《气味科学中的健康密码》课程教学资源（阅读材料）Sleep aromatherapy curbs conditioned fear

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 NEUROSCIENCE

1510 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

NEWS AND VIEWS Figure 1 Simplified illustration of the Phase 1:awake conditioning in scanner experimental protocol.In phase 1,two faces (face 1 and face 3)were presented without being Target odor Non-target odor paired with shock and two other faces (face 2 and face 4)were paired with shock.Face 1 (the target CS-)and face 2 (the target CS+)were presented in the presence of one odor(the target odor,here ace 2 Face 3: Face 4: oranges),and face 3(the non-target CS-)and face 4(the non-target CS+)were presented in the presence of a different odor (the non-target odor, here pine).After having been paired with shock, both face 2 and face 4 elicited fear (indicated by an elevated skin-conductance response).In Target CS Non-target CS- Non-target CS+ phase 2,the subject napped and the target odor was re-exposed during slow-wave sleep in 30-s on-off cycles.Finally,in phase 3,the faces were presented again.Face 2 (the target CS+)then elicited less fear than face 4(the non-target CS+). REM,rapid eye motion sleep. re-exposed.Presumably,no competing mem- ories were formed when context re-exposure occurred during slow-wave sleep (and probably not when animals were re-exposed to a famil- Phase 2:target odorant context re-exposure during sleep sy6u iar context in earlier studies either).In con- trast,awake subjects in Hauner et al.viewed a nature-themed documentary film during odorant context re-exposure.Memory for the documentary film was not subsequently tested, but it seems likely that,had it been tested,the subjects would have remembered much of Stage Stage 2 Slow-wave sleep REM what they had seen in the film.The encoding of these film-related memories during odor- ant context re-exposure undoubtedly activated Phase 3:awake testing in scanner hippocampal encoding and consolidation pro- cesses that could interfere with other memo- Target odor Non-target odor 8100 ries formed around the same time.Thus,for T FEAR O the awake controls,film-related memories may have competed with the consolidation of any Face 1: Face 3: F3084 CS+memories that were concomitantly cued by the presentation of the odorant context (perhaps preventing consolidation of memory for a safe version of that stimulus). In studies using rats,a distinction is often drawn between active wake versus quiet wake Target CS- Target CS+ Non-target CS- Non-target CS+ In Buzsaki's two-stage model ofencoding and consolidationo,for example,active wake (such as exploration of a novel environment) is associated with encoding activity,whereas quiet wake is associated with the consolida- tion of recently formed memories (perhaps via neural replay,which occurs not only dur- ing slow-wave sleep,but also during quiet wakell).Presumably,humans watching a re-exposure-memories that might otherwise be considerably greater if it were possible to nature-themed documentary film are not in have been consolidated if a state of quiet wake achieve in the awake state.Context stimuli a state of quiet wake,but are instead in a state had been in effect instead12.13.Indeed,inother often consist of visual cues,such as when a that is more akin to rats exploring a novel envi- kinds oflearning tasks,post-learning wakeful PTSD patient acquires an exaggerated fear of ronment(that is,in a state that is more akin to resting has yielded effects on the consolidation driving in close proximity to a truck following active wake).If so,the encoding of extrane- of memory not unlike the effects associated a serious motor vehicle accident.Obviously. ous memories that will inevitably occur dur- with slow-wave sleep4.15. visual context cues cannot be conveniently ing active wake may serve to interfere with The potential therapeutic benefit of extin- presented during sleep,but the results reported recently formed (and,therefore,still labile) guishing a feared CS without having to pre- by Hauner et als raise the possibility that memories of the safe CS+cued by context sent the CS itself is considerable and would context re-exposure during quiet wake may NATURE NEUROSCIENCE VOLUME 16 NUMBER 11I NOVEMBER 2013 1511

nature neuroscience volume 16 | number 11 | NOVEMber 2013 1511 news and views be considerably greater if it were possible to achieve in the awake state. Context stimuli often consist of visual cues, such as when a PTSD patient acquires an exaggerated fear of driving in close proximity to a truck following a serious motor vehicle accident. Obviously, visual context cues cannot be conveniently presented during sleep, but the results reported by Hauner et al.5 raise the possibility that context re-exposure during quiet wake may re-exposed. Presumably, no competing mem￾ories were formed when context re-exposure occurred during slow-wave sleep (and probably not when animals were re-exposed to a famil￾iar context in earlier studies either). In con￾trast, awake subjects in Hauner et al.5 viewed a nature-themed documentary film during odorant context re-exposure. Memory for the documentary film was not subsequently tested, but it seems likely that, had it been tested, the subjects would have remembered much of what they had seen in the film. The encoding of these film-related memories during odor￾ant context re-exposure undoubtedly activated hippocampal encoding and consolidation pro￾cesses that could interfere with other memo￾ries formed around the same time9. Thus, for the awake controls, film-related memories may have competed with the consolidation of any CS+ memories that were concomitantly cued by the presentation of the odorant context (perhaps preventing consolidation of memory for a safe version of that stimulus). In studies using rats, a distinction is often drawn between active wake versus quiet wake. In Buzsáki’s two-stage model of encoding and consolidation10, for example, active wake (such as exploration of a novel environment) is associated with encoding activity, whereas quiet wake is associated with the consolida￾tion of recently formed memories (perhaps via neural replay, which occurs not only dur￾ing slow-wave sleep, but also during quiet wake11). Presumably, humans watching a nature-themed documentary film are not in a state of quiet wake, but are instead in a state that is more akin to rats exploring a novel envi￾ronment (that is, in a state that is more akin to active wake). If so, the encoding of extrane￾ous memories that will inevitably occur dur￾ing active wake may serve to interfere with recently formed (and, therefore, still labile) memories of the safe CS+ cued by context re-exposure—memories that might otherwise have been consolidated if a state of quiet wake had been in effect instead12,13. Indeed, in other kinds of learning tasks, post-learning wakeful resting has yielded effects on the consolidation of memory not unlike the effects associated with slow-wave sleep14,15. The potential therapeutic benefit of extin￾guishing a feared CS without having to pre￾sent the CS itself is considerable and would Marina Corral Spence Figure 1 Simplified illustration of the experimental protocol. In phase 1, two faces (face 1 and face 3) were presented without being paired with shock and two other faces (face 2 and face 4) were paired with shock. Face 1 (the target CS–) and face 2 (the target CS+) were presented in the presence of one odor (the target odor, here oranges), and face 3 (the non-target CS–) and face 4 (the non-target CS+) were presented in the presence of a different odor (the non-target odor, here pine). After having been paired with shock, both face 2 and face 4 elicited fear (indicated by an elevated skin-conductance response). In phase 2, the subject napped and the target odor was re-exposed during slow-wave sleep in 30-s on-off cycles. Finally, in phase 3, the faces were presented again. Face 2 (the target CS+) then elicited less fear than face 4 (the non-target CS+). REM, rapid eye motion sleep. FEAR FEAR FEAR FEAR Phase 1: awake conditioning in scanner Phase 2: target odorant context re-exposure during sleep Target CS– Target CS+ Non-target CS– Non-target CS+ Target odor Non-target odor Stage 1 Stage 2 Slow-wave sleep REM Face 1: Face 2: Face 3: Face 4: Target CS– Target CS+ Non-target CS– Non-target CS+ Face 1: Face 2: Face 3: Face 4: Phase 3: awake testing in scanner Target odor Non-target odor npg © 2013 Nature America, Inc. All rights reserved

NEWS AND VIEWS reduce fear-related responses to a conditioned awake or asleep)?The answers to theoretically 5.Hauner,K.K.,Howard,J.D.,Zelano,C.Gottfried,J.A. stimulus that does not actually have to be pre- intriguing questions such as these are not yet Nat.Neurosci.16,1553-1555(2013). 6.Arzi,A.et al.Nat.Neurosci.15,1460-1465 sented to the patient.Testing the Hauner et al.5 known.Whether or not such effects can be (2012). context re-exposure procedure in humans who achieved during the awake state,the study by 7. Marlin,N.A.Leam.Motiv.13,526-541 (1982). 8.Stout,S.C.Miller,R.Behav.Processes 66,7-16 are in a state of quiet wake would seem to be a Hauner et al.s adds a new dimension to our (2004). logical next step to further evaluate the poten- understanding of the learning-or,to be more 9.Ben-Yakov,A.,Eshel,N.Dudai,Y.J.Exp.Psychol. tial clinical relevance of this procedure.These precise,unlearning-that can be achieved by Gen. published online,doi:10.1037/a0033558 (1July2013). results may show that the extinction-related the sleeping brain. 10.Buzsaki.G.Neurosci 31.551-570(1989). effects of procedures used during slow-wave 11.Karlsson,M.P.Frank,L.M.Nat.Neurosci.12, COMPETING FINANCIAL INTERESTS 913-918(2009). sleep are also true of procedures used during The author declares no competing financial interests. 12.Wixted,J.T.Annu.Rev.Psychol.55,235-269 quiet wake.Such a finding would have both (2004). clinical and theoretical relevance.Which 1.Rasch,B.,Buchel,C..Gais,S.Born,J.Science 315 13.Mednick,S.C.,Cai,D.J.,Shuman,T. 1426-1429(2007). Anagnostaras,S.Wixted,J.T.Trends Neurosci. consolidation-related effects are specific to sleep 2.Diekelmann,S.Born,J.Nat.Rev.Neurosci.11, 34.504-5142011). and which are instead specific to conditions in 114-126(2010). 14.Dewar,M.,Alber,J.,Butler,C.,Cowan,N.&Della Sala,S. 3.Maren,S.Neuron70.830-845(2011). Psychol..Sc1.23.955-960(2012). which the formation ofextraneous memories is 4. Lattal,K.M.Wood,M.A.Nat.Neurosci.16. 15.Tambini,A..Ketz,N.&Davachi,L.Neuron 65, reduced to a minimum(whether the subject is 124-12920131 280-290(2010). Best-laid schemes for interneuron origin of mice and men Zoltan Molnar Simon J B Butt 复 Two studies emphasize similarities in the developmental origin of cortical interneurons across mammals. They suggest that most interneurons in humans and macaques have a subcortical origin. The complex function of the mammalian tangential migration.Furthermore it would of neuronal precursors from the medial,lateral neocortical circuitry depends on the balance appear that interneuron precursors do not and caudal ganglionic eminences with genetic between diverse subpopulations of excitatory proliferate further after reaching the cor- profiles similar to those that we would expect in pyramidal projection neurons and inhibitory tical plate.Estimates are that,in the dor- the mouse. GABAergic interneurons.Understanding how sal telencephalon of rodents,less than 5% Although the basic organization of cortical these cell types sculpt behavior has become of GABAergic interneurons are generated microcircuits is conserved across mammals, increasingly reliant on genetic technologies locally.It has become evident that there are cell numbers and gene expression patterns to a priori identify cell types with distinct several distinct sources in the ventral tel- in adult and developing human and monkey morphological and electrophysiological encephalon for interneurons.Initial in vitro cortex are very different from those in the properties-aspects that in murine models and in vivo cell tracing and cell transplanta- mouse.Since the identification of distinct can be largely predicted by embryonic ori- tion experiments in rodents have suggested morphological subtypes of interneuron by gin.In primates,including humans,evidence that the medial ganglionic eminence (MGE) Ramon y Cajal,it has often been argued that has suggested there is a substantial difference is the primary source of cortical interneurons. the variety and diversity of these cells increases from rodents in the location from which cor- However,it was clear from these studies that in higher mammals3.These differences can tical interneurons originate.In this issue of other sources provide cells,and subsequent also be extended to the embryonic origin of Nature Neuroscience,Hansen et al.and Ma genetic fate mapping experiments identified interneurons,with monkey and human tel- et al.2 extensively characterize developmental the caudal ganglionic eminence (CGE)as a encephalic germinal zones possessing more gene expression patterns in the ganglionic major contributor to interneuron diversity. elaborate cytoarchitectonic distinctions and eminences.These patterns indicate that the How such complex processes could be scaled some striking differences in embryonic and vast majority of interneurons in human and up in the developing brain of primates has adult gene expression patterns4.5. macaque monkey have a subcortical origin. sparked debate,not least becauseofevidencethat The first indication that the dorsal VZ or It is generally accepted that most some,if not the majority,of cortical interneurons subventricular zone (SVZ)might produce GABAergic interneurons in the mouse are may originate from the dorsal,pallial ventricular interneuron subtypes came from a combination generated in ventral embryonic forebrain zone (VZ).Hansen et al.and Ma et al.2 revisited of immunohistochemistry and retrovirallabel- and reach the cortex-the site of pyramidal this question and analyzed the organization and ing of human fetal organotypic slice prepara- projection neuron neurogenesis-through expression pattern of the human and monkey tions6.As many as 65%of GABAergic neurons fetal ganglionic eminences and their contribu- in some human neocortical areas expressed Zoltan Molnar and Simon J.B.Butt are in the tions to the origin of cortical interneurons.By the DLX1,DLX2 and MASHI (also known as Department of Physiology,Anatomy and Genetics, doing so,they draw parallels between the ana- ASCLl)transcription factors(associated with University of Oxford,Oxford,UK. tomical and genetic organization of the ganglionic interneuron development in rodents)and origi- e-mail:simon.butt@dpag.ox.ac.uk or eminences in the mouse and the human.These nated from MASHI-expressing progenitors of zoltan.molnar@dpag.ox.ac.uk studies provide evidence for the production the VZ-SVZ of the dorsal forebrain.This view 1512 VOLUME 16 NUMBER 11I NOVEMBER 2013 NATURE NEUROSCIENCE

1512 volume 16 | number 11 | NOVEMber 2013 nature neuroscience news and views 5. Hauner, K.K., Howard, J.D., Zelano, C. & Gottfried, J.A. Nat. Neurosci. 16, 1553–1555 (2013). 6. Arzi, A. et al. Nat. Neurosci. 15, 1460–1465 (2012). 7. Marlin, N.A. Learn. Motiv. 13, 526–541 (1982). 8. Stout, S.C. & Miller, R. Behav. Processes 66, 7–16 (2004). 9. Ben-Yakov, A., Eshel, N. & Dudai, Y. J. Exp. Psychol. Gen. published online, doi:10.1037/a0033558 (1 July 2013). 10. Buzsáki, G. Neurosci 31, 551–570 (1989). 11. Karlsson, M.P. & Frank, L.M. Nat. Neurosci. 12, 913–918 (2009). 12. Wixted, J.T. Annu. Rev. Psychol. 55, 235–269 (2004). 13. Mednick, S.C., Cai, D.J., Shuman, T., Anagnostaras, S. & Wixted, J.T. Trends Neurosci. 34, 504–514 (2011). 14. Dewar, M., Alber, J., Butler, C., Cowan, N. & Della Sala, S. Psychol. Sci. 23, 955–960 (2012). 15. Tambini, A., Ketz, N. & Davachi, L. Neuron 65, 280–290 (2010). awake or asleep)? The answers to theoretically intriguing questions such as these are not yet known. Whether or not such effects can be achieved during the awake state, the study by Hauner et al.5 adds a new dimension to our understanding of the learning—or, to be more precise, unlearning—that can be achieved by the sleeping brain. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Rasch, B., Büchel, C., Gais, S. & Born, J. Science 315, 1426–1429 (2007). 2. Diekelmann, S. & Born, J. Nat. Rev. Neurosci. 11, 114–126 (2010). 3. Maren, S. Neuron 70, 830–845 (2011). 4. Lattal, K.M. & Wood, M.A. Nat. Neurosci. 16, 124–129 (2013). reduce fear-related responses to a conditioned stimulus that does not actually have to be pre￾sented to the patient. Testing the Hauner et al.5 context re-exposure procedure in humans who are in a state of quiet wake would seem to be a logical next step to further evaluate the poten￾tial clinical relevance of this procedure. These results may show that the extinction-related effects of procedures used during slow-wave sleep are also true of procedures used during quiet wake. Such a finding would have both clinical and theoretical relevance. Which consolidation-related effects are specific to sleep and which are instead specific to conditions in which the formation of extraneous memories is reduced to a minimum (whether the subject is Best-laid schemes for interneuron origin of mice and men Zoltán Molnár & Simon J B Butt Two studies emphasize similarities in the developmental origin of cortical interneurons across mammals. They suggest that most interneurons in humans and macaques have a subcortical origin. Zoltán Molnár and Simon J.B. Butt are in the Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. e-mail: simon.butt@dpag.ox.ac.uk or zoltan.molnar@dpag.ox.ac.uk of neuronal precursors from the medial, lateral and caudal ganglionic eminences with genetic profiles similar to those that we would expect in the mouse. Although the basic organization of cortical microcircuits is conserved across mammals, cell numbers and gene expression patterns in adult and developing human and monkey cortex are very different from those in the mouse. Since the identification of distinct morphological subtypes of interneuron by Ramón y Cajal, it has often been argued that the variety and diversity of these cells increases in higher mammals3. These differences can also be extended to the embryonic origin of interneurons, with monkey and human tel￾encephalic germinal zones possessing more elaborate cytoarchitectonic distinctions and some striking differences in embryonic and adult gene expression patterns4,5. The first indication that the dorsal VZ or subventricular zone (SVZ) might produce interneuron subtypes came from a combination of immunohistochemistry and retroviral label￾ing of human fetal organotypic slice prepara￾tions6. As many as 65% of GABAergic neurons in some human neocortical areas expressed the Dlx1, Dlx2 and Mash1 (also known as ASCL1) transcription factors (associated with interneuron development in rodents) and origi￾nated from Mash1-expressing progenitors of the VZ-SVZ of the dorsal forebrain. This view The complex function of the mammalian neocortical circuitry depends on the balance between diverse subpopulations of excitatory pyramidal projection neurons and inhibitory GABAergic interneurons. Understanding how these cell types sculpt behavior has become increasingly reliant on genetic technologies to a priori identify cell types with distinct morphological and electrophysiological properties—aspects that in murine models can be largely predicted by embryonic ori￾gin. In primates, including humans, evidence has suggested there is a substantial difference from rodents in the location from which cor￾tical interneurons originate. In this issue of Nature Neuroscience, Hansen et al.1 and Ma et al.2 extensively characterize developmental gene expression patterns in the ganglionic eminences. These patterns indicate that the vast majority of interneurons in human and macaque monkey have a subcortical origin. It is generally accepted that most GABAergic interneurons in the mouse are generated in ventral embryonic forebrain and reach the cortex—the site of pyramidal projection neuron neurogenesis—through tangential migration. Furthermore it would appear that interneuron precursors do not proliferate further after reaching the cor￾tical plate. Estimates are that, in the dor￾sal telencephalon of rodents, less than 5% of GABAergic interneurons are generated locally. It has become evident that there are several distinct sources in the ventral tel￾encephalon for interneurons. Initial in vitro and in vivo cell tracing and cell transplanta￾tion experiments in rodents have suggested that the medial ganglionic eminence (MGE) is the primary source of cortical interneurons. However, it was clear from these studies that other sources provide cells, and subsequent genetic fate mapping experiments identified the caudal ganglionic eminence (CGE) as a major contributor to interneuron diversity. How such complex processes could be scaled up in the developing brain of primates has sparked debate, not least because of evidence that some, if not the majority, of cortical interneurons may originate from the dorsal, pallial ventricular zone (VZ). Hansen et al.1 and Ma et al.2 revisited this question and analyzed the organization and expression pattern of the human and monkey fetal ganglionic eminences and their contribu￾tions to the origin of cortical interneurons. By doing so, they draw parallels between the ana￾tomical and genetic organization of the ganglionic eminences in the mouse and the human. These studies provide evidence for the production npg © 2013 Nature America, Inc. All rights reserved