A Window of Vulnerability - Impaired Fear Extinction in Adolescence (1)

Neurobiology of Learning and Memory xxx (2013) xxx–xxx

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Neurobiology of Learning and Memory

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Review

A window of vulnerability: Impaired fear extinction in adolescence

1074-7427/$ - see front matter � 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.nlm.2013.10.009

⇑ Corresponding author. Fax: +61 2 93853641.E-mail addresses: [email protected] (K.D. Baker), [email protected] (M.L.

Den), [email protected] (B.M. Graham), [email protected] (R.Richardson).

Please cite this article in press as: Baker, K. D., et al. A window of vulnerability: Impaired fear extinction in adolescence. Neurobiology of Learning anory (2013), http://dx.doi.org/10.1016/j.nlm.2013.10.009

Kathryn D. Baker ⇑, Miriam L. Den, Bronwyn M. Graham, Rick RichardsonSchool of Psychology, The University of New South Wales, Sydney 2052, Australia

a r t i c l e i n f o

Article history:Available online xxxx

Keywords:ExtinctionFearAdolescenceStressFunctional connectivity

a b s t r a c t

There have been significant advances made towards understanding the processes mediating extinction oflearned fear. However, despite being of clear theoretical and clinical significance, very few studies haveexamined fear extinction in adolescence, which is often described as a developmental window of vulner-ability to psychological disorders. This paper reviews the relatively small body of research examining fearextinction in adolescence. A prominent finding of this work is that adolescents, both humans and rodents,exhibit a marked impairment in extinction relative to both younger (e.g., juvenile) and older (e.g., adult)groups. We then review some potential mechanisms that could produce the striking extinction deficitobserved in adolescence. For example, one neurobiological candidate mechanism for impaired extinctionin adolescence involves changes in the functional connectivity within the fear extinction circuit, partic-ularly between prefrontal cortical regions and the amygdala. In addition, we review research on emotionregulation and attention processes that suggests that developmental changes in attention bias to threat-ening cues may be a cognitive mechanism that mediates age-related differences in extinction learning.We also examine how a differential reaction to chronic stress in adolescence impacts upon extinctionretention during adolescence as well as in later life. Finally, we consider the findings of several studiesillustrating promising approaches that overcome the typically-observed extinction impairments in ado-lescent rodents and that could be translated to human adolescents.

� 2013 Elsevier Inc. All rights reserved.

1. Introduction

Adolescence is often described as a developmental window ofvulnerability in which the majority of psychological disordersemerge (Paus, Keshavan, & Giedd, 2008; Spear, 2000). Anxiety dis-orders are the most common class of psychological disorder in ado-lescence (Kessler et al., 2012). Further, it has been estimated thatapproximately 75% of adults with fear-related disorders met diag-nostic criteria as children or adolescents (Kim-Cohen et al., 2003).As noted by McNally (2007), exposure-based treatments for anxi-ety disorders have been an undeniable success within psychology.An important component of these therapies is the process ofextinction, which involves repeatedly exposing the individual tothe feared stimulus/situation in the absence of any danger. Asnoted in several recent reviews (e.g., Milad & Quirk, 2012), sub-stantial progress has been made in the past decade on understand-ing the processes mediating extinction of learned fear. Althoughthere are over a thousand publications on fear extinction in ani-mals and humans since 2000 (Milad & Quirk, 2012), very few ofthese studies have examined fear extinction during development.

There have been a few recent studies in infants (for review seeKim & Richardson, 2010), but scarcely any in adolescents. In thispaper, we first review this relatively small body of research on fearextinction in adolescent rodents and humans. A major finding ofthis work has been that adolescents, both humans and rodents, ex-hibit a marked impairment in extinction compared to both youn-ger (e.g., juvenile) and older (e.g., adult) groups. We then moveonto a consideration of various factors/mechanisms that couldmediate this pronounced impairment in extinction in adolescence.We conclude that changes in the functional connectivity within thefear extinction circuit, particularly between prefrontal cortical re-gions and the amygdala, may be the neurobiological basis for theimpaired extinction observed during adolescence. We then de-scribe work examining the impact of chronic stress on fear extinc-tion in adolescence; this research shows that stress may increasethe likelihood of resistance to extinction earlier or later in life,depending on the age at which the stressor is experienced. We alsobriefly describe another body of research – on emotional regulationand attentional processes – for additional clues as to potential cog-nitive mechanisms that may mediate the observed impairments inextinction in adolescence. Finally, we describe several recent stud-ies that provide evidence for approaches that overcome extinctionimpairments in adolescent rodents, and that could be translated totreating adolescent humans with an anxiety disorder.

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2 K.D. Baker et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx

2. Fear extinction in adolescent rodents

Those studies that have examined extinction of fear in adoles-cence have all used Pavlovian procedures to first condition fear.This involves pairing an initially neutral conditioned stimulus(CS; e.g., a tone or a light) with a naturally aversive unconditionedstimulus (US; e.g., a shock or a loud noise). At some point followingthis, the CS is presented by itself, and over repeated trials the fearelicited by the CS diminishes. Before describing those studies, how-ever, it is important to define adolescence given that there aresome disagreements about exactly when adolescence begins andends, in both rodents and humans (Spear, 2000). In this reviewwe will be very inclusive and define adolescence in rodents asbeing between postnatal (P) day 28 to P50, and in humans as being12–17 years of age.

In perhaps the first study on fear extinction in adolescent ro-dents, Hefner and Holmes (2007) examined differences in condi-tioned fear acquisition and extinction between early adolescent(P28), mid-adolescent (P42), and young adult (P56) mice. Earlyadolescent mice showed enhanced fear acquisition as well ashigher levels of freezing during extinction training compared tomid-adolescent and young adult mice. However, there were noage differences in the rate of within-session extinction. Further,extinction retention was not tested in that study. Two subsequentstudies replicated this finding in rats, demonstrating that adoles-cents (P35) did not differ in rates of within-session extinctioncompared to juvenile (P24) and adult (P70) rats, and these studiesalso found a marked impairment in extinction retention in theadolescents (Kim, Li, & Richardson, 2011; McCallum, Kim, &Richardson, 2010). That is, although adolescent rats expressedthe same low-level of CS-elicited freezing at the end of the extinc-tion training session as did juvenile and adult rats, when tested thefollowing day they exhibited a striking return of fear, relative tothe other two age groups (see Fig. 1A; redrawn from McCallumet al., 2010). A more recent study did not detect any age-relateddifferences in extinction retention between adolescent and adultrats (Broadwater & Spear, 2013). Although adolescent (�P35) ratsin that study showed a remarkable recovery of fear when extinc-tion retention was tested, so too did adult (�P71) rats (i.e., ratsof both ages exhibited �80% CS-elicited freezing at test). This highlevel of fear at test makes it nearly impossible to detect any poten-tial extinction retention impairment in the adolescents. In contrastto those results, another study reported impaired extinctionlearning and retention in adolescent mice (Pattwell et al., 2012).Specifically, when extinction training was spread over several days(with 5 trials per day over 4 days), adolescent mice (P29) displayed

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Fig. 1. Adolescent rats show impaired extinction retention at test compared to juvenimproved extinction retention in adolescent rats (Panel B). Memory retrieval 10 min befThe data shown in Panels A and B were taken from McCallum, Kim, and Richardson (201(2013).

Please cite this article in press as: Baker, K. D., et al. A window of vulnerability:ory (2013), http://dx.doi.org/10.1016/j.nlm.2013.10.009

impaired extinction learning and retention compared to juvenile(P23) and adult (P70) mice. These deficits in fear extinction inadolescent rodents do not seem to be due to differences in fearconditioning. Although Hefner and Holmes (2007) observed en-hanced fear acquisition (as reflected by higher levels of CS-elicitedfreezing) in adolescents, such a difference was not observed in thethree studies that reported impaired extinction retention in ado-lescents. In addition, there are other studies that have reportedsimilar acquisition of fear in adolescent compared to adult rats(Brasser & Spear, 2004). Taken together, these studies demonstratea marked deficit in fear regulation in adolescence, but clearly moreresearch needs to be done in this area.

3. The study of fear extinction in adolescent humans

Neumann, Waters, and Westbury (2008) gave 13–17 year oldparticipants pairings of a geometric shape (CS+) with the unpleas-ant sound of metal scraping on a slate (US). Across a number ofdependent variables (including potentiated startle, skin conduc-tance, and self-report measures), robust fear conditioning andwithin-session extinction was observed. Contrary to this findingof robust within-session extinction, Haddad, Lissek, Pine, and Lau(2011) reported that adolescents were resistant to extinction. A so-cial threat cue task was used in that study; this type of task waschosen because negative social relationships are highly salient dur-ing adolescence and may contribute to the etiology and mainte-nance of anxiety disorders. Of course, the level of conditionedfear in this type of study is going to be much less than what occursin studies where painful stimulation (e.g., shock or loud noise) isused as the US. Nonetheless, the participants in the study by Had-dad and colleagues were 12–15 years of age and were given pair-ings of three different neutral face CSs with three different USs:(1) CS-positiveUS (i.e., a neutral face CS was paired with a US thatwas the same face displaying a positive facial expression and a po-sitive comment), (2) CS-negativeUS (i.e., a neutral face CS waspaired with a US that was the same face with a negative facialexpression and negative comment), and (3) CS-neutralUS (i.e., aneutral face CS was paired with the same neutral face and a neutralcomment). After conditioning, participants rated the CS that waspaired with the negative expression and comment as moreunpleasant and scary than both of the other two CSs. More impor-tantly, this difference persisted after extinction trials in which theCS that had been paired with the negative expression was repeat-edly presented alone. This finding supports the claim that adoles-cents show impaired within-session extinction. In both of the

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ile and adult rats (Panel A). D-cycloserine (DCS) and extended extinction trainingore or after extinction augmented extinction retention in adolescent rats (Panel C).0) and the data shown in Panel C were taken from Baker, McNally, and Richardson

Impaired fear extinction in adolescence. Neurobiology of Learning and Mem-


K.D. Baker et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx 3

abovementioned studies, conclusions about age-related differencesin within-session extinction were not possible as only adolescentparticipants were tested. However, a study by Pattwell et al.(2012) compared extinction in children, adolescents, and adults.The results showed that adolescents exhibited a marked deficitin within-session extinction compared to both children and adults.Specifically, in a discriminative fear conditioning procedure one CS(a colored square presented on a computer screen) was followedby an aversive noise US 50% of the time (i.e., CS+) and a secondCS (a different colored square) was not followed by anything aver-sive (i.e., CS�). A differential skin conductance response to the CS+versus CS� was used to compare within-session extinction acrossage groups; the average differential skin conductance responsefrom the last two extinction trials was subtracted from that ofthe first two trials. Adolescents (12–17 years old) showed attenu-ated fear-extinction learning compared with children (5–11 yearolds), and a trend (p = .078) towards poorer extinction learningcompared to adults (18–28 years). These differences were notattributable to age differences in fear acquisition, sex differencesin extinction learning, or trait anxiety. These studies suggest thathealthy adolescents are impaired at extinction learning, but it isnot known whether human adolescents also exhibit the same def-icits in extinction retention as do adolescent rodents (Kim et al.,2011; McCallum et al., 2010; Pattwell et al., 2012) because extinc-tion retention was not assessed in any of the above studies.

In another study, fear extinction in anxious versus non-anxiousadolescents was compared. Lau et al. (2008) employed a differen-tial fear conditioning procedure in which the CS+ (a neutral face)was paired with an aversive outcome (a loud scream and fearful fa-cial expression) whereas the CS� (a different neutral face) wasnever followed by the aversive outcome. Extinction training oc-curred over two sessions, with the first session immediately afterconditioning (3 presentations of each CS by itself), and the secondsession approximately 16 days after conditioning (12 presenta-tions of each CS by itself). Following conditioning, both anxiousand healthy adolescents rated the CS+ as more fear-provoking thanthe CS�, and the size of this difference was comparable across thetwo groups (a finding similarly observed in adults; for a review seeLissek et al., 2005). Participants, whether anxious or not, showed aresistance to extinction because higher fear ratings to the CS+ rel-ative to the CS� remained at the end of the second extinction ses-sion. However, given that only adolescents were tested in thatstudy, no developmental comparisons in either extinction learningor extinction retention can be made.

Although this body of research is very small at this point, thefindings strongly suggest that there are impairments in extinctionof fear during adolescence, in both rodents and humans. Given thatthis is the period of development during which many anxiety dis-orders first emerge, it will be important to determine what emo-tional and cognitive processes may mediate this impairment aswell as any contribution made by neural changes occurring in thisperiod of development. Therefore, in the subsequent sections ofthis review we examine how (1) significant structural and func-tional neural changes in the fear extinction circuit during adoles-cence may lead to impaired extinction, (2) fear extinction inadolescence is altered by adverse experiences, and (3) emotionalregulation and attentional biases may contribute to the impairedextinction observed in adolescence.

4. Neural changes in the fear extinction circuit duringadolescence

Significant structural and functional neural changes occur dur-ing adolescence. Of most relevance to fear extinction, several stud-ies have documented changes within the prefrontal cortex (PFC)


and amygdala during adolescence. To date, no studies have exam-ined functional neural activity in these regions in human adoles-cents during fear extinction tasks. However, findings fromresearch that has examined neural activity in adolescents duringother laboratory tasks (e.g., decision making and emotional pro-cessing) provide a potential framework that can be used to under-stand the reported behavioral deficits in fear extinction inadolescents, and to make novel hypotheses about the neural mech-anisms that mediate such deficits.

4.1. Structural changes in the prefrontal cortex and amygdala duringadolescence

Human adolescents exhibit a reduction in gray matter in thePFC. This reduction may be due to a decline in the number of syn-apses in cortical regions (‘‘synaptic pruning’’), as has been demon-strated in non-human animal studies, or alternatively due to anincrease in white matter (Paus et al., 2008; Sturman & Moghad-dam, 2011). In addition, both human and non-human animal stud-ies have demonstrated that maturation of the PFC is much moreprotracted than is the maturation of sub-cortical regions (reviewedin Casey, Duhoux, & Cohen, 2010; Casey, Getz, & Galvan, 2008).

Relative to the PFC, the amygdala is an earlier maturing struc-ture that undergoes much less structural change during adoles-cence (Giedd et al., 1996). However, recent raw volumetricanalyses of amygdala size in 4–18 year olds revealed that amyg-dala volume was greatest during early adolescence (at aroundthe age of 14 years for female participants, around 15–16 yearsfor male participants) and was smallest in the youngest and oldestparticipants in that cohort (Hu, Pruessner, Coupé, & Collins, 2013).This suggests that while PFC volume decreases during adolescence(Paus et al., 2008; Sturman & Moghaddam, 2011), amygdala vol-ume transiently increases during adolescence. It is also known thatadolescence is a period of relatively active cell proliferation in theamygdala compared to young adulthood. In fact, cell proliferationin the amygdala of adolescent rats occurs at a rate four-five timeshigher than in young adults (Saul, Helmreich, Callahan, & Fudge,2013), consistent with previous stereological studies showing ac-tive amygdala growth in adolescence relative to adulthood (Rubi-now & Juraska, 2009). The changes in amygdala growth may bedriven by increases in sex hormones, as other findings have dem-onstrated that adolescent boys in later stages of pubertal develop-ment exhibit larger amygdala volumes relative to age-matchedpeers in earlier stages of puberty (Neufang et al., 2009; Scherf,Smyth, & Delgado, 2013) and that growth of the amygdala duringpuberty is associated with circulating testosterone levels (Neufanget al., 2009).

4.2. Functional changes in the prefrontal cortex and amygdala duringadolescence

In addition to structural changes, numerous changes in thefunctional activation of the PFC and amygdala have been docu-mented in adolescence. In general, studies have reported PFC hyp-oactivation and amygdala hyperactivation in adolescents during arange of tasks. For example, adolescents recruit the medial PFC(mPFC) to a lesser extent than adults when viewing emotionalfaces (Hare et al., 2008) and when tracking changes in emotionalstate (Monk et al., 2003). In contrast, amygdala activation is aug-mented in adolescents compared to children (Hare et al., 2008)and adults (Guyer et al., 2008; Hare et al., 2008) when viewingemotional faces. Again, these functional changes in amygdalaactivity may be mediated by sex hormones, as a positive correla-tion has been reported between pubertal stage and amygdalahyperactivation during face presentations (Moore et al., 2012).However, it should be noted that there are some inconsistencies




in the literature with respect to patterns of functional PFC andamygdala activation during adolescence, where, in some cases,hyperactivity of the amygdala and hypoactivity of the PFC arenot observed (Somerville, Jones, & Casey, 2010). A more consistentpicture of the neurological characteristics of adolescence may begained through the study of neural circuits as opposed to discretestructures, as outlined next.

4.3. Functional connectivity between the prefrontal cortex andamygdala during adolescence

Recent neuroimaging research has moved towards the study ofneural circuits rather than the morphology and function of singleneural structures in isolation. Such an approach takes into accountthat the strength of coupling between two or more regions may bemore important in determining behavioral outcomes than theoverall activation of discrete neural regions. For example, it maybe that strong inverse functional connectivity between the PFCand amygdala (where PFC activation is associated with amygdalainhibition) is necessary for fear extinction to occur. If so, thenstrong PFC activity would be insufficient to support fear extinctionin the absence of functional connectivity with the amygdala. Fromthis perspective, it makes more sense to examine the functionalconnectivity within the fear extinction circuit, rather than theactivity within individual structures, to determine the neurobio-logical basis for impaired extinction during adolescence.

Only a few studies have investigated functional connectivity ofthese structures across development. Qin, Young, Supekar, Uddin,and Menon (2012) reported that resting-state connectivity be-tween the amygdala and PFC was reduced during childhood rela-tive to adulthood. Another study reported that effectiveconnectivity (i.e., the degree to which activity in one region im-pacts activity in another region) between the anterior cingulateand the amygdala during the presentation of emotional faces in-creased with age across childhood (Perlman & Pelphrey, 2011).However, adolescent participants were not examined in either ofthese studies.

A recent study by Roy et al. (2013) examined intrinsic (restingstate) functional connectivity in adolescents with and without gen-eralized anxiety disorder (GAD). They reported decreased connec-tivity between the amygdala and ventromedial PFC in adolescentswith GAD relative to adolescents without GAD, suggesting that re-duced connectivity between these regions may be a hallmark ofanxiety during adolescence. However, this study did not comparefunctional connectivity across development, and so it is unclearwhether or not amygdala–PFC connectivity is reduced in healthyadolescents compared to younger or older age groups. Gee et al.(2013) compared functional connectivity (while viewing happy,neutral, and fearful faces) between the amygdala and mPFC inhealthy children, adolescents, and young adults. They reported thatamygdala–mPFC connectivity became more strongly negative (i.e.,increased mPFC activity was more strongly associated with re-duced amygdala activity) with increases in age, and only when par-ticipants were viewing fearful faces. In particular, amygdala–mPFCfunctional connectivity was most strongly negatively correlated for18–22 year olds (i.e., they exhibited strong connectivity betweenthese regions), and was significantly greater in 18–22 years oldsthan all other age groups examined (4–9, 10–13, and 14–17 yearolds; i.e., connectivity between these regions was weaker in theseage groups). It is interesting to note that the pattern of increasedamygdala–mPFC connectivity from adolescence to adulthood mir-rors the observed improvement in extinction ability from adoles-cence to adulthood, suggesting that low connectivity betweenthese regions during early-/mid-adolescence, combined withamygdala hyperactivation, may underlie the deficits in fear extinc-tion during adolescence.


4.4. Current neurobiological models of adolescent behavior

Findings like those reviewed above have led to the emergenceof several neurobiological models that are designed to accountfor the myriad of affective and behavioral changes observed duringadolescence (Casey et al., 2008; Nelson, Leibenluft, McClure, &Pine, 2005; Steinberg, 2008). These models posit that as the PFCis a late-maturing structure, connectivity between it and sub-cor-tical structures does not develop until late adolescence or earlyadulthood. Thus, the PFC does not have the structural and/or func-tional connections to drive the inhibition of behaviors mediated bysub-cortical structures until later in life. During childhood, becausesub-cortical structures are still developing and are often hypo-responsive, a balance is maintained between brain systems thatregulate emotional and reward-driven behavior and those that ex-ert inhibitory control over such behavior. However, as sub-corticalstructures develop more rapidly than the PFC and are often hyper-responsive during adolescence, at this stage of development thereis an imbalance in activity due to an excess of activity within sub-cortical structures (that mediate emotional/reward driven behav-ior) that is not inhibited by the late-maturing PFC due to the lowlevel of connectivity between these neural regions.

While no studies have investigated whether these neurobiologi-cal models can account for adolescent deficits in fear extinction,extensive research has been conducted in applying these modelsto adolescent reward-driven behavior, with the aim of understand-ing why adolescents engage in risky behavior. Just as the amygdalais more active during processing of fearful faces in adolescence, sotoo is the ventral striatum more active in adolescents during re-ward-focused tasks. Furthermore, frontal–striatal connections in-crease both structurally and functionally across development,and the increased connectivity has been associated with increasedcapacity to recruit top-down inhibitory control during reward-focused tasks (reviewed in Casey, Duhoux, et al., 2010). Thus,increased risky behavior during adolescence can be accounted forby reduced prefrontal inhibitory control over excessive striatalactivation in the presence of appetitive stimuli. Similarly, impair-ments in extinction during adolescence may be due to reducedprefrontal inhibitory control over excessive amygdala activationin the presence of fearful stimuli.

This sort of neurobiological model where there is an imbalancein activity between prefrontal inhibitory regions and sub-corticalstructures mediating emotional behavior (i.e., the amygdala) pro-vides a nice account for why extinction is impaired in adolescence.Critically, this type of model needs to be explicitly tested in futureresearch. However, it is worth noting that in other populations inwhich extinction deficits are observed (e.g., adults with posttrau-matic stress disorder or schizophrenia), a reduction in ventrome-dial PFC activity combined with hyperactivity in the amygdala atthe time of extinction training/recall has been documented (Etkin& Wager, 2007; Holt, Coombs, Zeidan, Goff, & Milad, 2012; Jova-novic et al., 2013), which lends support to the possibility that sim-ilar mechanisms may be underlying the deficits observed inadolescents.

Some preliminary support for the above hypothesis comes fromseveral studies in rodents that have documented differences in thefunctional activity in the neural circuitry supporting fear extinctionduring adolescence versus adulthood. Notably, these studies dem-onstrated that the mPFC may not be recruited as efficiently duringfear extinction in adolescent rodents as in younger and older ani-mals. For example, immunohistochemical analyses using phos-phorylated mitogen-activated protein kinase (pMAPK) as amarker of neuronal activity have shown that adolescent rats donot exhibit the same extinction-induced increases in neuronalactivity in the infralimbic mPFC that are observed in juvenile andadult rats (Kim et al., 2011). Consistent with this observation, there




is a lack of synaptic plasticity associated with extinction in theinfralimbic mPFC of adolescent mice compared with what is ob-served in the juvenile and adult mPFC (Pattwell et al., 2012). Theadolescent mPFC also shows elevated basal excitatory synaptictransmission compared to juveniles and adults, which may con-tribute to a lack of prefrontal synaptic plasticity and impairedextinction in adolescence (Pattwell et al., 2012). Furthermore, dur-ing adolescence there is a dramatic increase in projections from thebasolateral amygdala to ventromedial PFC GABAergic inhibitoryinterneurons which could destablize and impair mPFC function(Cunningham, Bhattacharyya, & Benes, 2008). Together, these find-ings suggest that adolescents may be less efficient in utilizing pre-frontal regions to maintain the inhibition of fear followingextinction.

5. Fear extinction in adolescence is altered by adverseexperiences

5.1. Adolescence is a vulnerable developmental period to the effects ofstress

Adolescence is often characterized as a period of ‘‘storm andstress’’ (Casey, Jones, et al., 2010; Romeo, 2013). One factor thatmay contribute to adolescent vulnerability is that the hypotha-lamic–pituitary–adrenal (HPA) axis, which mediates the mamma-lian response to stress, undergoes subtle changes duringadolescence (reviewed in McCormick, Mathews, Thomas, &Waters, 2010; Romeo, 2013). In adults, the HPA stress response in-volves the protracted release of several hormones, including corti-cotropin releasing hormone (CRH) and adrenocorticotropichormone (ACTH), the latter of which stimulates the synthesis andsecretion of glucocorticoids by the adrenal glands. The primaryneural targets of the glucocorticoids include the hypothalamus,hippocampus, and PFC, and their overall function is to reduce theproduction and release of CRH and ACTH via negative feedback,effectively terminating the stress response. Dysfunctions in adultHPA-axis activity and reactivity have been implicated in a host ofmental health disorders, including anxiety and depression (Holsb-oer & Ising, 2010).

Although the consequences of stress during adulthood for HPA-axis function has received great attention (McEwen, 2007), fewerstudies have examined the impact of stress on HPA-axis functionduring adolescence. The few studies that have examined this issuehave demonstrated that under non-stressed conditions basal levelsof ACTH and corticosterone (a major glucocorticoid in rats) arecomparable between adolescent and adult rats (Foilb, Lui, &Romeo, 2011; Lui et al., 2012; Romeo, Lee, Chhua, McPherson, &McEwen, 2004; Romeo, Lee, & McEwen, 2004). When acutelystressed, however, the amount of ACTH and corticosterone re-leased is significantly greater in adolescent than adult rats (Foilbet al., 2011; Lui et al., 2012). Moreover, the stress-induced releaseof these hormones is significantly more protracted in adolescentrats, resulting in a much slower return to baseline levels of stresshormones compared to adult rats (Foilb et al., 2011; Romeo, Lee,Chhua, et al., 2004; Romeo, Lee, & McEwen, 2004). Adolescent ratsalso respond differently to chronic stress than do adults. For exam-ple, the HPA-axis response in adult rats habituates with chronicexposure to the same stressor, whereas adolescent rats fail to exhi-bit such habituation (i.e., they continue to exhibit robust release ofACTH and corticosterone whereas adult rats exhibit attenuated re-lease of these hormones; Lui et al., 2012).

Data from humans resemble the rodent findings, with one studyreporting that while there were no differences in baseline cortisollevels between children and adolescents pre-stressor, adolescentsexhibited greater cortisol responses during a performance stressor


compared to children, and these differences in cortisol levels per-sisted after stressor termination during a recovery period (Stroudet al., 2009). Another study demonstrated increased baseline corti-sol (the major glucocorticoid in humans) under non-stressed con-ditions in 15 year olds compared to 11 and 13 year olds; cortisollevels were also significantly higher amongst 15 year olds duringa social stressor task (Gunnar, Wewerka, Frenn, Long, & Griggs,2009). It should be noted that a limitation in the current literatureis that no studies using human participants to date have comparedHPA-axis activity in adolescents versus adults (baseline or understress conditions). Nevertheless, taking these human and rodentfindings together, it appears that both the sensitivity of the HPA-axis and the consequences of chronic stress are different in adoles-cence than other stages of development, where adolescence ischaracterized by an over-active, protracted stress response. It isthought that due to the continued maturation of the limbic andprefrontal cortical regions in adolescence, these structures are par-ticularly vulnerable to the effects of stress (Giedd & Rapoport,2010; Romeo, 2013). Adolescence would therefore be a vulnerabledevelopmental period to stressors, which would consequently in-crease sensitivity to the onset of stress-related mental disorders(Kessler et al., 2007; Lupien, McEwen, Gunnar, & Heim, 2009; Malt-er Cohen, Tottenham, & Casey, 2013). The following section re-views the impact of chronic stress on fear extinction inadolescent rodents. Consistent with neurobiological models sug-gesting that exposure to stress has different outcomes dependingon the age at which it is experienced (Lupien et al., 2009), the effectof stress on fear extinction differs depending on whether it is expe-rienced in early life, adolescence, or adulthood.

5.2. The impact of chronic stress on fear extinction in adolescentrodents

The results of several recent studies have suggested that expo-sure to chronic stress alters the nature of the extinction system inadolescence. The first example is that early-life stress has beenshown to accelerate the transition into and out of the adolescentprofile of fear extinction (Callaghan & Richardson, 2012). In thatstudy, infant rats were exposed to repeated bouts of maternal sep-aration (3 h per day from P2–14). Animals exposed to early-lifestress showed an early emergence of poor extinction retention dur-ing pre-adolescence (at P27) and good extinction retention duringadolescence (at P35). One explanation of these findings is thatexposure to early-life stress accelerated the maturation of neuralstructures, such as the PFC, required for adult-like extinctionbehavior (Callaghan & Richardson, 2012).

In contrast to early-life stress which causes an earlier emer-gence of the adolescent profile of extinction, chronic stress in earlyadolescence appears to cause deficits of extinction acquisition inadolescence as well as impaired extinction retention in adulthood.Although one study did not find an effect of chronic social instabil-ity stress in adolescence on fear extinction in adolescence (P46) oradulthood (Morrissey, Mathews, & McCormick, 2011), two studiesshowed a disruption of extinction acquisition with chronic stress inadolescent male rats, and one of these also demonstrated impairedextinction retention in adult male rats. Zhang and Rosenkranz(2013) examined the effect of chronic restraint stress (7 out of9 days from either P29 or P65) on the acquisition and extinctionof learned fear in male adolescent (P39) and adult (P76) rats. Atboth ages, restraint stress enhanced fear conditioning. However,repeated restraint led to impaired acquisition of fear extinctiononly in adolescence. The effect of restraint stress on extinctionretention was not tested in that study. A disruption of extinctionacquisition by chronic stress in early adolescence in male ratswas also found in an earlier study by Toledo-Rodriguez and Sandi(2007), but this disruption was sex-dependent as female rats were




unaffected. Male adolescent rats (P41) which experienced stress(exposure to predator odor followed by placement on an elevatedplatform on P28–P30) exhibited increased conditioned fear andfailed to show the same reduction in freezing across a 5 min testthat was observed in unstressed animals. In contrast, female rats,regardless of whether they received exposure to stress or not,exhibited within-session extinction. The detrimental effects ofstress were long-lasting in male rats because when the same ani-mals were tested in adulthood, those animals exposed to chronicstress during adolescence exhibited impaired extinction retention.One limitation of this study was that it did not include an adult-stressed group to examine whether adolescent animals were moresusceptible to the effects of stress than adults. However, the find-ings do show that chronic stress during adolescence increasesthe likelihood of impaired extinction retention later in life.

Exactly how chronic stress in adolescence contributes to deficitsin fear extinction is unclear at this stage. One possibility is thatstress in adolescence leads to a decrease in synaptic plasticity inthe neural regions that support fear extinction, and an increasein synaptic plasticity in the regions that support fear expression.For example, chronic stress in male and female adolescent ratsleads to dendritic retraction in the hippocampus and PFC, and den-dritic hypertrophy in the amygdala (Eiland, Ramroop, Hill, Manley,& McEwen, 2012). It is possible that this stress-induced dendriticremodeling tips the balance between prefrontal inhibition andamygdala excitation, leading to a disruption in the extinction offear. Future research is needed to determine whether such changesto the functional connectivity between the PFC and amygdala con-tribute to the impaired extinction retention observed in adulthoodfollowing stress encountered during adolescence.

In addition, stress-induced changes to the hippocampus arelikely to impact extinction in adolescence given the importanceof this structure in the contextual modulation of fear extinctionas well as the consolidation of extinction memories (reviewed inQuirk & Mueller, 2008). The hippocampus, implicated in the nega-tive feedback regulation of the HPA-axis, is particularly vulnerableto the effects of stress during adolescence and adulthood, due tothe high density of glucocorticoid receptors in that structure (re-viewed in McCormick et al., 2010). Chronic stress has been shownto impact hippocampal structure and function by causing dendriticretraction (McLaughlin, Gomez, Baran, & Conrad, 2007; Watanabe,Gould, & McEwen, 1992), reducing long-term potentiation (Foy,Stanton, Levine, & Thompson, 1987), and decreasing neurogenesis(Barha, Brummelte, Lieblich, & Galea, 2011). Interestingly, whileresearch suggests that in adulthood these stress-induced changesare transient and reversible (Luine, Villegas, Martinez, & McEwen,1994; Sousa, Lukoyanov, Madeira, Almeida, & Paula-Barbosa,2000), converging animal and human studies have demonstratedthat stress exposure during adolescence can have a profound andlong-lasting impact on the neural circuitry underlying fear extinc-tion, given that dramatic neuronal reorganization is taking place(reviewed in Koenig, Walker, Romeo, & Lupien, 2011). It is there-fore likely that stress-induced dendritic remodeling during adoles-cence would lead to impaired fear extinction both later inadolescence as well as in adulthood. Although studies of this kindhave not yet been conducted, they would have clear practicalimplications for the treatment of both adolescents with anxietydisorders as well as adults exposed to stress during their adoles-cent years.

6. Attentional bias to threatening cues may influence fearextinction in adolescence

Despite recent advances in our understanding of the neural cir-cuitry mediating extinction, and how this circuitry may change


during adolescence, few studies have examined how cognitive pro-cesses such as attention contribute to impaired extinction duringadolescence. During conditioning, repeated pairings of a CS withan aversive US results in anticipatory fear and attention biases to-wards the CS+ (Mackintosh, 1975). Then, subsequent extinctiontraining trials (i.e., CS+ alone presentations) reduce attention tothe CS+ (e.g., Van Damme, Crombez, Hermans, Koster, & Eccleston,2006). Persistent attention biases towards the CS+ during extinc-tion would be expected to result in poorer extinction learning,and this has been observed in adult patients with posttraumaticstress disorder (Fani et al., 2012).

Unfortunately, studies have not yet looked at whether develop-mental changes in attention bias to threatening cues contribute toage-related differences in extinction learning. However,age-related differences in the response to threatening stimuli havebeen the focus of a number of recent studies. For example, Hareet al. (2008) demonstrated that adolescents show an exaggeratedamygdala response to cues that signal possible threat (i.e., fearfulfaces), relative to both children and adults, and this was largelydue to inefficiency in recruiting prefrontal regions involved indampening the fear response. In another example, Lau et al.(2011) showed that adolescents exhibit poorer threat-safety dis-criminations compared to adults, perceiving both the CS+ (i.e.,the threat cue that actually predicted the aversive US) and theCS� (i.e., the safety cue that did not predict the aversive US) asthreatening. Given these findings, adolescents might be expectedto show a heightened sensitivity to learning fearful associations,relative to both children and adults. While this has not yet beendemonstrated in humans, a recent study by Den and Richardson(2013) demonstrated that adolescent (�P35), but not juvenile(P23) or adult (P90) rats, exhibit high levels of fear after beingtrained on a trace conditioning procedure (i.e., where long, stimu-lus-free intervals of up to 40 s separated the CS and US). Thesestudies raise a number of interesting questions for future researchon extinction in adolescence regarding (1) whether attention biasto the CS+ persists following extinction learning, (2) whether suchbias predicts a poorer response to extinction learning, and (3)whether attention bias differs in anxious versus healthy adolescentand adult populations. Research of this kind in humans would ulti-mately indicate whether current treatments need to be tailored sothat they optimally target potential underlying attentional dys-functions mediating anxiety during adolescence, compared toadulthood.

7. Development of the fear extinction circuit: an imbalanceduring adolescence

The fear extinction system undergoes many changes acrossdevelopment. Fig. 2 shows a schematic of how a balance withinthe fear circuit is important for appropriate fear regulation acrossdevelopment. Juveniles and adults can express and inhibit fearappropriately when various situations are encountered in theirenvironment. However, the reason behind this comparable balancein fear regulation may be different between these two age groups.For example, juveniles may have reduced connectivity between theamygdala and mPFC relative to adults (Gee et al., 2013), but theamygdala is less active/underdeveloped at this point of develop-ment so a balance is maintained. Adults have a fully developedamygdala and mPFC, and have strong connectivity between theseregions relative to younger ages, and so a balance in fear regulationis maintained. However, maturational changes in the brain duringadolescence have a striking impact on fear expression and fearinhibition. As reviewed above, during adolescence there is growthin amygdala volume and reduction in gray matter in the PFC (seeCasey et al., 2008; Hu et al., 2013; Saul et al., 2013), as well as



Juvenile Adolescent Adult

Fear inhibition

Fear expression

Fear inhibition

Fear expression

Fear inhibition

Fear expression

Fig. 2. A schematic of fear regulation across development. The circles with – and + symbols denote a variety of contributing factors to fear inhibition and expression, includingchanges to the volume, activity, and functional connectivity between brain regions within the fear circuit, as well as cognitive changes. Although juveniles and adults exhibit acomparable balance between fear inhibition and fear expression, the underlying reasons behind this balance may be different between the two age groups. In contrast, thebalance is tipped towards poor fear inhibition and heightened fear expression during adolescence.


changes in the functional connectivity between these regions fromchildhood, through adolescence and into adulthood (Gee et al.,2013). In addition, age-related differences in extinction learningmay also be mediated by cognitive mechanisms such as develop-mental changes in attention bias to threatening cues. We proposethat the combination of brain maturation and cognitive changesdisrupts the balance between PFC and amygdala activity and tipsthe balance towards poor fear inhibition (Fig. 2). Specifically, ahypoactivation of the PFC and hyperactivation of the amygdalawould result in the adolescent being primed to express more fearcompared to juveniles or adults. This imbalance model is well sup-ported by findings that adolescent rodents show heightened sensi-tivity to learning fearful associations (Den & Richardson, 2013) andimpaired fear inhibition (Kim et al., 2011; McCallum et al., 2010;Pattwell et al., 2012) compared to younger and older animals. Thatadolescents also show increased fear generalization to safety cues(i.e., poor threat-safety discrimination; Lau et al., 2011) and a com-bination of an exaggerated amygdala response and dampened pre-frontal activity to fearful faces compared to children and adults(Hare et al., 2008) is also consistent with an imbalance betweentop-down prefrontal inhibitory control of the amygdala in re-sponse to fearful stimuli. This imbalance in fear regulation maycontribute to an increased likelihood of anxiety symptoms emerg-ing during adolescence, consistent with the finding that anxiousadolescents have decreased connectivity between the amygdalaand ventromedial PFC relative to non-anxious adolescents (Royet al., 2013). Once the maturation of the brain is complete duringthe transition out of adolescence into adulthood and adult cogni-tive processes have developed, the balance between prefrontaland amygdala activity returns and appropriate fear regulation isrestored.

8. Manipulations which overcome deficits in fear extinctionduring adolescence

There are no studies to date which have examined ways to im-prove fear extinction in human adolescents. Fortunately, preclini-cal studies have suggested several promising pharmacologicaland non-pharmacological (e.g., behavioral) manipulations thatare effective at reducing the impaired extinction retention ob-served in adolescent rats. Understanding how to reduce the recov-ery of extinguished fear in adolescence may provide novel insightsinto therapeutic interventions for anxiety disorders.

One of the most effective pharmacological adjuncts for enhanc-ing extinction is the NMDA receptor partial agonist D-cycloserine(DCS). Numerous studies have shown that DCS enhances the effec-tiveness of fear extinction in adult rats (e.g., Baker, McNally, &Richardson, 2012; Langton & Richardson, 2008; Ledgerwood,


Richardson, & Cranney, 2003; Walker, Ressler, Lu, & Davis, 2002;reviewed in Graham, Langton, & Richardson, 2011). Importantly,DCS improves extinction retention in adolescent rats when admin-istered immediately after extinction. DCS was as effective as givingdouble the amount of extinction training (see Fig. 1B; re-drawnfrom McCallum et al., 2010). There is considerable translational va-lue of DCS as a treatment for human anxiety disorders given that ithas been shown to have positive therapeutic effects for severalanxiety disorders in adults (e.g., de Kleine, Hendriks, Kusters,Broekman, & van Minnen, 2012; Guastella et al., 2008; Hofmannet al., 2006; Ressler et al., 2004; reviewed in Hofmann, Wu, &Boettcher, 2013). With particular relevance to fear inhibition inadolescence, one preliminary study in youth (aged 8–17) withobsessive–compulsive disorder detected some promising treat-ment effects of DCS (Storch et al., 2010). Small to moderate treat-ment effects (d = .31–.47) were reported with cognitive-behavioral therapy sessions paired with DCS compared to placebo,suggesting the need for more extensive follow-up studies in ado-lescent populations.

With respect to the neural mechanisms underlying how DCSfacilitates fear extinction, it may produce treatment gains byenhancing activity in the amygdala or PFC during extinction.Although the neural effects of DCS in adolescent animals or hu-mans is unknown, there is some evidence in juvenile rats (24–28 days old) that DCS upregulates pMAPK activity in the mPFC(in both the infralimbic and prelimbic subregions) and amygdala(Gupta et al., 2013). Consistent with these findings, functionalstudies in adults with a snake phobia using fMRI have shown thatDCS can produce long-lasting changes to prefrontal activity. Oneweek after treatment, individuals that were given DCS before a sin-gle session of exposure therapy exhibited different activation ofthe ventromedial PFC and other prefrontal regions (i.e., increasedmedial orbitofrontal, subgenual anterior cingulate, and left dorso-lateral PFC activation) in response to fearful stimuli compared tothose given placebo (Nave, Tolin, & Stevens, 2012).

Considering that adolescence is a time of substantial brain mat-uration, non-pharmacological alternatives may be a preferable ap-proach provided that similar beneficial effects are obtained. Oneexample of an effective behavioral procedure is that doubling theamount of extinction training leads to adult-like extinction reten-tion in adolescent rats (see Fig. 1B; redrawn from McCallumet al., 2010) and adolescent mice (Clem & Huganir, 2010). In thelatter study, adolescent mice given a retrieval trial before extensiveextinction showed reduced fear relapse when tested one week la-ter (Clem & Huganir, 2010). Unfortunately, there are several rea-sons why extensive extinction training may be impractical inadolescent humans with an anxiety disorder (e.g., administeringextensive exposure-based therapy would be both time consuming




and costly, and also increase the likelihood of patients notcompleting treatment). A recent study by Baker, McNally, andRichardson (2013) demonstrated a reliable, but less time-consum-ing, manipulation which prevented the recovery of extinguishedfear in adolescent rats. In that study it was found that a single re-trieval trial (rather than 30 extra trials) given 10 min before extinc-tion training reduced fear in adolescent rats at test the followingday (see Fig. 1C; redrawn from Baker et al., 2013). The retrieval-extinction procedure not only overcame the impairment of extinc-tion retention typically observed in adolescent rats, but it alsoattenuated renewal of fear when animals were tested in the train-ing, rather than the extinction, context. The loss of fear reportedfollowing retrieval-extinction manipulations in adult rats and hu-mans is typically interpreted as a disruption of reconsolidation ofthe original fear memory (e.g., Flavell, Barber, & Lee, 2011; Monfils,Cowansage, Klann, & LeDoux, 2009; Schiller et al., 2010). However,a key result in the study by Baker et al. was that a single retrievaltrial given soon after extinction produced a similar loss of fear asthat produced by a retrieval trial before extinction (see Fig. 1C), afinding which is inconsistent with the disruption of reconsolida-tion perspective. As an alternative explanation, it has been sug-gested that a retrieval trial before or after extinction maypromote better discrimination at test between the competingtraining and extinction memories (Baker et al., 2013; Millan, Milli-gan-Saville, & McNally, 2013). An important implication from thisstudy is that a single retrieval trial around the time of extinctiontraining may offer a simple, effective way of enhancing long-termtreatment gains for human populations, including adolescents,when extinction deficits are seen.

9. Future directions

As noted above, the improvement in fear extinction retentionduring the transition from adolescence to adulthood may arisefrom increased prefrontal inhibitory control over the amygdala.There are a number of structural changes which occur during thematuration of the PFC across adolescence. One example is the for-mation of perineuronal nets (PNNs). PNNs are extracellular matrixstructures (containing chondroitin sulphate proteoglycans) whichenwrap many neurons in the brain, particularly the inhibitory neu-rons that contain the calcium-binding protein parvalbumin, as wellas excitatory pyramidal neurons (Brückner et al., 1993; Celio & Blu-mcke, 1994; Giamanco & Matthews, 2012). Past studies have dem-onstrated that the formation of PNNs in the brain is important inlimiting neural plasticity at the conclusion of several developmen-tal ‘critical periods’ (e.g., the critical period for ocular dominanceplasticity in the visual cortex; Pizzorusso et al., 2002). There arealso recent post-mortem studies in humans suggesting that PNNsincrease in the PFC across adolescence into adulthood and thataberrant PNN formation in humans may contribute to psychologi-cal disorders (e.g., schizophrenia; Mauney et al., 2013). Given thesefindings, it is tempting to speculate that the formation of PNNs inthe PFC at the conclusion of adolescence may help to support theadult fear extinction system. A corollary of this would be thatabnormal formation of PNNs in the prefrontal brain circuitry regu-lating fear during adolescence may contribute to the etiology ofanxiety disorders. There is already evidence that PNNs are involvedin the developmental regulation of fear extinction in young ro-dents. Specifically, the maturation of PNNs in the mouse amygdalacoincides with the transition from a relapse-resistant extinctionsystem in infants to relapse-prone extinction in juveniles (Gogolla,Caroni, Lüthi, & Herry, 2009). Thus, an exciting direction for futureresearch will be to examine whether the formation of PNNs in thelater maturing PFC modulates the transition from impaired extinc-tion in adolescence into good extinction retention in the adult.


Another important issue that requires greater attention isdetermining the unique contribution of developmental age versuspuberty (and the associated increase in fluctuations in sex hor-mones), as well as the interaction between the two, in mediatingthe impairment in extinction observed during adolescence. Thereare many examples in which the mere exposure to sex hormonesduring pre-adolescence is not sufficient to induce adolescent-likebehavior in rodents, suggesting that some changes in adolescenceare more to do with age (or the combination of age plus exposureto sex hormones) than with puberty stage per se. For example, thepre-pubertal removal of ovaries does not prevent the protractedHPA-axis reactivity to stress in adolescent female rats (Romeo,Lee, & McEwen, 2004). This suggests that the alteration in HPA-axisreactivity observed during adolescence is mediated by age ratherthan sex hormones. Preclinical research in rodents, which allowsfor the systematic manipulation of sex hormones, is required in or-der to determine whether the deficits in fear extinction observedduring adolescence are a consequence of age, sex hormone expo-sure, or an interaction between the two. This will be particularlyimportant in light of recent research suggesting that sex hormonesplay a significant role in the consolidation of fear extinction mem-ories in adult rodents and humans (Graham & Milad, 2013).

Another interesting issue to explore involves how the interac-tion of individual genetic variation and development may predis-pose some individuals to anxiety disorders. There are someexamples of polymorphisms in human genes which have been asso-ciated with deficits in fear extinction. For example, both adult hu-mans and adult inbred genetic knock-in mice that express thevariant BDNF allele (Val66Met), which is associated with reducedactivity-dependent release of BDNF, exhibit a slower rate of fearextinction learning (Soliman et al., 2010). Functional MRI imaginghas demonstrated that adult human Met allele carriers showed lessventromedial PFC activity, and greater amygdala activation, duringextinction compared to noncarriers, indicating alterations to activ-ity within the fear extinction circuit in Met allele carriers (Solimanet al., 2010). However, it is unknown when these genotype differ-ences in extinction learning and functional brain activity firstemerge; it is possible that such deficits may already be evident inadolescents. Related to this, Bath et al. (2012) argued that anxi-ety-like behaviors measured in the elevated plus maze increasedover the transition from adolescence to adulthood in female Met/Met mice but not wild-type Val/Val mice, however, the differencesbetween genotypes were primarily observed in adults over100 days of age, not in adolescents. Thus, the effect of BDNF genepolymorphisms on fear extinction in adolescent animals or humanshas not yet been investigated. Interestingly though there is someevidence that variation in the expression of mRNA coding for theserotonin transporter may modulate extinction learning and reten-tion in adolescent mice. There are two alternative mRNA forms cod-ing for the serotonin transporter. Human carriers of a commonpolymorphism which reduces expression of the form containingthe distal polyadenylation sequence exhibit impaired fear extinc-tion retention as adults and increased anxiety (Hartley et al.,2012) and also have an increased risk for panic disorder (Gyawaliet al., 2010). Variation in serotonin transporter genes may confera risk for impaired fear inhibition and increased anxiety in adoles-cence, but this has not been directly tested. However, Riddle et al.(2013) demonstrated that two manipulations which enhancedextinction learning and retention in adolescent female mice (specif-ically, caloric restriction and chronic fluoxetine treatment) wereassociated with increased expression of the particular distal poly-adenylation mRNA form. Further research examining the effect ofgene polymorphisms on fear extinction in adolescent animals andhumans may provide insight into whether individuals with a par-ticular genetic makeup may be more likely to develop symptomsof anxiety across the transition from adolescence to adulthood.




Finally, a further area of interest is the neural basis for howmanipulations such as DCS and memory retrieval around the timeof extinction improve the extinction of fear in adolescence. Forexample, extensive extinction training has been demonstrated toincrease neuronal activation in the infralimbic and prelimbic re-gions of the mPFC in adolescent rats (Kim et al., 2011); is a similareffect observed following retrieval-extinction manipulations? Thiswork may lead to the determination of whether manipulations thatimprove extinction retention in adolescents also enhance the func-tional coupling between the amygdala and PFC. Different types ofinterventions may not necessarily work through the same mecha-nisms, which would be both theoretically and practically impor-tant, in that such results would suggest that there are severaldifferent approaches by which fear inhibition in adolescence canbe enhanced.

In conclusion, there is emerging research suggesting that thereis a striking impairment in extinction in adolescence. This impair-ment in extinction during adolescence is likely to arise from re-duced prefrontal inhibitory control over excessive amygdalaactivation in the presence of fearful stimuli. In addition to the func-tional changes in the neural circuitry supporting fear extinction,developmental changes in attention bias to threatening cues mayalso contribute to age-related differences in extinction learning.A combination of such changes may result in an imbalance in fearregulation such that there is poor fear inhibition and heightenedfear expression during adolescence (see Fig. 2). Whatever is caus-ing the deficits in extinction during adolescence, there are severaleffective manipulations for improving the inhibition of fear in ado-lescent rodents, providing promising translational interventionsfor human adolescents. Given that anxiety during adolescence isa strong predictor of adult anxiety and other psychological disor-ders (Kessler et al., 2012), continued research into fear extinctionin adolescence will improve our ability to develop early and effec-tive interventions for anxiety.

Acknowledgments

Preparation of this manuscript was supported by an AustralianPostgraduate Award (MLD), and grants from the Australian Re-search Council (DP120104925) and the National Health and Medi-cal Research Council (APP1031688) to RR. KDB is a National Healthand Medical Research Council Peter Doherty Early Career Fellow(APP1054642).

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A Window of Vulnerability - Impaired Fear Extinction in Adolescence (1)

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