi.org/10.3389/fphar.2021.686845
17. Christiansen, D. M. ve Hansen, M. (2015). Accounting for sex differences in PTSD: A multi-variable mediation model. European Journal Of Psychotraumatology, 6, 26068. https://doi.org/10.3402/ejpt.v6.26068
18. Davis, M. (1997). Neurobiology of fear responses: The role of the amygdala. The Journal of Neuropsychiatry and Clinical Neurosciences, 9(3), 382–402. https://doi.org/10.1176/jnp.9.3.382
19. Delgado, M. R., Olsson, A. ve Phelps, E. A. (2006). Extending animal models of fear conditioning to humans. Biological Psychology, 73(1), 39–48. https://doi.org/10.1016/j.biopsycho.2006.01.006
20. Duvarcı, S. ve Nader, K. (2004). Characterization of fear memory reconsolidation. Journal of Neuroscience, 24(42), 9269–9275. https://doi.org/10.1523/JNEUROSCI.2971-04.2004
21. Fendt, M. ve Fanselow, M. S. (1999). The neuroanatomical and neurochemical basis of conditioned fear. Neuroscience and Biobehavioral Reviews, 23(5), 743–760. https://doi.org/10.1016/s0149-7634(99)00016-0
22. Finnie, P. S. B. ve Nader, K. (2012). The role of metaplasticity mechanisms in regulating memory destabilization and reconsolidation. Neuroscience & Biobehavioral Reviews, 36(7), 1667–1707. https://doi.org/10.1016/j.neubiorev.2012.03.008
23. Furmark, T., Fischer, H., Wik, G., Larsson, M. ve Fredrikson, M. (1997). The amygdala and individual differences in human fear conditioning. Neuroreport, 8(18), 3957–3960. https://doi.org/10.1097/00001756-199712220-00021
24. Goodman, J. ve Packard, M. G. (2019). There Is More Than One Kind of Extinction Learning. Frontiers in Systems Neuroscience, 13, 16. https://doi.org/10.3389/fnsys.2019.00016
25. Hassija, C. M. ve Gray, M. J. (2007). Behavioral interventions for trauma and posttraumatic stress disorder. International Journal of Behavioral Consultation and Therapy, 3(2), 166-175. http://dx.doi.org/10.1037/h0100797
26. Holmes, E. A., James, E. L., Coode-Bate, T. ve Deeprose, C. (2009). Can playing the computer game "Tetris" reduce the build-up of flashbacks for trauma? A proposal from cognitive science. PloS One, 4(1), e4153. https://doi.org/10.1371/journal.pone.0004153
27. Kimerling, R., Ouimette, P. ve Wolfe, J. (Edl.). (2002). Gender and PTSD. Guilford Press.
28. Kindt, M. ve Soeter, M. (2013). Reconsolidation in a human fear conditioning study: A test of extinction as updating mechanism. Biological Psychology, 92(1), 43–50. https://doi.org/10.1016/j.biopsycho.2011.09.016
29. Kindt, M., Soeter, M. ve Vervliet, B. (2009). Beyond extinction: Erasing human fear responses and preventing the return of fear. Nature Neuroscience, 12(3), 256–258. https://doi.org/10.1038/nn.2271
30. Knight, D. C., Nguyen, H. T. ve Bandettini, P. A. (2005). The role of the human amygdala in the production of conditioned fear responses. NeuroImage, 26(4), 1193–1200. https://doi.org/10.1016/j.neuroimage.2005.03.020
31. Kuijer, E. J., Ferragud, A. ve Milton, A. L. (2020). Retrieval-Extinction and Relapse Prevention: Rewriting Maladaptive Drug Memories? In Frontiers in Behavioral Neuroscience, 14. https://doi.org/10.3389/fnbeh.2020.00023
32. LeDoux, J. E. (2000). Emotion circuits in the brain. Annual Review of Neuroscience, 23(1), 155–184. https://doi.org/10.1146/annurev.neuro.23.1.155
33. Lee, J. L. ve Hynds, R. E. (2013). Divergent cellular pathways of hippocampal memory consolidation and reconsolidation. Hippocampus, 23(3), 233–244. https://doi.org/10.1002/hipo.22083
34. Lee, J. L., Milton, A. L. ve Everitt, B. J. (2006). Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26(22), 5881–5887. https://doi.org/10.1523/JNEUROSCI.0323-06.2006
35. Lewis, D. J. (1976). A cognitive approach to experimental amnesia. The American Journal Of Psychology, 89(1), 51–80. https://doi.org/10.2307/1421753
36. Lewis, D. J. (1979). Psychobiology of active and inactive memory. Psychological Bulletin, 86(5), 1054–1083. https://doi.org/10.1037/0033-2909.86.5.1054
37. Liu, J., Zhao, L., Xue, Y., Shi, J., Suo, L., Luo, Y., Chai, B., Yang, C., Fang, Q., Zhang, Y., Bao, Y., Pickens, C. L. ve Lu, L. (2014). An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory. Biological Psychiatry, 76(11), 895–901. https://doi.org/10.1016/j.biopsych.2014.03.027
38. Luo, Y. X., Xue, Y. X., Liu, J. F., Shi, H. S., Jian, M., Han, Y., Zhu, W. L., Bao, Y. P., Wu, P., Ding, Z. B., Shen, H. W., Shi, J., Shaham, Y. ve Lu, L. (2015). A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking. Nature Communications, 6(1). https://doi.org/10.1038/ncomms8675
39. Maddox, S. A., Kilaru, V., Shin, J., Jovanovic, T., Almli, L. M., Dias, B. G., Norrholm, S. D., Fani, N., Michopoulos, V., Ding, Z., Conneely, K. N., Binder, E. B., Ressler, K. J. ve Smith, A. K. (2018). Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Molecular Psychiatry, 23(3), 658–665. https://doi.org/10.1038/mp.2016.250
40. Makkar, S. R., Zhang, S. Q. ve Cranney, J. (2010). Behavioral and neural analysis of GABA in the acquisition, consolidation, reconsolidation, and extinction of fear memory. Official Publication Of The American College Of Neuropsychopharmacology, 35(8), 1625–1652. https://doi.org/10.1038/npp.2010.53
41. Mamou, C. B., Gamache, K. ve Nader, K. (2006). NMDA receptors are critical for unleashing consolidated auditory fear memories. Nature Neuroscience, 9(10), 1237–1239. https://doi.org/10.1038/nn1778
42. Maren, S. ve Fanselow, M. S. (1995). Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. The Journal f Neuroscience: The Official Journal of The Society For Neuroscience, 15(11), 7548–7564. https://doi.org/10.1523/JNEUROSCI.15-11-07548.1995
43. Meir Drexler, S., Merz, C. J., Lissek, S., Tegenthoff, M. ve Wolf, O. T. (2019). Reactivation of the Unconditioned Stimulus Inhibits the Return of Fear Independent of Cortisol. Frontiers In Behavioral Neuroscience, 13, 254. https://doi.org/10.3389/fnbeh.2019.00254
44. Milekic, M. H.ve Alberini, C. M. (2002). Temporally graded requirement for protein synthesis following memory reactivation. Neuron, 36(3), 521–525. https://doi.org/10.1016/s0896-6273(02)00976-5
45. Monfils, M. H., Cowansage, K. K., Klann, E. ve Ledoux, J. E. (2009). Extinction-Reconsolidation boundaries: Key to persistent attenuation of fear memories. Science, 324(5929), 951–955. https://doi.org/10.1126/science.1167975
46. Moser, J. S., Hajcak, G., Simons, R. F. ve Foa, E. B. (2007). Posttraumatic stress disorder symptoms in trauma-exposed college students: the role of trauma-related cognitions, gender, and negative affect. Journal Of Anxiety Disorders, 21(8), 1039–1049. https://doi.org/10.1016/j.janxdis.2006.10.009
47. Nader, K. (2003). Memory traces unbound. Trends in Neurosciences, 26(2), 65–72. https://doi.org/10.1016/S0166-2236(02)00042-5
48. Nader, K., Schafe, G. E. ve Le Doux, J. E. (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature, 406(6797), 722–726. https://doi.org/10.1038/35021052
49. Nielsen, S. E., Ahmed, I. ve Cahill, L. (2013). Sex and menstrual cycle phase at encoding influence emotional memory for gist and detail. Neurobiology of Learning and Memory, 106, 56–65. https://doi.org/10.1016/j.nlm.2013.07.015
50. Nillni, Y. I., Pineles, S. L., Patton, S. C., Rouse, M. H., Sawyer, A. T. ve Rasmusson, A. M. (2015). Menstrual Cycle Effects on Psychological Symptoms in Women With PTSD. Journal of Traumatic Stress, 28(1), 1–7. https://doi.org/10.1002/jts.21984
51. O'Dell, T. J., Connor, S. A., Guglietta, R. ve Nguyen, P. V. (2015). β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learning & Memory, 22(9), 461–471. https://doi.org/10.1101/lm.031088.113
52. Olff, M. (2017). Sex and gender differences in post-traumatic stress disorder: an update. European Journal of Psychotraumatology, 8, 1351204. https://doi.org/10.1080/20008198.2017.1351204
53. Pineles, S. L., Blumenthal, T. D., Curreri, A. J., Nillni, Y. I., Putnam, K. M., Resick, P. A., Rasmusson, A. M. ve Orr, S. P. (2016). Prepulse inhibition deficits in women with PTSD. Psychophysiology, 53(9), 1377–1385. https://doi.org/10.1111/psyp.12679
54. Rescorla, R. A. ve Heth, C. D. (1975). Reinstatement of fear to an extinguished conditioned stimulus. Journal of Experimental Psychology. Animal Behavior Processes, 1(1), 88–96. https://doi.org/10.1037/0097-7403.1.1.88
55. Schiller, D., Monfils, M. H., Raio, C. M., Johnson, D. C., Ledoux, J. E. ve Phelps, E. A. (2010). Preventing the return of fear in humans using reconsolidation update mechanisms. Nature, 463(7277), 49–53. https://doi.org/10.1038/nature08637
56. Soeter, M. ve Kindt, M. (2010). Dissociating response systems: Erasing fear from memory. Neurobiology of Learning and Memory, 94(1), 30–41. https://doi.org/10.1016/j.nlm.2010.03.004
57. Soeter, M. ve Kindt, M. (2015). An Abrupt Transformation of Phobic Behavior after a Post-Retrieval Amnesic Agent. Biological Psychiatry, 78(12), 880–886. https://doi.org/10.1016/j.biopsych.2015.04.006
58. Thanellou, A. ve Green, J. T. (2011). Spontaneous recovery but not reinstatement of the extinguished conditioned eyeblink response in the rat. Behavioral Neuroscience, 125(4), 613–625. https://doi.org/10.1037/a0023582
59. Théberge, F. R., Milton, A. L., Belin, D., Lee, J. L. ve Everitt, B. J. (2010). The basolateral amygdala and nucleus accumbens core mediate dissociable aspects of drug memory reconsolidation. Learning & Memory, 17(9), 444–453. https://doi.org/10.1101/lm.1757410
60. Thomas, B. L., Larsen, N. ve Ayres, J. J. B. (2003). Role of context similarity in ABA, ABC, and AAB renewal paradigms: Implications for theories of renewal and for treating human phobias. Learning and Motivation, 34(4), 410–436. https://doi.org/10.1016/S0023-9690(03)00037-7
61. Villain, H., Benkahoul, A., Drougard, A., Lafragette, M., Muzotte, E., Pech, S., Bui, E., Brunet, A., Birmes, P. ve Roullet, P. (2016). Effects of propranolol, a β-noradrenergic antagonist, on memory consolidation and reconsolidation in mice. Frontiers in Behavioral Neuroscience, 10. 49 https://doi.org/10.3389/fnbeh.2016.00049
62. Zeng, X. X., Du, J., Zhuang, C. Q., Zhang, J. H., Jia, Y. L. ve Zheng, X. F. (2014). Unconditioned stimulus revaluation to promote conditioned fear extinction in the memory reconsolidation window. PloS One, 9(7), e101589. https://doi.org/10.1371/journal.pone.0101589
63. Zhu, R. T., Liu, X. H., Shi, Y. W., Wang, X. G., Xue, L. ve Zhao, H. (2018). Propranolol can induce PTSD-like memory impairments in rats. Brain and Behavior, 8(2), e00905. https://doi.org/10.1002/brb3.905
64. Zimmerman, J. M. ve Maren, S. (2010). NMDA receptor antagonism in the basolateral but not central amygdala blocks the extinction of Pavlovian fear conditioning in rats. The European Journal Of Neuroscience, 31(9), 1664–1670. https://doi.org/10.1111/j.1460-9568.2010.07223.x