Adolescence What Do Transmission, Transition, and Translation Have To Do With It

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Neuron. Author manuscript; available in PMC 2011 September 9.
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Neuron. 2010 September 9; 67(5): 749–760. doi:10.1016/j.neuron.2010.08.033.
Adolescence: What do Transmission, Transition, and

Translation have to do with it?
BJ Casey, Stephanie Duhoux, and Matthew Malter Cohen
Sackler Institute for Developmental Psychobiology, Weil Cornell Medical College, 1300 York
Avenue, Box 140, New York, NY 10065 USA
Abstract
Negotiating the transition from dependence on parents to relative independence is not a unique
demand for today’s youth, but has a long evolutionary history (transmission) and is shared across
mammalian species (translation). Yet, behavioral changes observed during this period are often
described as delinquent. This review examines changes in explorative and emotive behaviors
during the transition into and out of adolescence and the underlying neurobiological bases in the
context of adaptive and maladaptive functions.
Keywords
adolescence; development; evolution; genetics; environment
Introduction
Adolescence is a transitional period from childhood to adulthood, with an onset that includes
pubertal maturation and an offset that is marked by independence from the parent. The
paradox observed for human adolescents is that while they are stronger, faster, more
resistant to disease, have better reasoning and decision making skills than children, mortality
increases 200% for them during this time (Dahl, 2001). This increase in deaths is not
attributable to disease, but rather preventable forms of death including accidental fatalities,
suicide and homicide (CDC, 2006) and related to difficulties in regulation of behavior and
emotion (Steinberg, 2008).
To understand this paradox, this review highlights central themes of the NIH Blueprint for
neuroscience research on neurodevelopment
(http://neuroscienceblueprint.nih.gov/blueprint_basics/Neurodevelopment%20Workshop
%20Report.htm) (NIH, 2006). This report underscores the importance of “periods of rapid
developmental transition, such as the transition into and out of puberty” and using
“translational developmental neuroscience” to understand how behavior is transmitted from
one generation to the next and translated across species. By examining the development of
adolescent behavior through this lens, what may appear to be aberrant behavior at first
glance may simply be adaptation of evolutionarily conserved mechanisms to the current
environment.
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Casey et al. Page 2
More and more, scientists are attempting to explain aberrant behavior in the context of gene
and environment interactions, with the environment accounting for much of the variance
(Caspi et al., 2010; Risch et al., 2009). In contrast to the argument of the environment being
variable and the genome being relatively stable, the environment can be an extreme source
of stability for nervous systems and behaviors (Finlay, 2007). A long evolutionary history
can lead to expected experiences and specialized mechanisms for adapting to these
experiences. Greenough (Greenough et al., 1987) coined the terms experience-expectant and
experience-dependent to differentiate processes that appear to have evolved as a neural
preparation for incorporating specific experiences versus specific processes to incorporate
experiences that are unique to the individual, such as learning about one's specific
environment. When an evolutionarily expected environment is altered, then evolutionarily
conserved mechanisms may be maladaptive for the current environment leading to altered or
aberrant behavior for that context.
One potential example of an altered environmental experience is the prolongation of

adolescence with the postponement of adulthood (Cline, 1941). Prolonged adolescence may
be lengthened further by earlier pubertal onset as suggested by recent studies showing a
declining age of secondary sex characteristics (e.g., breast development among girls) in the
United States (Biro et al., 2010) and in Copenhagen (Aksglaede et al., 2009). The resulting
prolongation of adolescence may result in a mismatch in the expected environment - based
on a long evolutionary history - and the actual one, that must be considered in understanding
how these neural systems develop and how behaviors emerge and are maintained.
Figure 1 depicts how prolongation of adolescence may result in increases in the duration and
the degree (magnitude) of an imbalance between hormonally sensitive limbic processes
relative to more age-dependent (experience) driven cognitive processes across development
during the transition from dependence to independence (Casey et al., 2008a) (Casey et al., in
press). We (Casey et al., 2008a;Casey et al., in press) and others ((Ernst et al., 2006;Ernst et
al., 2009;Geier and Luna, 2009;Steinberg, 2008) have suggested that adolescence is a period
of functional activation of basic motivational and emotional systems at a time when
prefrontal cortical systems involved rational decisions and actions are not fully mature. We
provide empirical evidence for this model, framing the review in the context of key
questions asked by ethologists to understand animal behavior (Tinbergen, 1974): 1) what
may cause or control adolescent behavior; 2) how does the behavior change across
development; and 3) how may the behavior be adaptive?
What causes or controls adolescent behavior?

Parents often attribute their adolescent’s mood swings and provocative behavior to surging
hormones. However, animal and human studies suggest that both puberty and age influence
changes in explorative and emotive behaviors in adolescents. To address causal influences
on behavior during adolescence, we begin by defining adolescence. Adolescence is the
transition between pubertal onset and parental independence where puberty refers to changes
in reproductive maturation (Graber and Brooks-Gunn, 1996) and adolescence refers to the
transition from dependence on parents to relative independence. The latter involves
emotional, psychological, social, mental and physical changes and growth (Schulz et al.,
2009; Spear, 2010). Pubertal onset occurs with the release of gonadal hormones –
testosterone released from the testes in males and estrogen and progesterone released by the
ovaries and uterus of females. These gonadal hormones contribute to the development of
secondary sexual characteristics influencing the physical body appearance and function that
the adolescent must adjust to, in addition to influencing neural function via binding to
testosterone and estrogen receptors in brain. The hormonal and brain changes coincide with
increased sexual activity and interest (Sisk and Zehr, 2005), and changes in arousal and the

Casey et al. Page 3
salience of motivational stimuli (Friemel et al., 2010). In contrast, chronological age

(experience) has been postulated to be associated with cognitive maturation and control
(Spear, 2010; Steinberg, 2005). Thus pubertal onset and chronological age appear to be two
causal forces shaping adolescent development.
Disentangling age and pubertal effects is more challenging, however (Blakemore et al.,
2010). Many factors influence pubertal onset including both genetic and environmental ones
(Chumlea et al., 2003; Herman-Giddens et al., 1997; Kaplowitz et al., 2001; Lee et al., 2001;
Tanner, 1989). Specifically, pubertal onset has been suggested to be accelerated in obese
individuals (Karlberg, 2002) but delayed in the malnourished (Argente, 1999), anorexic
(Munoz and Argente, 2002) or those engaged in activities where low body fat is reinforced
(e.g., ballet, wrestling) (Roemmich et al., 2001). Importantly, early puberty has been
associated with poor outcomes in both sexes. These outcomes include earlier use of alcohol
and illegal substances, earlier sexual behavior, higher risk for mental health problems and
increased risk for delinquency (Bratberg et al., 2007; Deardorff et al., 2005; Waylen and
Wolke, 2004)(Graber et al., 1997; Kaltiala-Heino et al., 2003).
Recent animal and human imaging studies support separate and interactive roles of puberty
and age in controlling behavior and altering brain development. Sisk and colleagues showed
that the presence or absence of testosterone during adolescence in male hamsters could
program adult sexual behavior (Schulz et al., 2009), but preadolescent exposure did not.
However, preadolescent testosterone exposure impacted brain development by altering

limbic circuitry (e.g., increases amygdala volume), important in social development (Schulz
et al., 2009; Sisk et al., 2003). Human imaging studies of individuals with endocrine
disruptions provide converging evidence for hormonal influences differing as a function of
age of exposure. In an imaging study of adolescents with congenital adrenal hyperplasia
which is associated with elevated testosterone in utero, Ernst and colleagues (2005) showed
enhanced amygdala activity to cues of empty threat (fearful faces) relative to controls that
was specific to females and similar to male controls. Using a similar behavioral probe in
adolescent males with familial hyper-androgenism that causes elevated testosterone
postnatally, Mueller and colleagues (Mueller et al., 2009) showed elevated limbic activity
and faster behavioral responses to fearful faces relative controls. Together, these animal and
human findings provide evidence of hormonal influences on brain systems that may play a
role in processing affective and social stimuli varying as a function of age.
Disentangling age and pubertal driven changes is difficult in typically developing organisms
given the strong associations between the two and the wide variability in timing of puberty
(Spear, 2010). Nonetheless, recent human behavioral and imaging studies have attempted to
disentangle these by examining adolescents of the same age but in different stages of sexual
maturation (Forbes et al., in press; Forbes et al., 2010) or by examining the effects of sexual
maturation using a wider age range but then statistically controlling for age (Silk et al.,
2009). Sexual maturation is typically assessed by physical exam or Tanner staging by the
individual or parent, but more and more hormonal measures are being assessed, which
present challenges given the large fluctuations in early stages of puberty and during the
menstrual cycle, yet, move the field forward beyond the use of age as a proxy for pubertal
maturation.
To date, these studies suggest that mid- to late puberty is positively associated with elevated
physiological reactivity to emotional cues (Silk et al., 2009) and that testosterone level is
positively associated with anticipation of reward in males (Forbes et al., 2010). These
findings suggest an important role of pubertal hormones in social and emotional processes
during adolescence. How these processes change as the individual transitions into and out of
adolescence is less clear from studies that limit the age range of the sample or statistically

Casey et al. Page 4
control for age effects, especially when these samples are younger than the age at which
inflections in risky behavior have been shown to peak (13 to 17 years, see (Steinberg et al.,
2009). To address this question, we review recent behavioral, imaging and animal studies of
this transitional period, highlighting changes specific to adolescents relative to children and
adults.
How does Behavior Change during Adolescence?

Changes in explorative and emotive behaviors have been observed across species as the
organism moves from parental dependence to independence during the transition into and
out of adolescence. These behavioral findings are reviewed and then discussed in the context
of changes in the underlying neurobiology with age.
Human Behavioral Studies

A corner stone of behavioral development is the ability to resist temptation in favor of long-
term goals. Lapses in this ability have been suggested to lie at the very core of adolescent
behavior (Steinberg et al., 2009). Resistance from temptation or delay of immediate
gratification has been studied in the context of social, developmental and cognitive
psychology. In preschoolers, this ability has been measured by assessing how long they can
resist an immediate reward (e.g., a marshmallow) in favor of a larger reward later (e.g., two
marshmallows) (Mischel et al., 1989). Although individuals vary in this ability even as
adults, developmental studies suggest periods when an individual may be particularly

susceptible to temptations, such as adolescence (e.g., (Eigsti et al., 2006).
There is a wealth of behavioral evidence from experimental paradigms in controlled

laboratory settings that show a steady improvement in the ability to suppress an
inappropriate response in favor of an appropriate one from infancy to adulthood, termed
cognitive control (Casey, 2005; Casey et al., 2005; Davidson et al., 2006). However, when it
is advantageous to suppress a response to incentive-related cues, cognitive control suffers
(Somerville et al., In review). This reduced control is especially evident during the period of
adolescence, when suboptimal choices in sexual and drug related behaviors have been
suggested to peak (Casey et al., 2008b; Eaton et al., 2008; Spear, 2000; Windle et al., 2008).
These observations imply that developmental trajectories in cognitive control can be
modulated by emotionally charged or reinforcing contexts (e.g., social and sexual
interactions), in which cognitive control demands interact with motivational drives.
Moreover, these data suggest the importance of distinguishing between cognitive and
motivational processes in understanding how they may interact across development.
Motivation has been shown to modulate cognitive control in at least two ways. First, being
rewarded for performance on a given task can improve performance more than when not
rewarded (Geier et al., 2010). Second, the capacity to exert control can be challenged when
required to suppress thoughts and actions toward appetitive cues (Somerville et al., In
review). Recent studies of adolescent development have begun to compare cognitive control
capacity in relatively neutral versus motivational contexts. These studies suggest a change in
sensitivity to environmental cues, especially reward-based ones at different points in
development, and suggest a unique influence of motivation on cognition during the
adolescent years (Casey and Jones, In press; Somerville and Casey, 2010).
Ernst and colleagues (Hardin et al., 2009; Jazbec et al., 2006) first showed that adolescent
behavior is differentially biased in motivationally charged contexts relative to adults. Using
an anti-saccade task with a promise of financial reward for accurate performance on some
trials but not others, they showed that promise of a reward facilitated adolescent
performance more than adults. Recently, this finding has been replicated (Geier et al., 2010).

Casey et al. Page 5
In contrast to enhancing performance, rewards can diminish performance when suppressing

responses to stimuli that lead to high gain. For example, using a gambling task in which
reward feedback was provided immediately during decision-making (“hot” trials which
heightened task-elicited arousal) or withheld until after the decision (“cold” deliberate
decision making trials), Figner and colleagues (Figner et al., 2009) showed that adolescents
made disproportionately more risky gambles compared to adults but only in the “hot”
condition. Using a similar gambling task, Cauffman and colleagues (Cauffman et al., 2010)
have shown that this sensitivity to rewards and incentives actually peaks during adolescence,
as demonstrated by a steady increase from late childhood to adolescence in tendency to play
with more advantageous decks of cards, followed by a subsequent decline from late
adolescence to adulthood. These findings illustrate a curvilinear function, peaking roughly
between 13 and 17, and subsequently declining (Steinberg et al., 2009).
More real word experiments have begun to examine how peers, as possible secondary
reinforcers, influence adolescent behavior more than adult behavior. Using a simulated
driving task, Gardner and Steinberg (Gardner and Steinberg, 2005) showed that adolescents
make riskier decisions in the presence of peers than when alone. The number of risky
decisions decrease by young adulthood (Chassin et al., 2004; Steinberg, 2008). Taken
together, these studies suggest that during adolescence, motivational cues of potential
reward are particularly salient and can lead to improved performance when provided as a
reinforcer or rewarded outcome, but to riskier choices or suboptimal choices when provided
as a cue. In the latter case, the motivational cue can diminish effective goal-oriented
behavior.
Finally, there is evidence to suggest that motivational processes related to sensitivity to

rewards and sensation-seeking behavior are distinct from impulsivity with very different
developmental patterns (curvilinear versus a linear function, respectively). This distinction is
further supported in a recent study by Steinberg et al. (Cauffman et al., 2010) using self-
report measures of sensation-seeking and impulsivity. They showed that the often-conflated
constructs of sensation-seeking and impulsivity developed along different timetables in over
900 individuals between the ages of 10 and 30. Specifically, differences in sensation-seeking
across age followed a curvilinear pattern, with a peak between 10 and 15 years, and
declining or remaining stable thereafter. In contrast, impulsivity followed a linear pattern,
decreasing with age. These findings suggest that heightened vulnerability to risk-taking in
adolescence may be due to a complex interaction of sensation seeking in the context of
relatively immature behavioral control abilities typical of this period of development
(Cauffman et al., 2010).
Human Imaging Studies

Over the past decade, developmental scientists have begun to use neuroimaging to
understand inflections in behavior during the developmental window of adolescence relative
to those preceding or following it (Galvan et al., 2007; Hare et al., 2008; Somerville and
Casey, 2010). Depicting how the brain changes during adolescence relative to both
childhood and adulthood is needed to explain the previously described inflections in
behavior. More over, this approach provides the opportunity to link neural processes with
cognitive and motivational ones. For example, neural correlates of cognitive control would
presumably develop linearly from childhood to adulthood, whereas neural correlates of
incentive and emotive processes related to desire, fight and flight may have a different
developmental pattern.
One of the first studies to examine incentive-related processes across the full spectrum of
development from childhood to adulthood was completed by Galvan and colleagues (Galvan
et al., 2006) in 7 to 29 year olds. Specifically, she focused on dopamine rich circuitry and

Casey et al. Page 6
manipulated the magnitude of reward outcome borrowing heavily from nonhuman primate
studies showing dopaminergic neuronal firing to rewards. Animal work has shown that
behavior can be altered by anticipated reward outcome (Pavlov, 1927), and
electrophysiological studies show that striatal neurons play an important role in rewarded
behavior, given their sensitivity to changes in reward magnitude and frequency (Cromwell
and Schultz, 2003; Fiorillo et al., 2003). Galvan thus examined whether dopamine related
neural circuitry showed differing responses to reward manipulation as a function of age. She
found that the ventral striatum, a dopamine rich area shown previously in adult imaging to
be associated with addiction and reward (Delgado et al., 2000; Elliott et al., 2000; Volkow et
al., 1997), was sensitive to varying magnitudes of monetary reward (Galvan et al., 2005).
Moreover, this response was exaggerated in adolescents, relative to both children and adults,
indicative of increased signal (Galvan et al., 2006) or more sustained activation (Delgado et
al., 2000). In contrast to the pattern in the ventral striatum, orbital prefrontal regions related
to optimizing gains in goal-oriented behavior, showed protracted development across these
ages in a more linear fashion.
How does this enhancement of signaling in the ventral striatum in adolescents relate to real
world behavior? In a follow-up study, Galvan and colleagues (Galvan et al., 2007) examined
the association between activity in the ventral striatum to large monetary reward and
anonymous self report ratings of risk-taking (Fromme et al., 1997; Katz et al., 2000) and
impulsivity (Conners et al., 1999) from a sample of 7 to 29 year olds. There was a positive
association between ventral striatal activity to monetary reward and the likelihood of
engaging in risky behavior, but no association between activity in this region and
impulsivity measures. These findings further support the dissociation of impulsivity and
exploratory processes of sensation-seeking and risk taking described earlier (Sternberg et al
2009).
Although several laboratories (Ernst et al., 2005; Galvan et al., 2006; Geier et al., 2010; Van
Leijenhorst et al., 2010a) have shown exaggerated ventral striatal responses to cues
signaling reward outcome in adolescents, at least one laboratory has shown diminished
activity of this region in adolescents in similar reward paradigms (Bjork et al., 2008; Bjork
et al., 2010). This diminished response has been suggested to be similar to reward-
deficiency syndrome, a condition often linked with addiction in adults. Since dopamine
helps to link actions to sensations of pleasure, its redistribution during development may
raise the threshold for stimulation (see Comparitive Studies). Accordingly, activities that
once caused excitement can cease to provide such thrills. However, understanding a change
in activities by adolescents may be informed by both considering the influence of the
developmental context and the role of dopamine in learning. For example, dopamine is
essential in learning to optimize gains and in detecting novelty or violations in the expected
environment as shown by Schultz (Cromwell and Schultz, 2003; Fiorillo et al., 2003).
Second, while behavior is largely shaped by parents in early childhood, peers may motivate
behavior more in adolescence (e.g. (Gardner and Steinberg, 2005). Accordingly, one can
imagine alternative explanations for why activities that once caused excitement can cease to
provide such thrills. For example, if previously approved or reinforced activities by parents
or teachers, are not reinforced by peers then these behaviors may be extinguished. New
activities shared with peers or which gain peer approval or reinforcement may then be the
new activities that the adolescent will seek. This later interpretation of adolescent behavior
based on learning theory would not be consistent with a reward or dopamine deficient
hypothesis of adolescence.
Further support of the role for an elevation in dopamine rich circuitry being related to risky
behavior and sensitivity to reward, comes form Van Leijenhorst and colleagues (Van
Leijenhorst et al., 2010a) in adolescents showing upregulation of this circuitry with high risk

Casey et al. Page 7
relative to low risk choices when gambling. In adults, Christopoulos and colleagues
(Christopoulos et al., 2009) have shown that a risky choice is more probable when striatal
activity is higher, whereas increased prefrontal activity correlates with increased probability
of a safe choice and with higher risk aversion. Thus elevated ventral striatal activity would
seem more consistent with the observed increase in risky behavior during this age (Figner et
al., 2009). Moreover, diminished activity of dopaminergic rich circuitry has been associated
with clinical populations characterized by impulsivity problems like ADHD (Durston et al.,
2003; Epstein et al., 2007; Vaidya et al., 1998) who do not show heightened ventral striatal
responses to incentives (Scheres et al., 2007).
A scientific area that has received less attention is determining how cognitive control and
motivational systems interact over the course of development. As mentioned earlier, Ernst
and colleagues (Hardin et al., 2009; Jazbec et al., 2006) showed that promise of a monetary
reward facilitated adolescent cognitive control behavior more than for adults. Geier et al.
(Geier et al., 2010) recently identified the neural substrates of this cognitive up regulation
using a variant of an anti-saccade task during functional brain imaging. In adolescents and
adults, trials for which money was at stake speeded performance and facilitated accuracy,
but this effect was larger in adolescents. Following a cue that the next trial would be
rewarded, adolescents showed exaggerated activation in the ventral striatum and
supplementary frontal eye fields, while preparing for and subsequently executing the anti-
saccade, suggesting a reward-related up-regulation in control of goal directed eye
movements.
Rewards can enhance or diminish goal-directed behavior. The capacity to exert control over
one’s actions is especially challenged when required to suppress an action toward positive or
appetitive cues. The observation that adolescents take more risks when appetitive cues are
present versus absent during gambling tasks makes this point (e.g., (Figner et al., 2009).
Recently, Somerville (2010) provided empirical evidence for a specific reduction of impulse
control in adolescents when faced with cues signaling appetitive value. Using a task that
contained social appetitive cues (e.g., happy faces) that facilitated approach responses, she
showed the developmental trajectory of subjects’ ability to flexibly approach or avoid
positive or neutral stimuli. Specifically, adolescents showed a unique pattern of errors
relative to both children and adults, characterized by a reduction in the capacity to suppress
an approach response toward a positive, appetitive social cue (see Figure 2).
The decrement in performance during adolescence was paralleled by enhanced activity in

the ventral striatum. Conversely, activation in the inferior frontal gyrus was associated with
overall accuracy and showed a linear pattern of change with age for the no-go versus go
trials (see Figure 3).
Recent studies have begun to provide support for strengthening in the connections of
dopamine rich frontostriatal circuitry, across development. Using diffusion tensor imaging
and functional magnetic resonance (fMRI), Casey and colleagues (Casey et al., 2007; Liston
et al., 2006) and others (Asato et al., 2010) have shown greater strength in distal connections
within these circuits across development and have linked connection strength between
prefrontal and striatal regions with the capacity to effectively engage cognitive control, in
typically and atypically developing individuals (Casey et al., 2007; Liston et al., 2006).
These studies illustrate the importance of signaling within corticostriatal circuitry, which
support the capacity to effectively engage in cognitive control and underscore the
importance of specific brain circuitry over individual regions.
Collectively, the developmental imaging literature suggests that the prefrontal cortex,
thought to support cognitive control (Astle and Scerif, 2009; Bitan et al., 2006; Bunge et al.,

Casey et al. Page 8
2002; Luna et al., 2010; Luna et al., 2001; Stevens et al., 2009; Tamm et al., 2002)
undergoes protracted maturation (Giedd et al., 1999; Huttenlocher, 1990; Sowell et al.,
2003) (Shaw et al., 2008) while striatal regions sensitive to novelty and reward
manipulations may develop earlier (Casey et al., 2002; Luna et al., 2001) or be more
functionally active with the onset of puberty. As noted, although several groups have shown
heightened activation of the ventral striatum in adolescents in anticipation and/or receipt of
rewards compared to adults (Ernst et al., 2005; Galvan et al., 2006; Geier et al., 2010; Van
Leijenhorst et al., 2010a) others have shown suppressed activity (Bjork et al., 2004; Bjork et
al., 2010). To understand and attempt to constrain interpretations of these imaging findings,
we turn to the recent animal literature on adolescence.
Comparative Studies
Adolescence is not special to humans. Rather, a variety of species must acquire the basic
skills of transitioning from dependence to relative independence from parental care (Spear,
2010). Nonhuman adolescents show age-typical ways of responding to their environment.
These behaviors include increases in peer interactions, novelty seeking and elevations in
consummatory behaviors (Spear 2000) thought to serve a number of adaptive functions
despite the effect risky behaviors may have on adolescent mortality rates (Crockett and
Pope, 1993; Irwin and Millstein, 1986; Spear, 2010). Adaptive functions include increasing
the probability of reproductive success among males across species, improving life
circumstances, enabling procurement of additional resources, as well as exploring adult
liberties and greater ability to face and surmount challenges (Belsky et al., 1991;
Csikszentmihalyi and Larson, 1987; Daly and Wilson, 1987; Meschke and Silbereisen,
1997). Risk-taking also encourages individuals within a species to emigrate away from the
home territory around the time of sexual maturation, thereby reducing inbreeding within the
population and avoiding the lower viability of inbred offspring due to greater expression of
recessive genes (Bixler, 1992; Moore, 1992). Within mammalian species, sexual maturation
marks the time when males emigrate away from the home territory (Pereira and Altmann,
1985; Schlegel and Barry III, 1991). So what are the neuroanatomical correlates of this
behavior?
Seminal animal work has delineated dopamine rich frontostriatal circuitry in motivated
behavior. For example, using single-unit recordings in monkeys, Pasupathy & Miller
(Pasupathy and Miller, 2005) showed that when flexibly learning a set of reward
contingencies, very early activity in the striatum provides the foundation for reward-based
associations, whereas later, more deliberative prefrontal mechanisms are engaged to
maintain the behavioral outputs that can optimize the greatest gains; these findings have
been replicated in lesion studies (Gill et al., 2010; Hauber and Sommer, 2009). A role for the
striatum in early temporal coding of reward contingencies prior to the onset of activation in
prefrontal regions has been extended to humans (Galvan et al., 2005). These findings
suggest that understanding the interactions between regions within frontostriatal circuitry is
critical for developing a model of cognitive and motivational control in adolescence.
Frontostriatal circuits undergo considerable elaboration during adolescence (Benes et al.,

2000; Brenhouse et al., 2008; Cunningham et al., 2008; Tseng and O’Donnell, 2007) that are
particularly dramatic in the dopamine system. Animal studies suggest that peaks in the
density of dopamine receptors, D1 and D2 in the striatum occur early in adolescence,
followed by a loss of these receptors by young adulthood (Seeman et al., 1987; Tarazi and
Baldessarini, 2000; Teicher et al., 2003). In contrast, the prefrontal cortex does not show
peaks in D1 and D2 receptor density until late adolescence and young adulthood (Andersen
et al., 2000; Weickert et al., 2007). It remains unclear how changes in dopamine systems
may relate to motivated behavior, as controversy remains as to whether it is a result of less
active or hypersensitive dopamine systems (e.g., (Robinson and Berridge, 2003; Volkow and

Casey et al. Page 9
Swanson, 2003). This controversary is consistent with the mixed adolescent imaging
findings of diminished or elevated ventral striatal activity in anticipation of appetitive
outcomes (e.g., (Bjork et al., 2010; Somerville et al., In press). However, given the dramatic
changes in dopamine rich circuitry during adolescence, it is likely to be related to changes in

sensitivity to rewards distinct from pre- and post puberty (Brenhouse et al., 2008; Spear,
2010). Nonetheless, equating the relative appetitive quality of rewards when investigating
reward related behavior across ages and species is an area that requires more investigation.
How is Adolescent Behavior Adaptive?

Because information about gender and social status are essential for reproduction and
survival of a species, it seems plausible that specialized mechanisms have evolved to
process socio-emotional cues when needed (Fernald, 2004; Finlay, 2007; Insel and Fernald,
2004). Changes in behavior during adolescence appear to occur in parallel with the increase
in pubertal hormones, resulting in more exploratory behavior and seeking sexual partners. In
conjunction with a “push” mechanism however, there would need to be a mechanism for
“pulling” back when detecting cues that signal threat or danger. In other words, if the
organism leaves the nest, but is immediately consumed by a predator, it has no more
increased the chances of reproduction and survival than it would have, had it stayed.
Over the past decade, a number of imaging studies have begun to examine the sensitivity of
adolescents to emotional cues and information (Ernst et al., 2005; Guyer et al., 2008a; Guyer
et al., 2009; Guyer et al., 2008b; Monk et al., 2003; Rich et al., 2006; Williams et al., 2006).
One of the most developmentally comprehensive of these studies was completed by Hare
and colleagues (Hare et al., 2008) based on an initial sample of 80 subjects between 7 and 32
years. Hare went beyond simple examination of the limbic activity, that has been shown by
several groups to be higher in adolescents than in adults, in order to: 1) show specific
changes in the brain and in behavior in adolescents relative to both adults and children; 2)
examine not only transient patterns of brain activity, but changes in activity over time with
repeated exposure to empty threat (Hare et al., 2008); and 3) assess whether these changes
related to self report ratings of everyday anxiety.
Hare showed that adolescents have an initial exaggerated amygdala response to cues that
signal threat (fearful faces) relative to children and adults (see Figure 4A and 4B). The
initial heightened response in amygdala activity is age-dependent and specific to adolescents
relative to children and adults. This developmental curvilinear pattern is strikingly similar to
previous findings of elevated accumbens activity to appetitive social and monetary cues
((Ernst et al., 2005; Galvan et al., 2006); (Ernst et al., 2005; Guyer et al., 2008a; Guyer et
al., 2009; Guyer et al., 2008b; Monk et al., 2003; Rich et al., 2006; Williams et al., 2006).
More in depth examination of the MR signal in the amygdala with repeated presentation of
the fearful face (i.e., repeated exposure to empty threat) across experimental trials showed
attenuation over time. The extent to which activation of this region diminished with repeated
trials was correlated with the anonymous self-report ratings of everyday anxiety (Figure 4B
and 4C). The failure of the amygdala response to return to baseline over time was associated
with coupling of the amygdala and ventromedial prefrontal cortex. Specifically, inverse
functional coupling of these regions, consistent with greater top-down regulation of the
amygdala from prefrontal projections, was correlated with greater diminished signal in the
amygdala over time.
These findings suggest that initial emotional reactivity to potential threat, as indexed by
elevated amygdala activity, is typical of, or normal for adolescence, but that failure of this
response to subside over time with no impending threat is atypical or maladaptive and may
be indicative of risk for anxiety. Consistent with this suggestion is clinical imaging data

Casey et al. Page 10
showing elevated amygdala activity to fearful faces using similar paradigms with children
and adolescents diagnosed with anxiety and depression (e.g., Thomas et al 2001). Future
studies of populations at risk for anxiety will need to examine carefully not only what
triggers a heightened threat response in the amygdala, but also the brain processes that
support anxiety responses that are sustained over time (Somerville et al., 2010).
The observation of imbalanced activity in the amygdala-ventromedial prefrontal network as

shown by elevated amygdala and less prefrontal activity in anxious individuals, is consistent
with a variety of work in animals (Baxter et al., 2000; Milad and Quirk, 2002), humans
(Delgado et al., 2006; Etkin et al., 2006; Haas et al., 2007; Johnstone et al., 2007; Urry et al.,
2006), and in childhood and adolescent mood and anxiety disorders (Guyer et al., 2008a;
Monk et al., 2008), implicating an inverse association between these structures that governs
affective output. In particular, increased ventromedial prefrontal activity is inversely
correlated with responding in the amygdala, and predicts behavioral outcomes such as fear
extinction, down-regulation of autonomic responses (Phelps et al., 2004), and more positive
interpretations of emotionally ambiguous information (Kim et al., 2004).
Recent translational studies using genetically altered mice and human genetic imaging
suggest one pathway to the uncoupling within this circuitry (Soliman et al., 2010) and
resulting variability across individuals. During adolescence, when the amygdala response is
heightened relative to that observed in children and adults (imbalance), more top down
control is needed. Environmental or genetic factors that result in less coupling between these
regions with development, to help provide that down-regulation, may lead to heightened
emotion, and ultimately, risk for anxiety related disorders.
Our model depicted in Figure 1 shows an imbalance between hormonally driven limbic and
more age-dependent cognitive systems during adolescence. We suggest that this imbalance
may be lengthened due to the mismatch between the expected experiences of mating with
sexual maturation and the delay in this behavior with the prolongation of adolescence (refer
back to Figure 1). Consistent with this view, is how the brain differs in sensitivity to
testosterone levels across development. Earlier onset of testosterone secretion engendered
either experimentally in animals or by altered dietary or behavioral patterns in humans
results in experience-dependent alterations in social and sexual development of the
adolescent (Schulz et al 2009). The degree of this imbalance between hormone-sensitive
brain regions and cortical ones would be lengthened and accentuated for individuals with
earlier pubertal onset when the cognitive systems are less fully developed, resulting in less
adaptive behavior for the current environment and greater risk for mental health problems
(Graber et al., 1997;Kaltiala-Heino et al., 2003)
Conclusions
Negotiating the transition from dependence on parents to relative independence is not a
unique demand for today’s youth, but has a long evolutionary history and is shared across
mammalian species. This period of transition has been prolonged in western civilization for
humans with the increasingly occurring postponement of parental independence in many
individuals. In this review, we highlighted recent neurobiological studies of adolescence to
address the questions of potential mechanisms of behavioral change, how changes from
childhood to adolescence to adulthood, and how is it adaptive from a comparative and
evolutionary framework. To theoretically ground the empirical findings, we provided a
plausible neurobiological model for understanding adolescence. The intention is to move
away from psychopathologizing adolescence in order to explain why some teens - but not
others - are more vulnerable to poor outcomes and why there is a 200% increase in mortality
during this developmental period. As such, we identified potential markers of risk for mental

health problems that go beyond, adaptive and typical exploratory and emotive behaviors of
adolescence.
The model builds on animal work (Laviola et al., 1999; Spear, 2000) and human behavioral
(e.g., (Figner et al., 2009; Gardner and Steinberg, 2005)) and imaging studies of adolescents
(Ernst et al., 2005; Galvan et al., 2007; Galvan et al., 2006; Geier et al., 2010; Hare et al.,
2008; Van Leijenhorst et al., 2010a; Van Leijenhorst et al., 2010b) to illustrate how
hormonally-sensitive subcortical limbic regions and age-dependent prefrontal cortical
regions must be considered together in understanding adolescent behavior. The cartoon is
consistent with different developmental trajectories for signaling in these regions, with
limbic projections developing earlier than prefrontal control regions. Accordingly, the
adolescent is biased by elevated subcortical limbic responses to motivational and emotional
cues relative to less mature cortical recruitment (i.e., imbalance theory), compared to
children, for whom this frontolimbic circuitry is still developing; and compared to adults, for
whom these systems are fully mature. With development and experience, the functional
connectivity between these regions is strengthened and provides a mechanism for top down
modulation of the subcortical systems (Hare et al., 2008). Thus it is the limbic
corticosubcortical circuitry, along with functional strengthening of connections within this
circuitry that develop with experience, that may provide a mechanism to explain changes in
both impulsivity and risk-taking observed across development. Atypical early experiences
can lead to failure in the typical development of functional circuitry resulting in a
heightened imbalance.
This view of adolescence is consistent with previous ones (Ernst et al., 2006; Ernst et al.,
2009; Geier and Luna, 2009; Steinberg, 2008) in that it provides a basis for nonlinear
inflections observed in behavior from childhood to adulthood, due to earlier maturation of
subcortical projections relative to less mature top down prefrontal ones. Specifically, the
triadic model (Ernst et al., 2006) proposes that motivated behavior has three distinct neural
circuits (approach, avoidance and regulatory). The approach system is largely controlled by
the ventral striatum, avoidance system by the amygdala and lastly, the regulatory system by
the prefrontal cortex (Hare et al., 2005). The current model differs from others in that it is
grounded in empirical evidence for brain changes not only in the transition from adolescence
to adulthood, but rather the transition into adolescence from childhood and later out of
adolescence into adulthood. Moreover, the model does not suggest that the ventral striatum
and amygdala are specific to approach and avoidant behavior given recent studies showing
valence independence of these structures (Levita et al., 2009), but rather are systems that are
important in detecting and learning about appetitive and emotive information in the
environment for the development of adaptive behavior.
In sum, we suggest that adolescence, as a transitional period from parental dependence to

adult independence, requires explorative and emotive mechanisms. These mechanisms have
evolved over generations, for successfully adapting to new information and environments.
From this perspective, aberrant behavior is the result of a change in an evolutionally stable
environment (experience-expectant) (Greenough et al., 1987). When there is a violation
between the expected and actual environment during development, mechanisms that have
evolved to survive in that environment will be altered. The result is a disruption of a
structured collaboration between the information in the organism and the environment
(Finlay, 2007) leaving the organism less prepared and functionally adaptive. Accordingly,
“development can no longer be viewed as a simple passage from the embryo to the mature
organism directed by the information encoded in the genes, but rather a structured
collaboration between the information in the organism and the environment” that occurs
throughout development (Finlay, 2007, p.34) and evolution.

Acknowledgments
This work was supported in part by NIDA R01 DA018879, NIMH P50 MH62196, NSF 06-509, and NSF 0720932
to BJC, the Mortimer D. Sackler family, the Dewitt- Wallace fund, and by the Weill Cornell Medical College
Citigroup Biomedical sImaging Center and Imaging Core.
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Figure 1. Model of adolescent development

Prolongation of adolescence may result in increases in the duration and the degree
(magnitude) of an imbalance between hormonally driven limbic processes relative to age-
dependent (experience) driven cortical processes, In the cartoon above, cortical control is
represented in blue, subcortical reactivity in pink, and red represents a further shift with
earlier pubertal onset. Increasing the duration and degree of this imbalance may lead to
greater difficulty as the individual moves from dependence on parents to relative

independence.

Figure 2. Behavioral performance to appetitive relative to non appetitive social cues across
development
Gray line represents missing a target go trial (misses); black line represents making a
commission error (false alarm) by inappropriately responding to a nontarget when instructed
to withhold a response. Behavioral performance is biased towards appetitive social cues
(happy faces) relative to nonappetitive social cues (calm faces) during adolescence relative
childhood or adulthood. Adapted from Somerville et al. (2010), Journal of Cognitive
Neuroscience.

Figure 3. Development of ventral frontostriatal function

A) Ventral striatal region showing differential activity as a function of age. B) Plot of
ventral striatal activity to appetitive cues as a function of age. C) Differential activity in the
inferior frontal gyrus as a function of task (nogo > go). D) Plot of inferior frontal gyrus
activity to nogo relative to go trials as a function of age. Recruitment decreases linearly with
age. From Somerville et al. (2010), Journal of Cognitive Neuroscience.

Figure 4. Developmental and individual differences in amygdala responses to empty threat

A) Greater engagement of the amygdala to empty threat (fearful faces) in adolescents
relative to children or adults. B) Localization of amygdala activation on a coronal image. C.
Association of habituation of amygdala response with repeated exposure to empty threat and
everyday ratings of anxiety. Adapted from Hare et al. (2008), Biological Psychiatry.

Adolescence What Do Transmission, Transition, and Translation Have To Do With It

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Neuron. 2010 September 9; 67(5): 749–760. doi:10.1016/j.neuron.2010.08.033.

Adolescence: What do Transmission, Transition, and

context of adaptive and maladaptive functions.

© 2010 Elsevier Inc. All rights reserved.

One potential example of an altered environmental experience is the prolongation of

What causes or controls adolescent behavior?

Neuron. Author manuscript; available in PMC 2011 September 9.

salience of motivational stimuli (Friemel et al., 2010). In contrast, chronological age

causal forces shaping adolescent development.

However, preadolescent testosterone exposure impacted brain development by altering

Neuron. Author manuscript; available in PMC 2011 September 9.

How does Behavior Change during Adolescence?

Human Behavioral Studies

adults, developmental studies suggest periods when an individual may be particularly

There is a wealth of behavioral evidence from experimental paradigms in controlled

Neuron. Author manuscript; available in PMC 2011 September 9.

In contrast to enhancing performance, rewards can diminish performance when suppressing

Finally, there is evidence to suggest that motivational processes related to sensitivity to

Human Imaging Studies

Neuron. Author manuscript; available in PMC 2011 September 9.

Neuron. Author manuscript; available in PMC 2011 September 9.

The decrement in performance during adolescence was paralleled by enhanced activity in

Neuron. Author manuscript; available in PMC 2011 September 9.

Frontostriatal circuits undergo considerable elaboration during adolescence (Benes et al.,

Neuron. Author manuscript; available in PMC 2011 September 9.

changes in dopamine rich circuitry during adolescence, it is likely to be related to changes in

How is Adolescent Behavior Adaptive?

Neuron. Author manuscript; available in PMC 2011 September 9.

The observation of imbalanced activity in the amygdala-ventromedial prefrontal network as

Neuron. Author manuscript; available in PMC 2011 September 9.

In sum, we suggest that adolescence, as a transitional period from parental dependence to

Neuron. Author manuscript; available in PMC 2011 September 9.

Belsky J, Steinberg L, Draper P. Childhood experience, interpersonal development, and reproductive

alcoholics. Addiction. 2008; 103:1308–1319. [PubMed: 18851716]

Neuron. Author manuscript; available in PMC 2011 September 9.

in primate striatum. J Neurophysiol. 2003; 89:2823–2838. [PubMed: 12611937]

Neuron. Author manuscript; available in PMC 2011 September 9.

Neuroimage. 2005; 25:1279–1291. [PubMed: 15850746]

Neuron. Author manuscript; available in PMC 2011 September 9.

Neuron. Author manuscript; available in PMC 2011 September 9.

Huttenlocher PR. Morphometric study of human cerebral cortex development. Neuropsychologia.

Annu Rev Neurosci. 2004; 27:697–722. [PubMed: 15217348]

Neuron. Author manuscript; available in PMC 2011 September 9.

Psychopharmacol. 2009; 19:41–50. [PubMed: 19232022]

Neuron. Author manuscript; available in PMC 2011 September 9.

Hypervigilant Threat Monitoring. Biol Psychiatry. 2010

Neuron. Author manuscript; available in PMC 2011 September 9.

Neuron. Author manuscript; available in PMC 2011 September 9.

Figure 1. Model of adolescent development

greater difficulty as the individual moves from dependence on parents to relative

Neuron. Author manuscript; available in PMC 2011 September 9.

Neuron. Author manuscript; available in PMC 2011 September 9.

Figure 3. Development of ventral frontostriatal function

Neuron. Author manuscript; available in PMC 2011 September 9.

Figure 4. Developmental and individual differences in amygdala responses to empty threat

Neuron. Author manuscript; available in PMC 2011 September 9.

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