A Window of Vulnerability - Impaired Fear Extinction in Adolescence

Review
A window of vulnerability: Impaired fear extinction in adolescence

Kathryn D. Baker
, Miriam L. Den, Bronwyn M. Graham, Rick Richardson

School 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:
Extinction
Fear
Adolescence
Stress
Functional connectivity
a b s t r a c t
There have been signicant advances made towards understanding the processes mediating extinction of
learned fear. However, despite being of clear theoretical and clinical signicance, very few studies have
examined 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 fear
extinction in adolescence. A prominent nding 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 decit
observed in adolescence. For example, one neurobiological candidate mechanism for impaired extinction
in 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 emotion
regulation 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 extinction
retention during adolescence as well as in later life. Finally, we consider the ndings of several studies
illustrating 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 of
vulnerability in which the majority of psychological disorders
emerge (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 that
approximately 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 of
extinction, which involves repeatedly exposing the individual to
the feared stimulus/situation in the absence of any danger. As
noted 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. Although
there are over a thousand publications on fear extinction in ani-
mals and humans since 2000 (Milad & Quirk, 2012), very few of
these studies have examined fear extinction during development.
There have been a few recent studies in infants (for review see
Kim & Richardson, 2010), but scarcely any in adolescents. In this
paper, we rst review this relatively small body of research on fear
extinction in adolescent rodents and humans. A major nding of
this 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 move
onto a consideration of various factors/mechanisms that could
mediate this pronounced impairment in extinction in adolescence.
We conclude that changes in the functional connectivity within the
fear extinction circuit, particularly between prefrontal cortical re-
gions and the amygdala, may be the neurobiological basis for the
impaired 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 increase
the likelihood of resistance to extinction earlier or later in life,
depending on the age at which the stressor is experienced. We also
briey describe another body of research on emotional regulation
and attentional processes for additional clues as to potential cog-
nitive mechanisms that may mediate the observed impairments in
extinction in adolescence. Finally, we describe several recent stud-
ies that provide evidence for approaches that overcome extinction
impairments in adolescent rodents, and that could be translated to
treating adolescent humans with an anxiety disorder.
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: k.baker@unsw.edu.au (K.D. Baker), m.den@unsw.edu.au (M.L.
Den), bgraham@psy.unsw.edu.au (B.M. Graham), r.richardson@unsw.edu.au (R.
Richardson).
Neurobiology of Learning and Memory xxx (2013) xxxxxx
Contents lists available at ScienceDirect
Neurobiology of Learning and Memory
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Please cite this article in press as: Baker, K. D., et al. A window of vulnerability: Impaired fear extinction in adolescence. Neurobiology of Learning and Mem-
ory (2013), http://dx.doi.org/10.1016/j.nlm.2013.10.009
2. Fear extinction in adolescent rodents
Those studies that have examined extinction of fear in adoles-
cence have all used Pavlovian procedures to rst condition fear.
This involves pairing an initially neutral conditioned stimulus
(CS; e.g., a tone or a light) with a naturally aversive unconditioned
stimulus (US; e.g., a shock or a loud noise). At some point following
this, the CS is presented by itself, and over repeated trials the fear
elicited by the CS diminishes. Before describing those studies, how-
ever, it is important to dene adolescence given that there are
some disagreements about exactly when adolescence begins and
ends, in both rodents and humans (Spear, 2000). In this review
we will be very inclusive and dene adolescence in rodents as
being between postnatal (P) day 28 to P50, and in humans as being
1217 years of age.
In perhaps the rst 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. Early
adolescent mice showed enhanced fear acquisition as well as
higher levels of freezing during extinction training compared to
mid-adolescent and young adult mice. However, there were no
age differences in the rate of within-session extinction. Further,
extinction retention was not tested in that study. Two subsequent
studies replicated this nding in rats, demonstrating that adoles-
cents (P35) did not differ in rates of within-session extinction
compared to juvenile (P24) and adult (P70) rats, and these studies
also found a marked impairment in extinction retention in the
adolescents (Kim, Li, & Richardson, 2011; McCallum, Kim, &
Richardson, 2010). That is, although adolescent rats expressed
the same low-level of CS-elicited freezing at the end of the extinc-
tion training session as did juvenile and adult rats, when tested the
following day they exhibited a striking return of fear, relative to
the other two age groups (see Fig. 1A; redrawn from McCallum
et al., 2010). A more recent study did not detect any age-related
differences in extinction retention between adolescent and adult
rats (Broadwater & Spear, 2013). Although adolescent (P35) rats
in that study showed a remarkable recovery of fear when extinc-
tion retention was tested, so too did adult (P71) rats (i.e., rats
of both ages exhibited 80% CS-elicited freezing at test). This high
level of fear at test makes it nearly impossible to detect any poten-
tial extinction retention impairment in the adolescents. In contrast
to those results, another study reported impaired extinction
learning and retention in adolescent mice (Pattwell et al., 2012).
Specically, when extinction training was spread over several days
(with 5 trials per day over 4 days), adolescent mice (P29) displayed
impaired extinction learning and retention compared to juvenile
(P23) and adult (P70) mice. These decits in fear extinction in
adolescent rodents do not seem to be due to differences in fear
conditioning. Although Hefner and Holmes (2007) observed en-
hanced fear acquisition (as reected by higher levels of CS-elicited
freezing) in adolescents, such a difference was not observed in the
three studies that reported impaired extinction retention in ado-
lescents. In addition, there are other studies that have reported
similar acquisition of fear in adolescent compared to adult rats
(Brasser & Spear, 2004). Taken together, these studies demonstrate
a marked decit in fear regulation in adolescence, but clearly more
research needs to be done in this area.
3. The study of fear extinction in adolescent humans
Neumann, Waters, and Westbury (2008) gave 1317 year old
participants pairings of a geometric shape (CS+) with the unpleas-
ant sound of metal scraping on a slate (US). Across a number of
dependent variables (including potentiated startle, skin conduc-
tance, and self-report measures), robust fear conditioning and
within-session extinction was observed. Contrary to this nding
of 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 was
chosen 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 conditioned
fear in this type of study is going to be much less than what occurs
in studies where painful stimulation (e.g., shock or loud noise) is
used as the US. Nonetheless, the participants in the study by Had-
dad and colleagues were 1215 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 that
was the same face displaying a positive facial expression and a po-
sitive comment), (2) CS-negativeUS (i.e., a neutral face CS was
paired with a US that was the same face with a negative facial
expression and negative comment), and (3) CS-neutralUS (i.e., a
neutral face CS was paired with the same neutral face and a neutral
comment). After conditioning, participants rated the CS that was
paired with the negative expression and comment as more
unpleasant and scary than both of the other two CSs. More impor-
tantly, this difference persisted after extinction trials in which the
CS that had been paired with the negative expression was repeat-
edly presented alone. This nding supports the claim that adoles-
cents show impaired within-session extinction. In both of the
Group
%
F
r
e
e
z
i
n
g
%
F
r
e
e
z
i
n
g
%
F
r
e
e
z
i
n
g
Juvenile Adolescent Adult
0
20
40
60
80
100
A
Group
Saline DCS Extended
Extinction
0
20
40
60
80
100
B
Group
No
Retrieval
Retrieval-
Extinction
Extinction-
Retrieval
0
20
40
60
80
100
C
Fig. 1. Adolescent rats show impaired extinction retention at test compared to juvenile and adult rats (Panel A). D-cycloserine (DCS) and extended extinction training
improved extinction retention in adolescent rats (Panel B). Memory retrieval 10 min before or after extinction augmented extinction retention in adolescent rats (Panel C).
The data shown in Panels A and B were taken from McCallum, Kim, and Richardson (2010) and the data shown in Panel C were taken from Baker, McNally, and Richardson
(2013).
2 K.D. Baker et al. / Neurobiology of Learning and Memory xxx (2013) xxxxxx
abovementioned studies, conclusions about age-related differences
in within-session extinction were not possible as only adolescent
participants 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 decit
in within-session extinction compared to both children and adults.
Specically, in a discriminative fear conditioning procedure one CS
(a colored square presented on a computer screen) was followed
by an aversive noise US 50% of the time (i.e., CS+) and a second
CS (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 across
age groups; the average differential skin conductance response
from the last two extinction trials was subtracted from that of
the rst two trials. Adolescents (1217 years old) showed attenu-
ated fear-extinction learning compared with children (511 year
olds), and a trend (p = .078) towards poorer extinction learning
compared to adults (1828 years). These differences were not
attributable to age differences in fear acquisition, sex differences
in extinction learning, or trait anxiety. These studies suggest that
healthy adolescents are impaired at extinction learning, but it is
not 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-anxious
adolescents 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) was
never followed by the aversive outcome. Extinction training oc-
curred over two sessions, with the rst session immediately after
conditioning (3 presentations of each CS by itself), and the second
session approximately 16 days after conditioning (12 presenta-
tions of each CS by itself). Following conditioning, both anxious
and healthy adolescents rated the CS+ as more fear-provoking than
the CS, and the size of this difference was comparable across the
two groups (a nding similarly observed in adults; for a review see
Lissek et al., 2005). Participants, whether anxious or not, showed a
resistance 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 that
study, no developmental comparisons in either extinction learning
or extinction retention can be made.
Although this body of research is very small at this point, the
ndings strongly suggest that there are impairments in extinction
of fear during adolescence, in both rodents and humans. Given that
this is the period of development during which many anxiety dis-
orders rst emerge, it will be important to determine what emo-
tional and cognitive processes may mediate this impairment as
well as any contribution made by neural changes occurring in this
period of development. Therefore, in the subsequent sections of
this review we examine how (1) signicant structural and func-
tional neural changes in the fear extinction circuit during adoles-
cence may lead to impaired extinction, (2) fear extinction in
adolescence is altered by adverse experiences, and (3) emotional
regulation and attentional biases may contribute to the impaired
extinction observed in adolescence.
4. Neural changes in the fear extinction circuit during
adolescence
Signicant 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, ndings from
research that has examined neural activity in adolescents during
other laboratory tasks (e.g., decision making and emotional pro-
cessing) provide a potential framework that can be used to under-
stand the reported behavioral decits in fear extinction in
adolescents, and to make novel hypotheses about the neural mech-
anisms that mediate such decits.
4.1. Structural changes in the prefrontal cortex and amygdala during
adolescence
Human adolescents exhibit a reduction in gray matter in the
PFC. 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 an
increase 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 more
protracted than is the maturation of sub-cortical regions (reviewed
in 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 volumetric
analyses of amygdala size in 418 year olds revealed that amyg-
dala volume was greatest during early adolescence (at around
the age of 14 years for female participants, around 1516 years
for male participants) and was smallest in the youngest and oldest
participants in that cohort (Hu, Pruessner, Coup, & 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 that
adolescence is a period of relatively active cell proliferation in the
amygdala compared to young adulthood. In fact, cell proliferation
in the amygdala of adolescent rats occurs at a rate four-ve times
higher 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 be
driven by increases in sex hormones, as other ndings have dem-
onstrated that adolescent boys in later stages of pubertal develop-
ment exhibit larger amygdala volumes relative to age-matched
peers in earlier stages of puberty (Neufang et al., 2009; Scherf,
Smyth, & Delgado, 2013) and that growth of the amygdala during
puberty is associated with circulating testosterone levels (Neufang
et al., 2009).
4.2. Functional changes in the prefrontal cortex and amygdala during
adolescence
In addition to structural changes, numerous changes in the
functional 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 a
range of tasks. For example, adolescents recruit the medial PFC
(mPFC) to a lesser extent than adults when viewing emotional
faces (Hare et al., 2008) and when tracking changes in emotional
state (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 viewing
emotional faces. Again, these functional changes in amygdala
activity may be mediated by sex hormones, as a positive correla-
tion has been reported between pubertal stage and amygdala
hyperactivation during face presentations (Moore et al., 2012).
However, it should be noted that there are some inconsistencies
K.D. Baker et al. / Neurobiology of Learning and Memory xxx (2013) xxxxxx 3
in the literature with respect to patterns of functional PFC and
amygdala activation during adolescence, where, in some cases,
hyperactivity of the amygdala and hypoactivity of the PFC are
not observed (Somerville, Jones, & Casey, 2010). A more consistent
picture of the neurological characteristics of adolescence may be
gained through the study of neural circuits as opposed to discrete
structures, as outlined next.
4.3. Functional connectivity between the prefrontal cortex and
amygdala during adolescence
Recent neuroimaging research has moved towards the study of
neural circuits rather than the morphology and function of single
neural structures in isolation. Such an approach takes into account
that the strength of coupling between two or more regions may be
more important in determining behavioral outcomes than the
overall activation of discrete neural regions. For example, it may
be that strong inverse functional connectivity between the PFC
and amygdala (where PFC activation is associated with amygdala
inhibition) is necessary for fear extinction to occur. If so, then
strong PFC activity would be insufcient to support fear extinction
in the absence of functional connectivity with the amygdala. From
this perspective, it makes more sense to examine the functional
connectivity within the fear extinction circuit, rather than the
activity within individual structures, to determine the neurobio-
logical basis for impaired extinction during adolescence.
Only a few studies have investigated functional connectivity of
these 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 effective
connectivity (i.e., the degree to which activity in one region im-
pacts activity in another region) between the anterior cingulate
and 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 of
these studies.
A recent study by Roy et al. (2013) examined intrinsic (resting
state) functional connectivity in adolescents with and without gen-
eralized anxiety disorder (GAD). They reported decreased connec-
tivity between the amygdala and ventromedial PFC in adolescents
with GAD relative to adolescents without GAD, suggesting that re-
duced connectivity between these regions may be a hallmark of
anxiety during adolescence. However, this study did not compare
functional connectivity across development, and so it is unclear
whether or not amygdalaPFC connectivity is reduced in healthy
adolescents 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 in
healthy children, adolescents, and young adults. They reported that
amygdalamPFC 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, amygdalamPFC
functional connectivity was most strongly negatively correlated for
1822 year olds (i.e., they exhibited strong connectivity between
these regions), and was signicantly greater in 1822 years olds
than all other age groups examined (49, 1013, and 1417 year
olds; i.e., connectivity between these regions was weaker in these
age groups). It is interesting to note that the pattern of increased
amygdalamPFC connectivity from adolescence to adulthood mir-
rors the observed improvement in extinction ability from adoles-
cence to adulthood, suggesting that low connectivity between
these regions during early-/mid-adolescence, combined with
amygdala hyperactivation, may underlie the decits in fear extinc-
tion during adolescence.
4.4. Current neurobiological models of adolescent behavior
Findings like those reviewed above have led to the emergence
of several neurobiological models that are designed to account
for the myriad of affective and behavioral changes observed during
adolescence (Casey et al., 2008; Nelson, Leibenluft, McClure, &
Pine, 2005; Steinberg, 2008). These models posit that as the PFC
is a late-maturing structure, connectivity between it and sub-cor-
tical structures does not develop until late adolescence or early
adulthood. Thus, the PFC does not have the structural and/or func-
tional connections to drive the inhibition of behaviors mediated by
sub-cortical structures until later in life. During childhood, because
sub-cortical structures are still developing and are often hypo-
responsive, a balance is maintained between brain systems that
regulate emotional and reward-driven behavior and those that ex-
ert inhibitory control over such behavior. However, as sub-cortical
structures develop more rapidly than the PFC and are often hyper-
responsive during adolescence, at this stage of development there
is 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 low
level of connectivity between these neural regions.
While no studies have investigated whether these neurobiologi-
cal models can account for adolescent decits in fear extinction,
extensive research has been conducted in applying these models
to adolescent reward-driven behavior, with the aim of understand-
ing why adolescents engage in risky behavior. Just as the amygdala
is more active during processing of fearful faces in adolescence, so
too is the ventral striatum more active in adolescents during re-
ward-focused tasks. Furthermore, frontalstriatal connections in-
crease both structurally and functionally across development,
and the increased connectivity has been associated with increased
capacity 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 for
by reduced prefrontal inhibitory control over excessive striatal
activation in the presence of appetitive stimuli. Similarly, impair-
ments in extinction during adolescence may be due to reduced
prefrontal inhibitory control over excessive amygdala activation
in the presence of fearful stimuli.
This sort of neurobiological model where there is an imbalance
in activity between prefrontal inhibitory regions and sub-cortical
structures 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 future
research. However, it is worth noting that in other populations in
which extinction decits 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 at
the 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 decits observed in
adolescents.
Some preliminary support for the above hypothesis comes from
several studies in rodents that have documented differences in the
functional activity in the neural circuitry supporting fear extinction
during adolescence versus adulthood. Notably, these studies dem-
onstrated that the mPFC may not be recruited as efciently during
fear extinction in adolescent rodents as in younger and older ani-
mals. For example, immunohistochemical analyses using phos-
phorylated mitogen-activated protein kinase (pMAPK) as a
marker of neuronal activity have shown that adolescent rats do
not exhibit the same extinction-induced increases in neuronal
activity in the infralimbic mPFC that are observed in juvenile and
adult rats (Kim et al., 2011). Consistent with this observation, there
is a lack of synaptic plasticity associated with extinction in the
infralimbic mPFC of adolescent mice compared with what is ob-
served in the juvenile and adult mPFC (Pattwell et al., 2012). The
adolescent mPFC also shows elevated basal excitatory synaptic
transmission compared to juveniles and adults, which may con-
tribute to a lack of prefrontal synaptic plasticity and impaired
extinction in adolescence (Pattwell et al., 2012). Furthermore, dur-
ing adolescence there is a dramatic increase in projections fromthe
basolateral amygdala to ventromedial PFC GABAergic inhibitory
interneurons which could destablize and impair mPFC function
(Cunningham, Bhattacharyya, & Benes, 2008). Together, these nd-
ings suggest that adolescents may be less efcient in utilizing pre-
frontal regions to maintain the inhibition of fear following
extinction.
5. Fear extinction in adolescence is altered by adverse
experiences
5.1. Adolescence is a vulnerable developmental period to the effects of
stress
Adolescence is often characterized as a period of storm and
stress (Casey, Jones, et al., 2010; Romeo, 2013). One factor that
may contribute to adolescent vulnerability is that the hypotha-
lamicpituitaryadrenal (HPA) axis, which mediates the mamma-
lian response to stress, undergoes subtle changes during
adolescence (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 adrenocorticotropic
hormone (ACTH), the latter of which stimulates the synthesis and
secretion of glucocorticoids by the adrenal glands. The primary
neural targets of the glucocorticoids include the hypothalamus,
hippocampus, and PFC, and their overall function is to reduce the
production and release of CRH and ACTH via negative feedback,
effectively terminating the stress response. Dysfunctions in adult
HPA-axis activity and reactivity have been implicated in a host of
mental 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), fewer
studies have examined the impact of stress on HPA-axis function
during adolescence. The few studies that have examined this issue
have demonstrated that under non-stressed conditions basal levels
of ACTH and corticosterone (a major glucocorticoid in rats) are
comparable between adolescent and adult rats (Foilb, Lui, &
Romeo, 2011; Lui et al., 2012; Romeo, Lee, Chhua, McPherson, &
McEwen, 2004; Romeo, Lee, & McEwen, 2004). When acutely
stressed, however, the amount of ACTH and corticosterone re-
leased is signicantly greater in adolescent than adult rats (Foilb
et al., 2011; Lui et al., 2012). Moreover, the stress-induced release
of these hormones is signicantly more protracted in adolescent
rats, resulting in a much slower return to baseline levels of stress
hormones compared to adult rats (Foilb et al., 2011; Romeo, Lee,
Chhua, et al., 2004; Romeo, Lee, & McEwen, 2004). Adolescent rats
also respond differently to chronic stress than do adults. For exam-
ple, the HPA-axis response in adult rats habituates with chronic
exposure to the same stressor, whereas adolescent rats fail to exhi-
bit such habituation (i.e., they continue to exhibit robust release of
ACTH and corticosterone whereas adult rats exhibit attenuated re-
lease of these hormones; Lui et al., 2012).
Data fromhumans resemble the rodent ndings, with one study
reporting that while there were no differences in baseline cortisol
levels between children and adolescents pre-stressor, adolescents
exhibited 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 (Stroud
et 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; cortisol
levels were also signicantly higher amongst 15 year olds during
a social stressor task (Gunnar, Wewerka, Frenn, Long, & Griggs,
2009). It should be noted that a limitation in the current literature
is that no studies using human participants to date have compared
HPA-axis activity in adolescents versus adults (baseline or under
stress conditions). Nevertheless, taking these human and rodent
ndings 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 is
characterized by an over-active, protracted stress response. It is
thought that due to the continued maturation of the limbic and
prefrontal 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 vulnerable
developmental 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 in
adolescent rodents. Consistent with neurobiological models sug-
gesting that exposure to stress has different outcomes depending
on the age at which it is experienced (Lupien et al., 2009), the effect
of 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 adolescent
rodents
The results of several recent studies have suggested that expo-
sure to chronic stress alters the nature of the extinction system in
adolescence. The rst example is that early-life stress has been
shown to accelerate the transition into and out of the adolescent
prole of fear extinction (Callaghan & Richardson, 2012). In that
study, infant rats were exposed to repeated bouts of maternal sep-
aration (3 h per day from P214). Animals exposed to early-life
stress showed an early emergence of poor extinction retention dur-
ing pre-adolescence (at P27) and good extinction retention during
adolescence (at P35). One explanation of these ndings is that
exposure to early-life stress accelerated the maturation of neural
structures, such as the PFC, required for adult-like extinction
behavior (Callaghan & Richardson, 2012).
In contrast to early-life stress which causes an earlier emer-
gence of the adolescent prole of extinction, chronic stress in early
adolescence appears to cause decits of extinction acquisition in
adolescence as well as impaired extinction retention in adulthood.
Although one study did not nd an effect of chronic social instabil-
ity stress in adolescence on fear extinction in adolescence (P46) or
adulthood (Morrissey, Mathews, & McCormick, 2011), two studies
showed a disruption of extinction acquisition with chronic stress in
adolescent male rats, and one of these also demonstrated impaired
extinction retention in adult male rats. Zhang and Rosenkranz
(2013) examined the effect of chronic restraint stress (7 out of
9 days from either P29 or P65) on the acquisition and extinction
of learned fear in male adolescent (P39) and adult (P76) rats. At
both ages, restraint stress enhanced fear conditioning. However,
repeated restraint led to impaired acquisition of fear extinction
only in adolescence. The effect of restraint stress on extinction
retention was not tested in that study. A disruption of extinction
acquisition by chronic stress in early adolescence in male rats
was 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 elevated
platform on P28P30) exhibited increased conditioned fear and
failed to show the same reduction in freezing across a 5 min test
that 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 of
stress were long-lasting in male rats because when the same ani-
mals were tested in adulthood, those animals exposed to chronic
stress 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 more
susceptible to the effects of stress than adults. However, the nd-
ings do show that chronic stress during adolescence increases
the likelihood of impaired extinction retention later in life.
Exactly howchronic stress in adolescence contributes to decits
in fear extinction is unclear at this stage. One possibility is that
stress in adolescence leads to a decrease in synaptic plasticity in
the neural regions that support fear extinction, and an increase
in synaptic plasticity in the regions that support fear expression.
For example, chronic stress in male and female adolescent rats
leads 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 dendritic
remodeling tips the balance between prefrontal inhibition and
amygdala excitation, leading to a disruption in the extinction of
fear. Future research is needed to determine whether such changes
to the functional connectivity between the PFC and amygdala con-
tribute to the impaired extinction retention observed in adulthood
following stress encountered during adolescence.
In addition, stress-induced changes to the hippocampus are
likely to impact extinction in adolescence given the importance
of this structure in the contextual modulation of fear extinction
as well as the consolidation of extinction memories (reviewed in
Quirk & Mueller, 2008). The hippocampus, implicated in the nega-
tive feedback regulation of the HPA-axis, is particularly vulnerable
to the effects of stress during adolescence and adulthood, due to
the high density of glucocorticoid receptors in that structure (re-
viewed in McCormick et al., 2010). Chronic stress has been shown
to impact hippocampal structure and function by causing dendritic
retraction (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, while
research suggests that in adulthood these stress-induced changes
are transient and reversible (Luine, Villegas, Martinez, & McEwen,
1994; Sousa, Lukoyanov, Madeira, Almeida, & Paula-Barbosa,
2000), converging animal and human studies have demonstrated
that stress exposure during adolescence can have a profound and
long-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 in
adolescence as well as in adulthood. Although studies of this kind
have not yet been conducted, they would have clear practical
implications for the treatment of both adolescents with anxiety
disorders as well as adults exposed to stress during their adoles-
cent years.
6. Attentional bias to threatening cues may inuence fear
extinction 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 during
adolescence. During conditioning, repeated pairings of a CS with
an aversive US results in anticipatory fear and attention biases to-
wards the CS+ (Mackintosh, 1975). Then, subsequent extinction
training trials (i.e., CS+ alone presentations) reduce attention to
the 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 posttraumatic
stress disorder (Fani et al., 2012).
Unfortunately, studies have not yet looked at whether develop-
mental changes in attention bias to threatening cues contribute to
age-related differences in extinction learning. However,
age-related differences in the response to threatening stimuli have
been the focus of a number of recent studies. For example, Hare
et al. (2008) demonstrated that adolescents show an exaggerated
amygdala response to cues that signal possible threat (i.e., fearful
faces), relative to both children and adults, and this was largely
due to inefciency in recruiting prefrontal regions involved in
dampening 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 the
CS (i.e., the safety cue that did not predict the aversive US) as
threatening. Given these ndings, adolescents might be expected
to show a heightened sensitivity to learning fearful associations,
relative to both children and adults. While this has not yet been
demonstrated 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 being
trained on a trace conditioning procedure (i.e., where long, stimu-
lus-free intervals of up to 40 s separated the CS and US). These
studies raise a number of interesting questions for future research
on extinction in adolescence regarding (1) whether attention bias
to the CS+ persists following extinction learning, (2) whether such
bias predicts a poorer response to extinction learning, and (3)
whether attention bias differs in anxious versus healthy adolescent
and adult populations. Research of this kind in humans would ulti-
mately indicate whether current treatments need to be tailored so
that they optimally target potential underlying attentional dys-
functions mediating anxiety during adolescence, compared to
adulthood.
7. Development of the fear extinction circuit: an imbalance
during adolescence
The fear extinction system undergoes many changes across
development. Fig. 2 shows a schematic of how a balance within
the fear circuit is important for appropriate fear regulation across
development. Juveniles and adults can express and inhibit fear
appropriately when various situations are encountered in their
environment. However, the reason behind this comparable balance
in fear regulation may be different between these two age groups.
For example, juveniles may have reduced connectivity between the
amygdala and mPFC relative to adults (Gee et al., 2013), but the
amygdala is less active/underdeveloped at this point of develop-
ment so a balance is maintained. Adults have a fully developed
amygdala and mPFC, and have strong connectivity between these
regions relative to younger ages, and so a balance in fear regulation
is maintained. However, maturational changes in the brain during
adolescence have a striking impact on fear expression and fear
inhibition. As reviewed above, during adolescence there is growth
in amygdala volume and reduction in gray matter in the PFC (see
Casey et al., 2008; Hu et al., 2013; Saul et al., 2013), as well as
changes in the functional connectivity between these regions from
childhood, through adolescence and into adulthood (Gee et al.,
2013). In addition, age-related differences in extinction learning
may also be mediated by cognitive mechanisms such as develop-
mental changes in attention bias to threatening cues. We propose
that the combination of brain maturation and cognitive changes
disrupts the balance between PFC and amygdala activity and tips
the balance towards poor fear inhibition (Fig. 2). Specically, a
hypoactivation of the PFC and hyperactivation of the amygdala
would result in the adolescent being primed to express more fear
compared to juveniles or adults. This imbalance model is well sup-
ported by ndings that adolescent rodents show heightened sensi-
tivity to learning fearful associations (Den & Richardson, 2013) and
impaired fear inhibition (Kim et al., 2011; McCallum et al., 2010;
Pattwell et al., 2012) compared to younger and older animals. That
adolescents 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 between
top-down prefrontal inhibitory control of the amygdala in re-
sponse to fearful stimuli. This imbalance in fear regulation may
contribute to an increased likelihood of anxiety symptoms emerg-
ing during adolescence, consistent with the nding that anxious
adolescents have decreased connectivity between the amygdala
and ventromedial PFC relative to non-anxious adolescents (Roy
et al., 2013). Once the maturation of the brain is complete during
the transition out of adolescence into adulthood and adult cogni-
tive processes have developed, the balance between prefrontal
and amygdala activity returns and appropriate fear regulation is
restored.
8. Manipulations which overcome decits in fear extinction
during 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 pharmacological
and non-pharmacological (e.g., behavioral) manipulations that
are 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 insights
into 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 giving
double the amount of extinction training (see Fig. 1B; re-drawn
from McCallum et al., 2010). There is considerable translational va-
lue of DCS as a treatment for human anxiety disorders given that it
has been shown to have positive therapeutic effects for several
anxiety disorders in adults (e.g., de Kleine, Hendriks, Kusters,
Broekman, & van Minnen, 2012; Guastella et al., 2008; Hofmann
et al., 2006; Ressler et al., 2004; reviewed in Hofmann, Wu, &
Boettcher, 2013). With particular relevance to fear inhibition in
adolescence, one preliminary study in youth (aged 817) with
obsessivecompulsive 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 DCS
facilitates fear extinction, it may produce treatment gains by
enhancing 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 ndings, functional
studies in adults with a snake phobia using fMRI have shown that
DCS can produce long-lasting changes to prefrontal activity. One
week after treatment, individuals that were given DCS before a sin-
gle session of exposure therapy exhibited different activation of
the ventromedial PFC and other prefrontal regions (i.e., increased
medial orbitofrontal, subgenual anterior cingulate, and left dorso-
lateral PFC activation) in response to fearful stimuli compared to
those 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 benecial effects are obtained. One
example of an effective behavioral procedure is that doubling the
amount of extinction training leads to adult-like extinction reten-
tion in adolescent rats (see Fig. 1B; redrawn from McCallum
et al., 2010) and adolescent mice (Clem & Huganir, 2010). In the
latter study, adolescent mice given a retrieval trial before extensive
extinction 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 in
adolescent humans with an anxiety disorder (e.g., administering
extensive exposure-based therapy would be both time consuming
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, including
changes to the volume, activity, and functional connectivity between brain regions within the fear circuit, as well as cognitive changes. Although juveniles and adults exhibit a
comparable balance between fear inhibition and fear expression, the underlying reasons behind this balance may be different between the two age groups. In contrast, the
balance is tipped towards poor fear inhibition and heightened fear expression during adolescence.
and costly, and also increase the likelihood of patients not
completing treatment). A recent study by Baker, McNally, and
Richardson (2013) demonstrated a reliable, but less time-consum-
ing, manipulation which prevented the recovery of extinguished
fear 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 following
day (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 also
attenuated renewal of fear when animals were tested in the train-
ing, rather than the extinction, context. The loss of fear reported
following retrieval-extinction manipulations in adult rats and hu-
mans is typically interpreted as a disruption of reconsolidation of
the original fear memory (e.g., Flavell, Barber, & Lee, 2011; Monls,
Cowansage, Klann, & LeDoux, 2009; Schiller et al., 2010). However,
a key result in the study by Baker et al. was that a single retrieval
trial given soon after extinction produced a similar loss of fear as
that produced by a retrieval trial before extinction (see Fig. 1C), a
nding 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 may
promote better discrimination at test between the competing
training and extinction memories (Baker et al., 2013; Millan, Milli-
gan-Saville, & McNally, 2013). An important implication from this
study is that a single retrieval trial around the time of extinction
training may offer a simple, effective way of enhancing long-term
treatment gains for human populations, including adolescents,
when extinction decits are seen.
9. Future directions
As noted above, the improvement in fear extinction retention
during the transition from adolescence to adulthood may arise
from increased prefrontal inhibitory control over the amygdala.
There are a number of structural changes which occur during the
maturation of the PFC across adolescence. One example is the for-
mation of perineuronal nets (PNNs). PNNs are extracellular matrix
structures (containing chondroitin sulphate proteoglycans) which
enwrap many neurons in the brain, particularly the inhibitory neu-
rons that contain the calcium-binding protein parvalbumin, as well
as excitatory pyramidal neurons (Brckner 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 in
limiting neural plasticity at the conclusion of several developmen-
tal critical periods (e.g., the critical period for ocular dominance
plasticity in the visual cortex; Pizzorusso et al., 2002). There are
also recent post-mortem studies in humans suggesting that PNNs
increase in the PFC across adolescence into adulthood and that
aberrant PNN formation in humans may contribute to psychologi-
cal disorders (e.g., schizophrenia; Mauney et al., 2013). Given these
ndings, it is tempting to speculate that the formation of PNNs in
the PFC at the conclusion of adolescence may help to support the
adult fear extinction system. A corollary of this would be that
abnormal formation of PNNs in the prefrontal brain circuitry regu-
lating fear during adolescence may contribute to the etiology of
anxiety disorders. There is already evidence that PNNs are involved
in the developmental regulation of fear extinction in young ro-
dents. Specically, the maturation of PNNs in the mouse amygdala
coincides with the transition from a relapse-resistant extinction
system in infants to relapse-prone extinction in juveniles (Gogolla,
Caroni, Lthi, & Herry, 2009). Thus, an exciting direction for future
research will be to examine whether the formation of PNNs in the
later 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 is
determining the unique contribution of developmental age versus
puberty (and the associated increase in uctuations in sex hor-
mones), as well as the interaction between the two, in mediating
the impairment in extinction observed during adolescence. There
are many examples in which the mere exposure to sex hormones
during pre-adolescence is not sufcient to induce adolescent-like
behavior in rodents, suggesting that some changes in adolescence
are more to do with age (or the combination of age plus exposure
to sex hormones) than with puberty stage per se. For example, the
pre-pubertal removal of ovaries does not prevent the protracted
HPA-axis reactivity to stress in adolescent female rats (Romeo,
Lee, & McEwen, 2004). This suggests that the alteration in HPA-axis
reactivity observed during adolescence is mediated by age rather
than sex hormones. Preclinical research in rodents, which allows
for the systematic manipulation of sex hormones, is required in or-
der to determine whether the decits in fear extinction observed
during adolescence are a consequence of age, sex hormone expo-
sure, or an interaction between the two. This will be particularly
important in light of recent research suggesting that sex hormones
play a signicant 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 some
examples of polymorphisms in human genes which have been asso-
ciated with decits in fear extinction. For example, both adult hu-
mans and adult inbred genetic knock-in mice that express the
variant BDNF allele (Val66Met), which is associated with reduced
activity-dependent release of BDNF, exhibit a slower rate of fear
extinction learning (Soliman et al., 2010). Functional MRI imaging
has demonstrated that adult human Met allele carriers showed less
ventromedial PFC activity, and greater amygdala activation, during
extinction compared to noncarriers, indicating alterations to activ-
ity within the fear extinction circuit in Met allele carriers (Soliman
et al., 2010). However, it is unknown when these genotype differ-
ences in extinction learning and functional brain activity rst
emerge; it is possible that such decits may already be evident in
adolescents. Related to this, Bath et al. (2012) argued that anxi-
ety-like behaviors measured in the elevated plus maze increased
over the transition from adolescence to adulthood in female Met/
Met mice but not wild-type Val/Val mice, however, the differences
between genotypes were primarily observed in adults over
100 days of age, not in adolescents. Thus, the effect of BDNF gene
polymorphisms on fear extinction in adolescent animals or humans
has not yet been investigated. Interestingly though there is some
evidence that variation in the expression of mRNA coding for the
serotonin 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 common
polymorphism which reduces expression of the form containing
the 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 (Gyawali
et al., 2010). Variation in serotonin transporter genes may confer
a 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 enhanced
extinction learning and retention in adolescent female mice (specif-
ically, caloric restriction and chronic uoxetine treatment) were
associated with increased expression of the particular distal poly-
adenylation mRNA form. Further research examining the effect of
gene polymorphisms on fear extinction in adolescent animals and
humans may provide insight into whether individuals with a par-
ticular genetic makeup may be more likely to develop symptoms
of anxiety across the transition from adolescence to adulthood.
Finally, a further area of interest is the neural basis for how
manipulations such as DCS and memory retrieval around the time
of extinction improve the extinction of fear in adolescence. For
example, extensive extinction training has been demonstrated to
increase neuronal activation in the infralimbic and prelimbic re-
gions of the mPFC in adolescent rats (Kim et al., 2011); is a similar
effect observed following retrieval-extinction manipulations? This
work may lead to the determination of whether manipulations that
improve extinction retention in adolescents also enhance the func-
tional coupling between the amygdala and PFC. Different types of
interventions 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 several
different approaches by which fear inhibition in adolescence can
be enhanced.
In conclusion, there is emerging research suggesting that there
is 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 amygdala
activation 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 may
also contribute to age-related differences in extinction learning.
A combination of such changes may result in an imbalance in fear
regulation such that there is poor fear inhibition and heightened
fear expression during adolescence (see Fig. 2). Whatever is caus-
ing the decits in extinction during adolescence, there are several
effective manipulations for improving the inhibition of fear in ado-
lescent rodents, providing promising translational interventions
for human adolescents. Given that anxiety during adolescence is
a strong predictor of adult anxiety and other psychological disor-
ders (Kessler et al., 2012), continued research into fear extinction
in adolescence will improve our ability to develop early and effec-
tive interventions for anxiety.
Acknowledgments
Preparation of this manuscript was supported by an Australian
Postgraduate 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 Health
and Medical Research Council Peter Doherty Early Career Fellow
(APP1054642).
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A window of vulnerability: Impaired fear extinction in adolescence

, Miriam L. Den, Bronwyn M. Graham, Rick Richardson

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