NEWS AND VIEWS Sleep aromatherapy curbs conditioned fear John T Wixted We know that humans are capable of learning during sleep.Research now shows that they are also capable of unlearning during sleep,and in a way that alters the neural representation of a feared stimulus:re-exposure to an odor during slow-wave sleep promotes extinction of an aversive visual association learned in that odor context. Over the past 20 years,two intriguing lines CS-faces.During a later nap,one of the two consolidation either updated the previous of research on the consolidation of memory odors was repeatedly presented to subjects as memory representation of the CS+being asso- have developed more or less independently of soon as they entered slow-wave sleep.The ques- ciated with shock (thereby recoding the tar- each other.One line of research has studied tion was whether the CS+previously paired get CS+as a safe stimulus)or instead created the role of sleep in the consolidation of emo- with shock in the presence of the re-exposed additional safe memories of the target CS+ tionally neutral memories.2and the other has odor(termed the target CS+)would lose any of face-memories that would inhibit the acces- studied the role of consolidation in extinguish- its ability to elicit a fear response and,if so,what sibility of older (but still available)memories ing conditioned fear(emotionally arousing changes in target CS+brain activity (before of the CS+paired with shock.Either way,the memories).In this issue,Hauner et al.5 bring versus after sleep)would be observed. accelerated consolidation of safe memories of these two lines of research together by showing Previous work with animals7.8 found that, the target CS+theoretically accounts for the that,in humans,a conditioned fear response to after pairing a tone CS+with shock,unrein- reduced hippocampal and entorhinal activity a stimulus that was previously associated with forced presentations of the fear-conditioning associated with post-exposure CS+presenta- mild electric shock can be extinguished during context(that is,exposure to the context by tions,and the newly encoded version of the slow-wave sleep without ever having to pres- itself)have the surprising effect of extinguish- safe CS+accounts for the altered pattern of ent the feared stimulus itself.Moreover,this ing the fear response previously elicited by the activity in the amygdala. effect is accompanied by changes in the neural CS+(as if CS+extinction trials had also been The idea that the presentation of the con- representation of the conditioned stimulus in presented).Hauner et al.5 observed the same ditioning context prompts the retrieval of the hippocampus and the amygdala. effect in humans when context re-exposure the previously conditioned CS+(thereby A recent study using classical conditioning was presented during slow-wave sleep. explaining why the CS+itself becomes extin- revealed that humans can acquire new learn- When the participants were later tested in guished despite not having been re-exposed) ing during sleep.Hauner et al.s took this the scanner while awake,the target CS+elic- is consistent with explanations of the con- further by investigating the 'un-conditioning ited a reduced fear response,but no such effect text re-exposure effect dating back to when of a learned response during sleep (Fig.1). was observed for the non-target CS+(that is, the phenomenon was first observed in rats?. While awake and in a scanner,human sub. for the CS+that was paired with shock in the However,a somewhat puzzling result reported jects underwent contextual fear conditioning presence of the non-re-exposed odor).Hauner by Hauner et al.is that context re-exposure in which two faces were paired with mild elec- et al.5 also found that hippocampal activity had the effect of extinguishing the previously tric shock (CS+stimuli)and two other faces associated with the target CS+following sleep conditioned CS+only when the odorant con- were not paired with shock (CS-stimuli). was reduced in comparison with pre-sleep lev- text was re-exposed during sleep.When the Two of the faces (one CS+and one CS-) els,whereas no changes were observed for the same context re-exposure procedure was used always appeared in the presence of one odor, non-target CS+.In addition,post-sleep ento- with an awake control group,the target CS+ whereas the other two faces always appeared rhinal activity associated with the target CS+ showed no evidence of extinction (and,not in the presence of a different odor.The odors was negatively correlated with the duration of surprisingly,no pre-versus post-sleep changes were conceptualized as context stimuli.As odorant re-exposure during slow-wave sleep in brain activity).Why would an effect that is expected,after having been paired with shock, (which varied across subjects)and,finally,the consistently observed in awake animals only both of the CS+faces elicited a significantly pattern of activity in the amygdala(assessed by be observed in sleeping humans?The answer elevated fear response (indicated by increased multivariate pattern analysis)was selectively is not known,but one possibility may be that skin conductance)in comparison with the altered for the target CS+. the awake state is not as homogenous as is The authors interpreted these findings to sometimes thought. mean that re-exposure to the odorant context An important variable determining the John T.Wixted is in the Department of Psychology, during slow-wave sleep cued retrieval ofthe tar- effectiveness of context re-exposure in creat- University of California San Diego,La Jolla, get CS+,perhaps accelerating the consolidation ing a safe memory of the CS+may be the rate California,USA. of memory for a new (safe')version of that face at which other memories are being formed e-mail:jwixted@ucsd.edu in the amygdala.Theoretically,this accelerated at the same time that the odorant context is 1510 VOLUME 16I NUMBER 11 I NOVEMBER 2013 NATURE NEUROSCIENCE1510 volume 16 | number 11 | NOVEMber 2013 nature neuroscience news and views consolidation either updated the previous memory representation of the CS+ being asso￾ciated with shock (thereby recoding the tar￾get CS+ as a safe stimulus) or instead created additional safe memories of the target CS+ face—memories that would inhibit the acces￾sibility of older (but still available) memories of the CS+ paired with shock. Either way, the accelerated consolidation of safe memories of the target CS+ theoretically accounts for the reduced hippocampal and entorhinal activity associated with post-exposure CS+ presenta￾tions, and the newly encoded version of the safe CS+ accounts for the altered pattern of activity in the amygdala. The idea that the presentation of the con￾ditioning context prompts the retrieval of the previously conditioned CS+ (thereby explaining why the CS+ itself becomes extin￾guished despite not having been re-exposed) is consistent with explanations of the con￾text re-exposure effect dating back to when the phenomenon was first observed in rats7. However, a somewhat puzzling result reported by Hauner et al.5 is that context re-exposure had the effect of extinguishing the previously conditioned CS+ only when the odorant con￾text was re-exposed during sleep. When the same context re-exposure procedure was used with an awake control group, the target CS+ showed no evidence of extinction (and, not surprisingly, no pre- versus post-sleep changes in brain activity). Why would an effect that is consistently observed in awake animals only be observed in sleeping humans? The answer is not known, but one possibility may be that the awake state is not as homogenous as is sometimes thought. An important variable determining the effectiveness of context re-exposure in creat￾ing a safe memory of the CS+ may be the rate at which other memories are being formed at the same time that the odorant context is John T. Wixted is in the Department of Psychology, University of California San Diego, La Jolla, California, USA. e-mail: jwixted@ucsd.edu Sleep aromatherapy curbs conditioned fear John T Wixted We know that humans are capable of learning during sleep. Research now shows that they are also capable of unlearning during sleep, and in a way that alters the neural representation of a feared stimulus: re-exposure to an odor during slow-wave sleep promotes extinction of an aversive visual association learned in that odor context. Over the past 20 years, two intriguing lines of research on the consolidation of memory have developed more or less independently of each other. One line of research has studied the role of sleep in the consolidation of emo￾tionally neutral memories1,2 and the other has studied the role of consolidation in extinguish￾ing conditioned fear3,4 (emotionally arousing memories). In this issue, Hauner et al.5 bring these two lines of research together by showing that, in humans, a conditioned fear response to a stimulus that was previously associated with mild electric shock can be extinguished during slow-wave sleep without ever having to pres￾ent the feared stimulus itself. Moreover, this effect is accompanied by changes in the neural representation of the conditioned stimulus in the hippocampus and the amygdala. A recent study using classical conditioning revealed that humans can acquire new learn￾ing during sleep6. Hauner et al.5 took this further by investigating the ‘un-conditioning’ of a learned response during sleep (Fig. 1). While awake and in a scanner, human sub￾jects underwent contextual fear conditioning in which two faces were paired with mild elec￾tric shock (CS+ stimuli) and two other faces were not paired with shock (CS– stimuli). Two of the faces (one CS+ and one CS–) always appeared in the presence of one odor, whereas the other two faces always appeared in the presence of a different odor. The odors were conceptualized as context stimuli. As expected, after having been paired with shock, both of the CS+ faces elicited a significantly elevated fear response (indicated by increased skin conductance) in comparison with the CS– faces. During a later nap, one of the two odors was repeatedly presented to subjects as soon as they entered slow-wave sleep. The ques￾tion was whether the CS+ previously paired with shock in the presence of the re-exposed odor (termed the target CS+) would lose any of its ability to elicit a fear response and, if so, what changes in target CS+ brain activity (before versus after sleep) would be observed. Previous work with animals7,8 found that, after pairing a tone CS+ with shock, unrein￾forced presentations of the fear-conditioning context (that is, exposure to the context by itself) have the surprising effect of extinguish￾ing the fear response previously elicited by the CS+ (as if CS+ extinction trials had also been presented). Hauner et al.5 observed the same effect in humans when context re-exposure was presented during slow-wave sleep. When the participants were later tested in the scanner while awake, the target CS+ elic￾ited a reduced fear response, but no such effect was observed for the non-target CS+ (that is, for the CS+ that was paired with shock in the presence of the non-re-exposed odor). Hauner et al.5 also found that hippocampal activity associated with the target CS+ following sleep was reduced in comparison with pre-sleep lev￾els, whereas no changes were observed for the non-target CS+. In addition, post-sleep ento￾rhinal activity associated with the target CS+ was negatively correlated with the duration of odorant re-exposure during slow-wave sleep (which varied across subjects) and, finally, the pattern of activity in the amygdala (assessed by multivariate pattern analysis) was selectively altered for the target CS+. The authors interpreted these findings to mean that re-exposure to the odorant context during slow-wave sleep cued retrieval of the tar￾get CS+, perhaps accelerating the consolidation of memory for a new (‘safe’) version of that face in the amygdala. Theoretically, this accelerated npg © 2013 Nature America, Inc. All rights reserved