远期恐惧记忆再巩固更新机制的线索选择性特点
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摘要
已有动物和人类研究均表明,通过记忆的再巩固更新机制能有效削弱新形成的条件性恐惧记忆(1天),并且存在线索选择性特点。然而创伤后应激障碍(PTSD)往往在形成相当一段时间后才能得到治疗,且现实生活中人们通常一次习得对多个线索的恐惧。因此找到针对多线索创伤记忆的有效治疗方法显得尤为重要。目前未有人研究远期恐惧记忆的再巩固更新机制是否存在线索选择性特点。为探究远期恐惧记忆(>7天)的再巩固更新机制是否同样存在线索选择性特点,本研究采用被试内实验设计,以皮肤电作为恐惧反应指标,多个线索作为条件刺激进行恐惧习得,习得14天后给被试单独呈现一个线索进行恐惧记忆提取,10分钟后进行消退训练,24小时后对不同线索进行自发恢复测试。结果显示:未提取线索的自发恢复程度显著高于提取线索。说明远期记忆(14天)的再巩固更新机制同样存在线索选择性特点,并确认了提取消退作为一种行为手段对远期恐惧记忆再巩固进行干预的有效性,对临床干预具有一定指导意义。
Recent studies of fear memories conducted in both humans and animals have suggested that new fear memories(1-day old) can be attenuated using a reconsolidation update mechanism, which is selective to the reactivated cue. In real life, patients with post-traumatic stress disorder(PTSD) usually receive treatment much after the traumatic memories form, and a traumatic event can be associated with multiple cues. However, the cue specificity of reconsolidation update mechanism in remote fear memories(> 7 days) remains largely unknown.To assess the cue specificity of remote fear memories(14 days) reconsolidation, we explored whether retrieval-extinction during the reconsolidation time window of remote fear memories is selective to the reactivated cue. We used a within-subject design, and skin-conductance response(SCR) served as the measurement. All subjects underwent fear conditioning by three coloured squares on day 1. Two squares(CSa+and CSb+) were paired with the shock on 38% of the trials. The third square(CS.) was never paired with the shock. Fourteen days later, subjects received a single presentation of CSa+(reactivated CS+) but not CSb+(non-reactivated CS+). Ten minutes after the reminder trial, extinction training was conducted(within the reconsolidation window). Twenty-four hours later, all subjects returned to the experiment room and received spontaneous recovery test of the remote fear memories.Results showed that there is no recovery for the reminded CS+, but significant recovery for non-reminded CS+ during spontaneous recovery testing. The recovery index(which was calculated as the first trial on day 16 minus the last trial on day 15 by differential SCR) of non-reminded CS+ was found to be significantly higher than that of the reminded CS+(p < 0.05). Thus, retrieval-extinction during reconsolidation window only attenuates the fear memory of the reactivated cue.Our findings demonstrated that the reconsolidation update mechanism is effective for attenuating remote fear memories, and that this mechanism is selective to the reactivated cue of remote memories. We provide evidence to support the ongoing efforts in the development of novel strategies to combat remote pathogenic memories, which we think could lead to a more effective application of the reconsolidation update mechanism.
Recent studies of fear memories conducted in both humans and animals have suggested that new fear memories(1-day old) can be attenuated using a reconsolidation update mechanism, which is selective to the reactivated cue. In real life, patients with post-traumatic stress disorder(PTSD) usually receive treatment much after the traumatic memories form, and a traumatic event can be associated with multiple cues. However, the cue specificity of reconsolidation update mechanism in remote fear memories(> 7 days) remains largely unknown.To assess the cue specificity of remote fear memories(14 days) reconsolidation, we explored whether retrieval-extinction during the reconsolidation time window of remote fear memories is selective to the reactivated cue. We used a within-subject design, and skin-conductance response(SCR) served as the measurement. All subjects underwent fear conditioning by three coloured squares on day 1. Two squares(CSa+and CSb+) were paired with the shock on 38% of the trials. The third square(CS.) was never paired with the shock. Fourteen days later, subjects received a single presentation of CSa+(reactivated CS+) but not CSb+(non-reactivated CS+). Ten minutes after the reminder trial, extinction training was conducted(within the reconsolidation window). Twenty-four hours later, all subjects returned to the experiment room and received spontaneous recovery test of the remote fear memories.Results showed that there is no recovery for the reminded CS+, but significant recovery for non-reminded CS+ during spontaneous recovery testing. The recovery index(which was calculated as the first trial on day 16 minus the last trial on day 15 by differential SCR) of non-reminded CS+ was found to be significantly higher than that of the reminded CS+(p < 0.05). Thus, retrieval-extinction during reconsolidation window only attenuates the fear memory of the reactivated cue.Our findings demonstrated that the reconsolidation update mechanism is effective for attenuating remote fear memories, and that this mechanism is selective to the reactivated cue of remote memories. We provide evidence to support the ongoing efforts in the development of novel strategies to combat remote pathogenic memories, which we think could lead to a more effective application of the reconsolidation update mechanism.
引文
Alberini,C.M.(2005).Mechanisms of memory stabilization:Are consolidation and reconsolidation similar or distinct processes?.Trends in Neurosciences,28(1),51-56.
Anagnostaras,S.G.,Maren,S.,&Fanselow,M.S.(1999).Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats:Within-subjects examination.Journal of Neuroscience,19(3),1106-1114.
Barlow,D.H.,Allen,L.B.,&Choate,M.L.(2016).Toward a unified treatment for emotional disorders.Behav Ther,35(2),205-230.
Bontempi,B.,Laurent-Demir,C.,Destrade,C.,&Jaffard,R.(1999).Time-dependent reorganization of brain circuitry underlying long-term memory storage.Nature,400(6745),671-675.
Bouton,M.E.(2002).Context,ambiguity,and unlearning:Sources of relapse after behavioral extinction.Biological Psychiatry,52(10),976-986.
Clem,R.L.,&Huganir,R.L.(2010).Calcium-permeable ampa receptor dynamics mediate fear memory erasure.Science,330(6007),1108-1112.
Debiec,J.,Ledoux,J.E.,&Nader,K.(2002).Cellular and systems reconsolidation in the hippocampus.Neuron,36(3),527-538.
Dudai,Y.(2004).The neurobiology of consolidations,or,how stable is the engram?Annual Review of Psychology,55(1),51-86.
Doyère,V.,Debiec,J.,Monfils,M-H.,Schafe,G.E.,&Ledoux,J.E.(2007).Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala.Nature Neuroscience,10(4),414-416.
Dutta,S.,&Sengupta,P.(2016).Men and mice:relating their ages.Life Sciences,152,244-248.
Eichenbaum,H.,Otto,T.,&Cohen,N.J.(1994).Two functional components of the hippocampal memory system.Behavioral&Brain Sciences,17(3),449-581.
Frankland,P.W.,O'Brien,C.,Ohno,M.,Kirkwood,A.,&Silva,A.J.(2001).α-camkii-dependent plasticity in the cortex is required for permanent memory.Nature,411(6835),309-313.
Kim,J.J.,&Fanselow,M.S.(1992).Modality-specific retrograde amnesia of fear.Science,256(5057),675-677.
Kindt,M.,Soeter,M.,&Vervliet,B.(2009).Beyond extinction:Erasing human fear responses and preventing the return of fear.Nature Neuroscience,12(3),256-258.
Ledoux,J.E.(1999).Emotion circuits in the brain.Annual Review of Neuroscience,23(23),155-184.
Mcclelland,J.L.,Mcnaughton,B.L.,&O'Reilly,R.C.(1995).Why there are complementary learning systems in the hippocampus and neocortex:Insights from the successes and failures of connectionist models of learning and memory.Psychological Review,102(3),419-457.
Mcgaugh,J.L.(2000).Memory--A century of consolidation.Science,287(5451),248-251.
Milekic,M.H.,&Alberini,C.M.(2002).Temporally graded requirement for protein synthesis following memory reactivation.Neuron,36(3),521-525.
Mineka,S.,&Zinbarg,R.(2006).A contemporary learning theory perspective on the etiology of anxiety disorders:It's not what you thought it was.American Psychologist,61(1),10-26.
Monfils,M.H.,Cowansage,K.K.,Klann,E.,&Ledoux,J.E.(2009).Extinction-reconsolidation boundaries:Key to Acta Psychol persistent attenuation of fear memories.Science,324(5929),951-955.Nader,K.(2003).Memory traces unbound.Trends in Neuroscience,26(2),65-72.
Nader,K.,Schafe,G.E.,&Le,D.J.(2000).Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature,406(6797),722-726.
Quevedo,J.,Vianna,M.R.M.,Roesler,R.,De-Paris,F.,Izquierdo,I.,&Rose,S.P.R.(1999).Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats:Protection from amnesia by pretraining but not pre-exposure to the task apparatus.Learning&Memory,6(6),600-607.
Quinn,R.(2005).Comparing rat's to human's age:How old is my rat in people years?Nutrition,21(6),775-777.Rie,I.,Hotaka,F.,Frankland,P.W.,&Satoshi,K.(2016).Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval.Elife,5:e17464.
Schiller,D.,Monfils,M-H.,Raio,C.M.,Johnson,D.C.,Ledoux,J.E.,&Phelps,E.A.(2010).Preventing the return of fear in humans using reconsolidation update mechanisms.Nature,463(7277),49-53.
Sotres-Bayon,F.,Diaz-Mataix,L.,Bush,D.E.A.,&Ledoux,J.E.(2009).Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction:Nr2b contribution.Cerebral Cortex,19(2),474-482.
Squire,L.R.,&Alvarez,P.(1995).Retrograde amnesia and memory consolidation:A neurobiological perspective.Current Opinion in Neurobiology,5(2),169-177.
Steinfurth,E.C.K.,Kanen,J.W.,Raio,C.M.,Clem,R.L.,Huganir,R.L.,&Phelps,E.A.(2014).Young and old pavlovian fear memories can be modified with extinction training during reconsolidation in humans.Learning&Memory,21(7),338-341.
Suzuki,A.,Josselyn,S.A.,Frankland,P.W.,Masushige,S.,Silva,A.J.,&Kida,S.(2004).Memory reconsolidation and extinction have distinct temporal and biochemical signatures.Journal of Neuroscience the Official Journal of the Society for Neuroscience,24(20),4787-4795.
Warren,V.T.,Anderson,K.M.,Kwon,C.,Bosshardt,L.,Jovanovic,T.,&Bradley,B.,Norrholm,S.D.(2014).Human fear extinction and return of fear using reconsolidation update mechanisms:The contribution of on-line expectancy ratings.Neurobiology of Learning&Memory,113(3),165-173.
Yang,Y.L.,Chao,P.K.,&Lu,K.T.(2006).Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear.Neuropsychopharmacology,31(5),912-924.
Anagnostaras,S.G.,Maren,S.,&Fanselow,M.S.(1999).Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats:Within-subjects examination.Journal of Neuroscience,19(3),1106-1114.
Barlow,D.H.,Allen,L.B.,&Choate,M.L.(2016).Toward a unified treatment for emotional disorders.Behav Ther,35(2),205-230.
Bontempi,B.,Laurent-Demir,C.,Destrade,C.,&Jaffard,R.(1999).Time-dependent reorganization of brain circuitry underlying long-term memory storage.Nature,400(6745),671-675.
Bouton,M.E.(2002).Context,ambiguity,and unlearning:Sources of relapse after behavioral extinction.Biological Psychiatry,52(10),976-986.
Clem,R.L.,&Huganir,R.L.(2010).Calcium-permeable ampa receptor dynamics mediate fear memory erasure.Science,330(6007),1108-1112.
Debiec,J.,Ledoux,J.E.,&Nader,K.(2002).Cellular and systems reconsolidation in the hippocampus.Neuron,36(3),527-538.
Dudai,Y.(2004).The neurobiology of consolidations,or,how stable is the engram?Annual Review of Psychology,55(1),51-86.
Doyère,V.,Debiec,J.,Monfils,M-H.,Schafe,G.E.,&Ledoux,J.E.(2007).Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala.Nature Neuroscience,10(4),414-416.
Dutta,S.,&Sengupta,P.(2016).Men and mice:relating their ages.Life Sciences,152,244-248.
Eichenbaum,H.,Otto,T.,&Cohen,N.J.(1994).Two functional components of the hippocampal memory system.Behavioral&Brain Sciences,17(3),449-581.
Frankland,P.W.,O'Brien,C.,Ohno,M.,Kirkwood,A.,&Silva,A.J.(2001).α-camkii-dependent plasticity in the cortex is required for permanent memory.Nature,411(6835),309-313.
Kim,J.J.,&Fanselow,M.S.(1992).Modality-specific retrograde amnesia of fear.Science,256(5057),675-677.
Kindt,M.,Soeter,M.,&Vervliet,B.(2009).Beyond extinction:Erasing human fear responses and preventing the return of fear.Nature Neuroscience,12(3),256-258.
Ledoux,J.E.(1999).Emotion circuits in the brain.Annual Review of Neuroscience,23(23),155-184.
Mcclelland,J.L.,Mcnaughton,B.L.,&O'Reilly,R.C.(1995).Why there are complementary learning systems in the hippocampus and neocortex:Insights from the successes and failures of connectionist models of learning and memory.Psychological Review,102(3),419-457.
Mcgaugh,J.L.(2000).Memory--A century of consolidation.Science,287(5451),248-251.
Milekic,M.H.,&Alberini,C.M.(2002).Temporally graded requirement for protein synthesis following memory reactivation.Neuron,36(3),521-525.
Mineka,S.,&Zinbarg,R.(2006).A contemporary learning theory perspective on the etiology of anxiety disorders:It's not what you thought it was.American Psychologist,61(1),10-26.
Monfils,M.H.,Cowansage,K.K.,Klann,E.,&Ledoux,J.E.(2009).Extinction-reconsolidation boundaries:Key to Acta Psychol persistent attenuation of fear memories.Science,324(5929),951-955.Nader,K.(2003).Memory traces unbound.Trends in Neuroscience,26(2),65-72.
Nader,K.,Schafe,G.E.,&Le,D.J.(2000).Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval.Nature,406(6797),722-726.
Quevedo,J.,Vianna,M.R.M.,Roesler,R.,De-Paris,F.,Izquierdo,I.,&Rose,S.P.R.(1999).Two time windows of anisomycin-induced amnesia for inhibitory avoidance training in rats:Protection from amnesia by pretraining but not pre-exposure to the task apparatus.Learning&Memory,6(6),600-607.
Quinn,R.(2005).Comparing rat's to human's age:How old is my rat in people years?Nutrition,21(6),775-777.Rie,I.,Hotaka,F.,Frankland,P.W.,&Satoshi,K.(2016).Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval.Elife,5:e17464.
Schiller,D.,Monfils,M-H.,Raio,C.M.,Johnson,D.C.,Ledoux,J.E.,&Phelps,E.A.(2010).Preventing the return of fear in humans using reconsolidation update mechanisms.Nature,463(7277),49-53.
Sotres-Bayon,F.,Diaz-Mataix,L.,Bush,D.E.A.,&Ledoux,J.E.(2009).Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction:Nr2b contribution.Cerebral Cortex,19(2),474-482.
Squire,L.R.,&Alvarez,P.(1995).Retrograde amnesia and memory consolidation:A neurobiological perspective.Current Opinion in Neurobiology,5(2),169-177.
Steinfurth,E.C.K.,Kanen,J.W.,Raio,C.M.,Clem,R.L.,Huganir,R.L.,&Phelps,E.A.(2014).Young and old pavlovian fear memories can be modified with extinction training during reconsolidation in humans.Learning&Memory,21(7),338-341.
Suzuki,A.,Josselyn,S.A.,Frankland,P.W.,Masushige,S.,Silva,A.J.,&Kida,S.(2004).Memory reconsolidation and extinction have distinct temporal and biochemical signatures.Journal of Neuroscience the Official Journal of the Society for Neuroscience,24(20),4787-4795.
Warren,V.T.,Anderson,K.M.,Kwon,C.,Bosshardt,L.,Jovanovic,T.,&Bradley,B.,Norrholm,S.D.(2014).Human fear extinction and return of fear using reconsolidation update mechanisms:The contribution of on-line expectancy ratings.Neurobiology of Learning&Memory,113(3),165-173.
Yang,Y.L.,Chao,P.K.,&Lu,K.T.(2006).Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear.Neuropsychopharmacology,31(5),912-924.
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