条件性恐惧消退记忆的编码、巩固、提取及其干预*

doi:10.16719/j.cnki.1671-6981.20240405

摘要/Abstract

摘要： 促进和保持条件性恐惧消退是改善暴露疗法的关键。恐惧消退并没有消除原来的恐惧记忆,而是形成新的消退记忆与其竞争。良好的消退记忆需要成功的编码、巩固与提取,杏仁核、前额叶、海马以及中脑多巴胺系统在其不同阶段具有不同作用。增大预期错误、口服认知增强剂、神经调控、口服左旋多巴胺等方法能够有效干预消退记忆编码和巩固。未来研究还需扩充各阶段神经机制,探讨如何增强消退记忆稳定性以及干预消退记忆提取。

关键词: 条件性恐惧, 消退记忆, 编码, 巩固, 提取, 干预

Abstract: Exposure interventions based on the principles of extinction are effective methods for the treatment of anxiety disorders, but some patients still have problems such as spontaneous recovery, renewal, and reinstatement of fear. Therefore, how to promote and maintain fear extinction has been the key and difficulty of this field. Fear extinction refers to the formation of a new extinction memory established by presenting the conditioned stimulus (CS) repeatedly without the unconditioned stimulus (US). Good extinction learning is manifested not only in successful extinction, but also in retention of learned safety responses during subsequent extinction recall. This suggests that we need to explore the neural basis of extinction memory encoding, consolidation, and retrieval stages separately. The purpose of this paper is to discuss the effective intervention methods at each stage on the basis of systematically expounding the neural mechanism of memory extinction, and to provide some guidance for clinical treatment.
The Basolateral amygdala (BLA), infralimbic (IL) region of the prefrontal cortex, hippocampus, and the Dopamine (DA) system of the Ventral Tegmental Area (VTA) play distinct roles in the extinction of Pavlovian conditioned fear. (1) Successful extinction coding depends on the formation of "extinction memory neurons" in the BLA and the DA activity caused by anticipation errors. Furthermore, we suggest that the formation of "extinction memory neurons" in the BLA is regulated by DA caused by anticipation errors, but the neural circuit of this regulatory process is currently unclear. (2) The consolidation of extinction memory is mainly dependent on infralimbic-centered neural circuits, including the BLA, hippocampus, and DA system. The BLA mainly transmits the CS+-no US conditioned connection, the hippocampus inputs extinction memory context information, and DA is a key regulator of IL spontaneous activity. (3) The success of retrieval in extinction memory depends on whether the fear circuit or the extinction circuit is activated. There is another case of successful extinction recall: when CS+ is presented alone, it evokes fear memory but is immediately inhibited, that is, the retrieval stopping model, indicating that the individual consciously prevents negative thought intrusion. The two retrieval circuits do not conflict, and the prefrontal cortex is the center that provides inhibition.
According to the neural mechanism of extinction memory, we explore the intervention methods for different stages. Enhancing anticipatory errors during extinction learning and oral administration of DCS before extinction learning can enhance extinction memory encoding. To enhance extinction memory consolidation, neuromodulation, and L-DOPA after extinction learning are considered to be effective approaches. In addition, it can also be combined with proper exercise, and good sleep. In conclusion, although there are some methods of intervening in memory extinction, it is still necessary to explore diverse methods to maximize the optimization of clinical treatment.
The following aspects should be considered in future research. (1) Extinction memory traces weaken over time and are impaired in non-extinction contexts, suggesting that we need to deepen extinction memory traces and promote extinction generalization in the future. (2) Future research needs to continue to expand the neural mechanism of extinction memory at each stage, including enriching the neural mechanism of memory coding, exploring the regulation mechanism of the dopamine system, and the effect of prefrontal activity during sleep on consolidation. (3) Interfering with extinction memory retrieval is a new direction to enhance fear, such as the use of neuromodulation, positive emotion induction, and repetition strategies.

Key words: conditioned fear, extinction memory, encoding, consolidation, retrieval, intervention

黄益霞, 王金霞, 雷怡. 条件性恐惧消退记忆的编码、巩固、提取及其干预^*[J]. 心理科学, 2024, 47(4): 803-811.

Huang Yixia, Wang Jinxia, Lei Yi. Encoding, Consolidation, Retrieval and Intervention of Conditioned Fear Extinction Memory[J]. Journal of Psychological Science, 2024, 47(4): 803-811.

参考文献

[1] 雷怡, 王金霞, 陈庆飞, 张文海, 梅颖. (2017). 分类和概念对恐惧泛化的影响机制. 心理科学, 40(5), 1266-1273.
[2] Aksoy-Aksel A., Gall A., Seewald A., Ferraguti F., & Ehrlich I. (2021). Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms in male mice. eLife, 10, Article e63708.
[3] Anderson, M. C., & Floresco, S. B. (2022). Prefrontal-hippocampal interactions supporting the extinction of emotional memories: The retrieval stopping model. Neuropsychopharmacology, 47(1), 180-195.
[4] Apšvalka D., Ferreira C. S., Schmitz T. W., Rowe J. B., & Anderson M. C. (2022). Dynamic targeting enables domain-general inhibitory control over action and thought by the prefrontal cortex. Nature Communications, 13(1), Article 274.
[5] Berretta S., Pantazopoulos H., Caldera M., Pantazopoulos P., & Paré D. (2005). Infralimbic cortex activation increases c-fos expression in intercalated neurons of the amygdala. Neuroscience, 132(4), 943-953.
[6] Bloodgood D. W., Sugam J. A., Holmes A., & Kash T. L. (2018). Fear extinction requires infralimbic cortex projections to the basolateral amygdala. Translational Psychiatry, 8(1), Article 60.
[7] Born, J., & Wilhelm, I. (2012). System consolidation of memory during sleep. Psychological Research, 76(2), 192-203.
[8] Bottary R., Seo J., Daffre C., Gazecki S., Moore K. N., Kopotiyenko K., & Pace-Schott E. F. (2020). Fear extinction memory is negatively associated with REM sleep in insomnia disorder. Sleep, 43(7), Article zsaa007.
[9] Burgos-Robles A., Vidal-Gonzalez I., Santini E., & Quirk G. J. (2007). Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron, 53(6), 871-880.
[10] Chen W. H., Wang Y., Wang X. Q., & Li H. (2017). Neural circuits involved in the renewal of extinguished fear. IUBMB Life, 69(7), 470-478.
[11] Cho J. H., Deisseroth K., & Bolshakov V. Y. (2013). Synaptic encoding of fear extinction in mPFC-amygdala circuits. Neuron, 80(6), 1491-1507.
[12] Cisler J. M., Privratsky A. A., Sartin-Tarm A., Sellnow K., Ross M., Weaver S., & Kilts C. D. (2020). L-DOPA and consolidation of fear extinction learning among women with posttraumatic stress disorder. Translational Psychiatry, 10(1), Article 287.
[13] Craske M. G., Kircanski K., Zelikowsky M., Mystkowski J., Chowdhury N., & Baker A. (2008). Optimizing inhibitory learning during exposure therapy. Behaviour Research and Therapy, 46(1), 5-27.
[14] Craske M. G., Waters A. M., Bergman R. L., Naliboff B., Lipp O. V., Negoro H., & Ornitz E. M. (2008). Is aversive learning a marker of risk for anxiety disorders in children? Behaviour Research and Therapy, 46(8), 954-967.
[15] De Jong J. W., Afjei S. A., Dorocic I. P., Peck J. R., Liu C., Kim C. K., & Lammel S. (2019). A Neural circuit mechanism for encoding aversive stimuli in the mesolimbic dopamine system. Neuron, 101(1), 133-151.e7.
[16] De Kleine R. A., Smits J. A. J., Hendriks G. J., Becker E. S., & van Minnen A. (2015). Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder. Journal of Anxiety Disorders, 34, 63-67.
[17] Depue B. E., Curran T., & Banich M. T. (2007). Prefrontal regions orchestrate suppression of emotional memories via a two-phase process. Science, 317(5835), 215-219.
[18] Do-Monte F. H., Manzano-Nieves G., Quiñones-Laracuente K., Ramos-Medina L., & Quirk G. J. (2015). Revisiting the role of infralimbic cortex in fear extinction with optogenetics. The Journal of Neuroscience, 35(8), 3607-3615.
[19] Dunsmoor J. E., Campese V. D., Ceceli A. O., LeDoux J. E., & Phelps E. A. (2015). Novelty-facilitated extinction: Providing a novel outcome in place of an expected threat diminishes recovery of defensive responses. Biological Psychiatry, 78(3), 203-209.
[20] Ebrahimi C., Gechter J., Lueken U., Schlagenhauf F., Wittchen H. U., Hamm A. O., & Ströhle A. (2020). Augmenting extinction learning with D-cycloserine reduces return of fear: A randomized, placebo-controlled fMRI study. Neuropsychopharmacology, 45(3), 499-506.
[21] Ebrahimi C., Koch S. P., Friedel E., Crespo I., Fydrich T., Ströhle A., & Schlagenhauf F. (2017). Combining D-cycloserine with appetitive extinction learning modulates amygdala activity during recall. Neurobiology of Learning and Memory, 142, 209-217.
[22] Gerlicher A. M. V., Tüscher O., & Kalisch R. (2018). Dopamine-dependent prefrontal reactivations explain long-term benefit of fear extinction. Nature Communications, 9(1), Article 4294.
[23] Gerlicher A. M. V., Tüscher O., & Kalisch R. (2019). L-DOPA improves extinction memory retrieval after successful fear extinction. Psychopharmacology, 236(12), 3401-3412.
[24] Gold A. L., Abend R., Britton J. C., Behrens B., Farber M., Ronkin E., & Pine D. S. (2020). Age differences in the neural correlates of anxiety disorders: An fMRI study of response to learned threat. The American Journal of Psychiatry, 177(5), 454-463.
[25] Guo Y. H., Schmitz T. W., Mur M., Ferreira C. S., & Anderson M. C. (2018). A supramodal role of the basal ganglia in memory and motor inhibition: Meta-analytic evidence. Neuropsychologia, 108, 117-134.
[26] Hikind, N., & Maroun, M. (2008). Microinfusion of the D1 receptor antagonist, SCH23390 into the IL but not the BLA impairs consolidation of extinction of auditory fear conditioning. Neurobiology of Learning and Memory, 90(1), 217-222.
[27] Hugues S., Deschaux O., & Garcia R. (2004). Postextinction infusion of a mitogen-activated protein kinase inhibitor into the medial prefrontal cortex impairs memory of the extinction of conditioned fear. Learning and Memory, 11(5), 540-543.
[28] Keller N. E., Hennings A. C., & Dunsmoor J. E. (2020). Behavioral and neural processes in counterconditioning: Past and future directions. Behaviour Research and Therapy, 125, Article 103532.
[29] Kensinger, E. A., & Ford, J. H. (2020). Retrieval of emotional events from memory. Annual Review of Psychology, 71, 251-272.
[30] Keyan, D., & Bryant, R. A. (2019). Acute exercise-induced enhancement of fear inhibition is moderated by BDNF Val66Met polymorphism. Translational Psychiatry, 9(1), Article 131.
[31] Kim, W. B., & Cho, J. H. (2017). Synaptic targeting of double-projecting ventral CA1 hippocampal neurons to the medial prefrontal cortex and basal amygdala. The Journal of Neuroscience, 37(19), 4868-4882.
[32] Lacagnina A. F., Brockway E. T., Crovetti C. R., Shue F., McCarty M. J., Sattler K. P., & Drew M. R. (2019). Distinct hippocampal engrams control extinction and relapse of fear memory. Nature Neuroscience, 22(5), 753-761.
[33] Laurent, V., & Westbrook, R. F. (2008). Distinct contributions of the basolateral amygdala and the medial prefrontal cortex to learning and relearning extinction of context conditioned fear. Learning and Memory, 15(9), 657-666.
[34] Laurent V., Westbrook R. F., & Balleine B. W. (2022). Affective valence regulates associative competition in Pavlovian conditioning. Frontiers in Behavioral Neuroscience, 16, Article 801474.
[35] Lee J. H., Lee S., & Kim J. H. (2017). Amygdala circuits for fear memory: A key role for dopamine regulation. The Neuroscientist, 23(5), 542-553.
[36] Lucas K., Luck C. C., & Lipp O. V. (2018). Novelty-facilitated extinction and the reinstatement of conditional human fear. Behaviour Research and Therapy, 109, 68-74.
[37] Luo R., Uematsu A., Weitemier A., Aquili L., Koivumaa J., McHugh T. J., & Johansen J. P. (2018). A dopaminergic switch for fear to safety transitions. Nature Communications, 9(1), Article 2483.
[38] Marek R., Jin J. J., Goode T. D., Giustino T. F., Wang Q., Acca G. M., & Sah P. (2018). Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. Nature Neuroscience, 21(3), 384-392.
[39] Marek R., Sun Y. J., & Sah P. (2019). Neural circuits for a top-down control of fear and extinction. Psychopharmacology, 236(1), 313-320.
[40] Marián M., Szőllősi Á., & Racsmány M. (2018). Anodal transcranial direct current stimulation of the right dorsolateral prefrontal cortex impairs long-term retention of reencountered memories. Cortex, 108, 80-91.
[41] McGarry, L. M., & Carter, A. G. (2017). Prefrontal cortex drives distinct projection neurons in the basolateral amygdala. Cell Reports, 21(6), 1426-1433.
[42] McLean C. P., Levy H. C., Miller M. L., & Tolin D. F. (2022). Exposure therapy for PTSD: A meta-analysis. Clinical Psychology Review, 91, Article 102115.
[43] Ney L. J., Vicario C. M., Nitsche M. A., & Felmingham K. L. (2021). Timing matters: Transcranial direct current stimulation after extinction learning impairs subsequent fear extinction retention. Neurobiology of Learning and Memory, 177, Article 107356.
[44] Otis J. M., Namboodiri V. M. K., Matan A. M., Voets E. S., Mohorn E. P., Kosyk O., & Stuber G. D. (2017). Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature, 543(7643), 103-107.
[45] Quirk, G. J. (2002). Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery. Learning and Memory, 9(6), 402-407.
[46] Rothbaum B. O., Price M., Jovanovic T., Norrholm S. D., Gerardi M., Dunlop B., & Ressler K. J. (2014). A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. The American Journal of Psychiatry, 171(6), 640-648.
[47] Salinas-Hernández X. I., Vogel P., Betz S., Kalisch R., Sigurdsson T., & Duvarci S. (2018). Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes. eLife, 7, Article e38818.
[48] Schultz, W. (2016). Dopamine reward prediction error coding. Dialogues in Clinical Neuroscience, 18(1), 23-32.
[49] Senn V., Wolff S. B. E., Herry C., Grenier F., Ehrlich I., Gründemann J., & Lüthi A. (2014). Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron, 81(2), 428-437.
[50] Shiban Y., Schelhorn I., Pauli P., & Mühlberger A. (2015). Effect of combined multiple contexts and multiple stimuli exposure in spider phobia: A randomized clinical trial in virtual reality. Behaviour Research and Therapy, 71, 45-53.
[51] Singewald, N., & Holmes, A. (2019). Rodent models of impaired fear extinction. Psychopharmacology, 236(1), 21-32.
[52] Smits J. A. J., Pollack M. H., Rosenfield D., Otto M. W., Dowd S., Carpenter J., & Hofmann S. G. (2020). Dose timing of D-cycloserine to augment exposure therapy for social anxiety disorder: A randomized clinical trial. JAMA Network Open, 3(6), Article e206777.
[53] Soler-Cedeño O., Torres-Rodríguez O., Bernard F., Maldonado L., Hernández A., & Porter J. T. (2019). Plasticity of NMDA receptors at ventral hippocampal synapses in the infralimbic cortex regulates cued fear. eNeuro, 6(2), Article ENEURO.0354-18.2019.
[54] Squire, L. R. (1986). Mechanisms of memory. Science, 232(4758), 1612-1619.
[55] Strobel C., Marek R., Gooch H. M., Sullivan R. K. P., & Sah P. (2015). Prefrontal and auditory input to intercalated neurons of the amygdala. Cell Reports, 10(9), 1435-1442.
[56] Suarez-Jimenez B., Albajes-Eizagirre A., Lazarov A., Zhu X., Harrison B. J., Radua J., & Fullana M. A. (2020). Neural signatures of conditioning, extinction learning, and extinction recall in posttraumatic stress disorder: A meta-analysis of functional magnetic resonance imaging studies. Psychological Medicine, 50(9), 1442-1451.
[57] Van't Wout M., Longo S. M., Reddy M. K., Philip N. S., Bowker M. T., & Greenberg B. D. (2017). Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder. Brain and Behavior, 7(5), Article e00681.
[58] Wang Q., Jin J. J., & Maren S. (2016). Renewal of extinguished fear activates ventral hippocampal neurons projecting to the prelimbic and infralimbic cortices in rats. Neurobiology of Learning and Memory, 134, 38-43.
[59] Waters A. M., Kershaw R., & Lipp O. V. (2018). Multiple fear-related stimuli enhance physiological arousal during extinction and reduce physiological arousal to novel stimuli and the threat conditioned stimulus. Behaviour Research and Therapy, 106, 28-36.
[60] Weele C. M. V., Siciliano C. A., & Tye K. M. (2019). Dopamine tunes prefrontal outputs to orchestrate aversive processing. Brain Research, 1713, 16-31.
[61] Xia J., Du Y. Q., Han J. Y., Liu G., & Wang X. M. (2015). D-cycloserine augmentation in behavioral therapy for obsessive-compulsive disorder: A meta-analysis. Drug Design, Development and Therapy, 9, 2101-2117.
[62] Zbozinek T. D., Holmes E. A., & Craske M. G. (2015). The effect of positive mood induction on reducing reinstatement fear: Relevance for long term outcomes of exposure therapy. Behaviour Research and Therapy, 71, 65-75.
[63] Zhang X. Y., Kim J., & Tonegawa S. (2020). Amygdala reward neurons form and store fear extinction memory. Neuron, 105(6), 1077-1093.e7.
[64] Zimmerman, J. M., & 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.

条件性恐惧消退记忆的编码、巩固、提取及其干预^*

Encoding, Consolidation, Retrieval and Intervention of Conditioned Fear Extinction Memory

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