Chapter 26
Adolescent dopamine development:
connecting experience with vulnerability
or resilience to psychiatric disease
Lauren M. Reynolds1, 2, 3 and Cecilia Flores3
1
McGill University, Integrated Program in Neuroscience, Montreal, QC, Canada; 2Sorbonne Université, CNRS UMR 8246, INSERM U1130,
Neuroscience Paris Seine - Institut de Biologie Paris Seine, Paris, France; 3McGill University, Department of Psychiatry, Douglas Mental Health
University Institute, Montreal, QC, Canada
List of abbreviations
DCC Deleted in colorectal cancer
GWAS Genome-wide association studies
MRI Magnetic resonance imaging
mRNA Messenger RNA
NAc Nucleus accumbens
PFC Prefrontal cortex
PND Postnatal day
SNP Single nucleotide polymorphism
VTA Ventral tegmental area
Mini-dictionary of terms
Adolescence A developmental period marking the transition from a juvenile state to independence/adulthood.
Axon Long neurite extending from the soma of one neuron to its signaling partner.
Dopamine A chemical neurotransmitter with a modulatory effect over postsynaptic neurons.
Guidance cue Secreted or cell-bound molecules that exist in the extracellular environment. Axons navigate to their destination by interpreting
the guidance cues in their environment, a process that depends on the guidance cue receptors each axon expresses.
Mesocortical dopamine projection Dopaminergic neurons with cell bodies in the ventral tegmental area and axons that project to the prefrontal
cortex.
Mesolimbic dopamine projection Dopaminergic neurons with cell bodies in the ventral tegmental area and axons that project to limbic regions,
including the nucleus accumbens.
microRNA A small noncoding RNA molecule that represses the expression of specific target genes.
Psychostimulant drugs A class of drugs that produce a temporary increase in motor activity, mental processing, attention, and/or euphoria.
Psychostimulant drugs are used medically or recreationally, and the effects of this class of drugs generally depend on the dose taken.
Adolescence is a critical period for prefrontal cortex development
Psychiatric diseases are more likely to emerge during adolescence than during any other period of life (Fig. 26.1;
Kessler et al., 2007; Lee et al., 2014; Paus, Keshavan, & Giedd, 2008). A common denominator of disorders that have
an adolescent onset, particularly drug addiction, depression, and schizophrenia, are deficits in the function of the
prefrontal cortex (PFC) and cognitive impairments (Goldstein & Volkow, 2011; Rice et al., 2019; Tan, Callicott, &
Weinberger, 2009). The PFC and cognitive behaviors continue to mature across adolescence (Liston et al., 2006;
Diagnosis, Management and Modeling of Neurodevelopmental Disorders. https://doi.org/10.1016/B978-0-12-817988-8.00026-9
Copyright © 2021 Elsevier Inc. All rights reserved.
295
296 PART | II Impairments and diseases
Adolescent PFC development
Synaptogenesis
Synapse pruning
Myelination
Psychiatric disease onset
Addiction
Depression
Schizophrenia
Age (years) 0
5
10
15
20
25+
FIGURE 26.1 Psychiatric disease onset coincides with adolescent prefrontal cortex development. During adolescence, the prefrontal cortex undergoes a dynamic period of development including synaptogenesis, synaptic pruning, and myelination. This critical developmental period coincides with
the onset of psychiatric disorders marked by prefrontal cortex dysfunction, including addiction, depression, and schizophrenia (Kessler et al., 2007; Lee
et al., 2014; Paus et al., 2008).
Somerville, Hare, & Casey, 2011), and variations in their developmental trajectories likely contribute to individual
differences in vulnerability to psychopathology. Environmental factors, such as drug use, are known to increase the
risk of later psychiatric disease and may do so by interfering with PFC development (Andréasson, Engström,
Allebeck, & Rydberg, 1987; Anthony & Petronis, 1995; Brook, Brook, Zhang, Cohen, & Whiteman, 2002; French
et al., 2015; Hallfors, Waller, Bauer, Ford, & Halpern, 2005; Weiser, Knobler, Noy, & Kaplan, 2002).
The PFC is among the final brain regions to fully develop (Fig. 26.1). Longitudinal and cross-sectional magnetic
resonance imaging (MRI) studies have mapped the trajectory of human brain development and found dynamic changes in
the PFC during adolescence. Gray matter thickness in the PFC decreases across adolescence before stabilizing in adulthood, while white matter volume increases (Gogtay et al., 2004; Sowell et al., 2003). Postmortem human brain analysis
further suggests that these macroscale changes likely result from modifications at the cellular level, with dramatic
developmental changes in neuronal architecture, synapse density, and neurotransmitter concentration occurring across the
adolescent period (Catts et al., 2013; Fung et al., 2010; Petanjek et al., 2011). Since the PFC is essential for cognitive
function, including behavioral inhibition and flexibility, motivation, and reward processing, cognitive ability matures in
parallel to PFC structural development (Larsen & Luna, 2018).
Sex differences in brain structure emerge across human adolescence (Ingalhalikar et al., 2014; Lenroot & Giedd, 2010;
Sowell et al., 2007); however, this dimorphism does not translate into pronounced cognitive performance disparities
between adult men and women. Instead, research indicates that men and women engage different cognitive strategies in
order to produce similarly advantageous behavioral outcomes (Grissom & Reyes, 2018; Lenroot & Giedd, 2010). It is
therefore critical to understand adolescent neurodevelopment in both sexes, as exposure to the same risk factors for
psychopathologies targeting PFC function may lead to divergent outcomes.
Developmental rodent models for psychiatric-like traits are valuable for research. However, defining the adolescent
period in rodents can prove challenging, as there are not clear-cut boundaries. While puberty and adolescence necessarily
overlap temporally, the terms are not interchangeable. Puberty is defined by the onset of sexual maturity, while adolescence
is a more diffuse period representing the gradual transition from a juvenile state to independence. Work from our group and
others suggests that adolescence extends from the age of weaning (postnatal day (PND) 21) until adulthood (PND 60) and
can be further subdivided into early, middle, and late periods that represent discrete developmental timepoints (Fig. 26.2;
Adolescence
Developmental period
Age (PND) 0
Early
21
28
Mid
35
42
Late
49
56
Adulthood
60+
FIGURE 26.2 Defining adolescence in rodent models. Adolescence in rodents can be considered to extend from postnatal day (PND) 21 (weaning)
until PND 60 (the start of adulthood) and can be further subdivided into early (PND 21 e 34), mid (PND 35 e 46) and late (PND 47 e 59) adolescent
periods.
Adolescence, dopamine, and mental health Chapter | 26
297
Hoops & Flores, 2017; Reynolds, Pokinko, et al., 2018; Reynolds, Yetnikoff, et al., 2018; Schneider, 2013; Spear, 2000;
Tirelli, Laviola, & Adriani, 2003).
The maturational trajectory of the PFC in rodents is similar to humans, with cortical thickness peaking around 30 days
of age and stabilizing after PND 60 in both rats and mice (Hammelrath et al., 2016; Mengler et al., 2014). These
macroscale changes are also linked to alterations to the structure of PFC neurons, synaptic density, and myelination of
axons (Caballero, Granberg, & Tseng, 2016; Delevich, Thomas, & Wilbrecht, 2019; Juraska & Willing, 2017). Cognitive
and goal-directed behaviors in rodents are likewise refined across adolescence, mirroring what has been observed in
humans (Andrzejewski et al., 2011; Naneix, Marchand, Scala, Pape, & Coutureau, 2012).
Mesocortical dopamine development drives prefrontal cortex maturation
Adult
Dopamine innervation
PFC excitatory neuron maturity
PFC inhibitory neuron maturity
Juvenile
PFC functional maturity
Dopaminergic input to the PFC is a driver of PFC development. In contrast to other neurotransmitter systems innervating
this region, dopamine axons continue to grow from the ventral tegmental area (VTA) to the PFC during adolescence
(Reynolds, Pokinko, et al., 2018), resulting in a progressive increase in innervation between PNDs 21 and 60 (Fig. 26.3;
Hoops & Flores, 2017). During this protracted process, growing dopamine axons undergo substantial modifications in fiber
density, shape, and organization (Hoops & Flores, 2017). Prolonged development of PFC dopamine connectivity extrapolates to primates, including humans (Rosenberg & Lewis, 1995; Rothmond, Weickert, & Webster, 2012; Weickert
et al., 2007).
PFC neurons receiving dopamine input, pyramidal neurons in particular, also undergo a dynamic period of structural
changes during adolescence in both rodents and primates, including humans (Juraska & Willing, 2017; Lambe, Krimer, &
Goldman-Rakic, 2000; Manitt et al., 2011; Petanjek et al., 2011). This structural development is linked to the maturation of
their intrinsic electrophysiological properties (Manitt et al., 2013). The expression and functionality of dopamine receptors
in the PFC change across adolescence in rats (Fig. 26.3; Caballero et al., 2016; Jordan & Andersen, 2017; Naneix,
Marchand, Scala, Pape, & Coutureau, 2012), although this age-dependent expression pattern is less apparent in mice
(Cullity, Madsen, Perry, & Kim, 2018; Pokinko et al., 2017). The changing influence of dopamine over PFC neurons is
proposed to establish the precise balance of excitation and inhibition necessary for information processing (Caballero et al.,
2016). In fact, we have recently confirmed that dopamine development in the PFC drives the establishment of local
networks because alterations to the extent and/or organization of dopamine input to the PFC result in significant reorganization of postsynaptic pyramidal neuron morphology and function, ultimately manifesting as changes in the performance of PFC-dependent cognitive tasks (Reynolds, Pokinko, et al., 2018).
The same developmental pattern of PFC dopamine receptor expression seen in rodents has been observed in humans
(Rothmond, Weickert, & Webster, 2012; Weickert et al., 2007), suggesting that the role of dopamine as a driver of PFC
development is conserved. The maturation of dopamine input to the PFC has indeed been proposed to drive both dendritic
spine pruning from pyramidal neurons across human adolescence (Petanjek et al., 2011) and adolescent cognitive
development (Galvan, 2017; Luciana, Wahlstrom, Porter, & Collins, 2012; Wahlstrom, White, & Luciana, 2010).
While an adolescent increase in PFC dopamine innervation density has been observed in both male and female rodents
(Willing, Cortes, Brodsky, Kim, & Juraska, 2017), the extent of sex differences in this process remains understudied.
Age (PND) 0
21
35
49
60
75
90
FIGURE 26.3 Dopaminergic maturation of the prefrontal cortex in adolescence. In primates and in rodents (highlighted here), dopamine innervation
density increases across adolescence before stabilizing in adulthood (>PND 60). Postsynaptic neurons mature across the same timeline, with mature
responses to dopaminergic modulation emerging over the adolescent period. Together, these maturation changes are thought to calibrate cognitive function
in adolescence (Caballero et al., 2016).
298 PART | II Impairments and diseases
Given that sex hormone receptor expression by dopamine neurons differs significantly between male and female rodents
(Kritzer & Creutz, 2008), whether the adolescent development of PFC dopamine innervation is a puberty-dependent or
puberty-independent process remains a key question (Juraska & Willing, 2017; Walker et al., 2017).
The Netrin-1/DCC guidance cue system is a molecular regulator of PFC dopamine
development
In the search for molecular mechanisms controlling adolescent brain development, the Netrin-1/DCC guidance cue system
has emerged as a critical regulator of the establishment of dopamine input to the PFC in adolescence. Guidance cues are
secreted soluble or cell-bound molecules in the extracellular environment that act as a signal for growing axons. Dopamine
neurons highly and conspicuously express DCC receptors from embryonic life to adulthood across species including
humans (Flores, 2011), whereas its ligand Netrin-1 is expressed in the terminal regions that dopamine axons innervate,
including nucleus accumbens (NAc) and PFC (Manitt et al., 2011). Expression levels of DCC and Netrin-1 are high during
embryonic and early postnatal development and wane across adolescence until reaching a plateau in adulthood (Cuesta
et al., 2018; Manitt et al., 2010). Their function also seems to change from early life to adulthood: once axon growth is
completed, they contribute to synaptic plasticity and maintenance (Glasgow et al., 2018; Horn et al., 2013; Yetnikoff,
Labelle-Dumais, & Flores, 2007).
Netrin-1 signaling through DCC receptors mediates guidance “decisions” that axons make at intermediate choice points
along their pathfinding trajectory or once they reach their target (Deiner et al., 1997; Nelson & Colón-Ramos, 2013).
During adolescence, DCC signaling within dopamine neurons actively segregates between axons that will innervate the
NAc (mesolimbic) and those that will grow to the PFC (mesocortical) (Fig. 26.4; Manitt et al., 2013, 2011; Reynolds,
Pokinko, et al., 2018). Reduced DCC function within dopamine neurons during adolescence induces targeting errors in
mesolimbic dopamine axons, leading to their ectopic growth to the PFC (Reynolds, Pokinko, et al., 2018). Shifting the
balance of DCC-dependent dopamine axon growth to the PFC in adolescence leads to profound changes in the structure
and function of postsynaptic neurons, altered sensitivity to psychostimulant drugs of abuse, and enduring changes to
performance on PFC-dependent cognitive tasks that persist into adulthood (Manitt et al., 2013, 2011; Pokinko, Moquin,
Torres-Berrío, Gratton, & Flores, 2015; Reynolds, Pokinko, et al., 2018). DCC haploinsufficiency also occurs in humans
and results in altered VTA-PFC connectivity and behavioral phenotypes related to addiction (Vosberg et al., 2018).
Prefrontal cortex
Dopamine neuron
DCC receptor
Netrin-1 expression
Ventral tegmental area
Nucleus Accumbens
FIGURE 26.4 Netrin-1/DCC signaling in dopamine neurons determines their targeting in adolescence. Dopamine neurons with high DCCexpressing axons innervate the nucleus accumbens (NAc), a region of low Netrin-1 expression. Dopamine neurons that express little or no DCC in
their axons do not recognize the NAc as their final target and instead continue to grow toward the prefrontal cortex (PFC). DCC receptors actively
segregate axons into the mesocortical (PFC-projecting) and mesolimbic (NAc- projecting) pathways during adolescence.
Adolescence, dopamine, and mental health Chapter | 26
299
Evidence for the involvement of DCC signaling in psychopathologies is rapidly exploding (Vosberg, Leyton, & Flores,
2019). Multiple independent genome-wide association studies (GWAS) have linked polymorphisms in the human DCC
gene to psychopathologies marked by PFC dysfunction and adolescent onset. Single nucleotide polymorphisms (SNPs) in
DCC have been found in patients suffering from major depressive disorder (Vosberg et al., 2019), and both postmortem
and translational studies suggest a causal role for PFC DCC in depression-like behaviors (Manitt et al., 2013; Torres-Berrío
et al., 2017). SNPs in the DCC gene have also been identified in schizophrenia, Parkinson’s disease, and addiction patient
populations (Grant, Fathalli, Rouleau, Joober, & Flores, 2012; Kim et al., 2011; Li et al., 2016; Smeland et al., 2017).
Drugs of abuse alter adolescent dopamine development via DCC signaling
During adolescence organisms are often navigating complex environments alone for the first time, setting the occasion for
a unique period of sensitivity to environmental influence over PFC development (Kolb et al., 2012). Among environmental
factors, drug use in adolescence is common and is known to increase vulnerability to later psychiatric diseases, particularly
those involving PFC impairments such as addiction (Anthony & Petronis, 1995; Grant & Dawson, 2003; Robins &
Przybeck, 1985), schizophrenia (Andréasson et al., 1987; French et al., 2015; Weiser, Knobler, Noy, & Kaplan, 2002), and
depression (Brook et al., 2002; Hallfors et al., 2005). Despite this risk, adolescence remains a period of drug experimentation, and over half of drug use initiates in any given year are under the age of 18 years old (SAMHSA, 2012;
Swendsen et al., 2012).
Because this time of high likelihood to begin taking drugs overlaps with ongoing PFC development, drug use in
adolescence has been suggested to confer later addiction risk by disrupting ongoing cortical and cognitive maturation.
Individuals struggling with addiction in adulthood show deficits in cognitive behaviors and PFC function (Goldstein &
Volkow, 2011), and PFC activation during a cognitive task in adolescence is associated with later substance use level,
particularly when that individual is already a drug user (Mahmood et al., 2013). However, the causal relationship between
cognitive function, adolescent drug use, and later addiction cannot be determined from clinical studies. Preclinical studies
have shed light into this matter, indicating that adolescent exposure to drugs alters the development and function of the
mesocorticolimbic dopamine system and the PFC in particular (Gulley & Juraska, 2013; Jordan & Andersen, 2017).
While many classes of drugs may impact adolescent development, the stimulant drug amphetamine is of particular
translational relevance: it is taken for therapeutic purposes, but also prescription drug misuse by adolescents is an
increasingly common pathway to drug abuse (McCabe, West, Morales, Cranford, & Boyd, 2007). Exposure to amphetamine at recreational-like doses in adolescent rats has been shown to alter PFC dopamine receptor levels, change the
electrophysiological properties of pyramidal neurons, and lead to cognitive impairments (Gulley & Juraska, 2013).
Until recently, the molecular mechanisms by which amphetamine interferes with adolescent PFC development
remained unknown. We have found that repeated exposure to a recreational-like dose of amphetamine downregulates the
expression of DCC only during early adolescence (Cuesta et al., 2019, 2018; Yetnikoff, Almey, Arvanitogiannis, & Flores,
2011; Yetnikoff et al., 2007; Yetnikoff, Pokinko, Arvanitogiannis, & Flores, 2014). We also showed that early adolescence
is a critical period where exposure to amphetamine leads to long-term impairments in cognitive function and dopamine
function in the PFC of mice (Reynolds & Flores, 2019; Reynolds et al., 2015; Reynolds, Yetnikoff, et al., 2018). These
negative long-term effects of exposure to amphetamine in early adolescence are limited to doses corresponding to those
taken recreationally by humans, as exposure to a dose that reaches a therapeutic-like plasma concentration upregulates
DCC protein expression in the VTA (Cuesta et al., 2019). In turn, therapeutic-like exposure in adolescence does not disrupt
PFC dopamine organization and leads to improved cognitive performance in adulthood (Cuesta et al., 2019), in line with
studies in nonhuman primates (Soto et al., 2012). Thus, the type of the experience, positive or negative, can bidirectionally
regulate DCC expression, suggesting that DCC functions as a plasticity gene rather than a vulnerability gene (Barth,
Portella, Dubé, Meaney, & Silveira, 2019; Belsky, Jonassaint, Pluess, antonBrummett, & Williams, 2009).
MicroRNAs: linking experience, DCC expression, and adolescent dopamine
development
Experiences in adolescence can regulate Dcc messenger RNA (mRNA) and protein expression by recruiting the microRNA, miR-218 (Cuesta et al., 2018; Torres-Berrío et al., 2017, 2019). MicroRNAs are potent regulators of mRNA stability
and translation and can link experience to alterations in protein expression, neuronal structure, and function across
development (Hollins & Cairns, 2016). We identified miR-218 as a powerful repressor of DCC expression in mouse and
human adult PFC pyramidal neurons and showed that it mediates stress-induced dysregulation of DCC expression and
300 PART | II Impairments and diseases
Normal Adolescent Development
Dopamine neuron
Amphetamine exposure in adolescence
DCC receptor
miR-218 expression
Low / therapeutic dose
High / recreational dose
FIGURE 26.5 Amphetamine in adolescence regulates DCC expression in dopamine neurons via microRNA miR-218. The microRNA miR-218 is
a posttranscriptional repressor of Dcc and is differentially expressed across the lifetime. Amphetamine in adolescence regulates DCC expression in a miR218-dependent manner as a function of drug dose. Low doses that produce a therapeutic-like plasma amphetamine concentration do not regulate miR-218
expression, but increase DCC protein expression most likely via posttranslational mechanisms. In contrast, high doses that reach a recreational use-like
plasma amphetamine concentration upregulate miR-218 expression and, in turn, decrease DCC mRNA and protein levels. Thus, positive and negative
experiences can bidirectionally regulate DCC expression via miR-218.
depression-like outcomes (Torres-Berrío et al., 2017), acting as a molecular switch of susceptibility and resilience (TorresBerrío et al., 2019).
MiR-218 is expressed in dopamine neurons at levels inversely correlated with DCC expression across the lifetime
(Cuesta et al., 2018), and amphetamine in adolescence recruits miR-218 to decrease DCC levels in dopamine neurons in an
age- and dose-dependent manner (Fig. 26.5; Cuesta et al., 2019). Thus, miR-218/DCC interaction may be a molecular
mechanism by which adolescent experiences program adult brain structure, regulating vulnerability or resilience to psychiatric disease.
Conclusion
Adolescence is a dynamic developmental period defined in part by a changing PFC. The extended maturation of the
PFC is a unique window of plasticity for environmental factors to confer risk for, or protection from, psychiatric
disorders. The gradual unfolding of dopamine connectivity dictates PFC development and is controlled by Netrin-1/
DCC guidance cue signaling. Susceptibility factors, such as abused drugs, regulate Netrin-1/DCC function via
posttranscriptional mechanisms, influencing PFC and cognitive trajectories. Micro-RNA regulation of Dcc expression
in adolescence controls PFC development allowing experience to construct adult networks. Emerging evidence that
both positive and negative interventions regulate DCC levels, albeit in an opposite manner, suggests that DCC is a
plasticity gene rather than a vulnerable gene. This molecular pathway represents an opportunity to develop interventions aimed at reducing the incidence of psychiatric disease by promoting healthy brain development and
cognitive maturation in adolescence.
Applications to other areas of development
Here we reviewed the role of dopamine innervation in organizing the maturation of the prefrontal cortex, identified a key
molecular pathway regulating adolescent dopamine development, and described how environmental factors impact the
molecular, anatomical, and functional development of the adolescent brain conferring either susceptibility or resilience to
psychiatric disease. We focus on the mesocortical dopamine pathway; however, recent evidence also suggests that later
postnatal axon growth may extend to other pathways (Arruda-Carvalho, Wu, Cummings, & Clem, 2017; Yetnikoff,
Reichard et al., 2014).
Adolescence, dopamine, and mental health Chapter | 26
301
Key facts
Key facts of axon growth
l
l
l
l
l
Axons are the projections of neurons that conduct action potentials away from the soma toward downstream signaling
partners.
Axons grow long distances to reach their targets using guidance cues to navigate their path.
Most long-distance axonal growth occurs during embryonic and early postnatal development.
Mesocortical dopamine axons continue to grow long distances across adolescence, undergoing targeting “decisions”
along their path.
Adolescent axon growth is particularly vulnerable to environmental insult.
Summary points
l
l
l
l
l
l
l
l
Adolescence is a period of dynamic physical, hormonal, and behavioral changes.
Psychiatric conditions, including major depression, addiction, and schizophrenia, are most likely to emerge in
adolescence.
The prefrontal cortex continues to develop in adolescence and is dysfunctional in psychiatric disease.
Experience in adolescence shapes prefrontal cortex development.
Dopamine input to the prefrontal cortex drives its maturation.
Guidance cue genes organize the targeting and growth of dopamine pathways, are regulated by experience in adolescence, and are altered in psychiatric disorders.
The mesocortical system in adolescence remains sensitive to both positive and negative environmental influences.
Guidance cues may be a promising site to promote healthy brain development in adolescence.
References
Andréasson, S., Engström, A., Allebeck, P., & Rydberg, U. (1987). Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. The Lancet,
330(8574), 1483e1486.
Andrzejewski, M. E., Schochet, T. L., Feit, E. C., Harris, R., McKee, B. L., & Kelley, A. E. (2011). A comparison of adult and adolescent rat behavior in
operant learning, extinction, and behavioral inhibition paradigms. Behavioral Neuroscience, 125(1), 93e105.
Anthony, J. C., & Petronis, K. R. (1995). Early-onset drug use and risk of later drug problems. Drug and Alcohol Dependence, 40(1), 9e15.
Arruda-Carvalho, M., Wu, W.-C., Cummings, K. A., & Clem, R. L. (2017). Optogenetic examination of prefrontal-amygdala synaptic development.
Journal of Neuroscience, 37(11), 2976e2985.
Barth, B., Portella, A. K., Dubé, L., Meaney, M. J., & Silveira, P. (2019). Early life origins of ageing and longevity (pp. 121e140). https://doi.org/
10.1007/978-3-030-24958-8_7.
Belsky, J., Jonassaint, C., Pluess, M., anton, Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14(8).
mp200944.
Brook, D. W., Brook, J. S., Zhang, C., Cohen, P., & Whiteman, M. (2002). Drug use and the risk of major depressive disorder, alcohol dependence, and
substance use disorders. Archives of General Psychiatry, 59(11), 1039e1044.
Caballero, A., Granberg, R., & Tseng, K. Y. (2016). Mechanisms contributing to prefrontal cortex maturation during adolescence. Neuroscience and
Biobehavioral Reviews, 70.
Catts, V. S., Fung, S. J., Long, L. E., Joshi, D., Vercammen, A., Allen, K. M., … Weickert, C. (2013). Rethinking schizophrenia in the context of normal
neurodevelopment. Frontiers in Cellular Neuroscience, 7, 60.
Cuesta, S., Restrepo-Lozano, J., Popescu, C., He, S., Reynolds, L. M., Israel, S., … Flores, C. (2019). DCC-related developmental effects of abusedversus therapeutic-like amphetamine doses in adolescence. Addiction Biology, e12791.
Cuesta, S., Restrepo-Lozano, J., Silvestrin, S., Nouel, D., Torres-Berrío, A., Reynolds, L. M., … Flores, C. (2018). Non-contingent exposure to
amphetamine in adolescence recruits miR-218 to regulate Dcc expression in the VTA. Neuropsychopharmacology, 43(4), 900e911.
Cullity, E., Madsen, H., Perry, C., & Kim, J. (2018). Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal
brain regions. The Journal of Comparative Neurology, 527(6).
Deiner, M. S., Kennedy, T. E., Fazeli, A., Serafini, T., Tessier-Lavigne, M., & Sretavan, D. W. (1997). Netrin-1 and DCC mediate axon guidance locally
at the optic disc: Loss of function leads to optic nerve hypoplasia. Neuron, 19(3), 575e589.
Delevich, K., Thomas, W. A., & Wilbrecht, L. (2019). Adolescence and “late blooming” synapses of the prefrontal cortex. Cold Spring Harbor Symposia
on Quantitative Biology, 037507.
Flores, C. (2011). Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system. Journal of Psychiatry and Neuroscience:
Journal of Psychiatry and Neuroscience, 36(5), 296e310.
302 PART | II Impairments and diseases
French, L., Gray, C., Leonard, G., Perron, M., Pike, B. G., Richer, L., … Paus, T. (2015). Early cannabis use, polygenic risk score for schizophrenia and
brain maturation in adolescence. JAMA Psychiatry, 72(10), 1002e1011.
Fung, S. J., Webster, M. J., Sivagnanasundaram, S., Duncan, C., Elashoff, M., & Weickert, C. (2010). Expression of interneuron markers in the
dorsolateral prefrontal cortex of the developing human and in schizophrenia. American Journal of Psychiatry, 167(12), 1479e1488.
Galvan, A. (2017). Adolescence, brain maturation and mental health. Nature Neuroscience, 20(4), 503e504.
Glasgow, S. D., Labrecque, S., Beamish, I. V., Aufmkolk, S., Gibon, J., Han, D., … Kennedy, T. E. (2018). Activity-dependent netrin-1 secretion drives
synaptic insertion of GluA1-containing AMPA receptors in the hippocampus. Cell Reports, 25(1), 168 182.e6.
Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, C. A., … Thompson, P. M. (2004). Dynamic mapping of human cortical
development during childhood through early adulthood. Proceedings of the National Academy of Sciences of the United States of America, 101(21),
8174e8179.
Goldstein, R. Z., & Volkow, N. D. (2011). Dysfunction of the prefrontal cortex in addiction: Neuroimaging findings and clinical implications. Nature
Reviews Neuroscience, 12(11), 652e669.
Grant, B., & Dawson, D. (2003). Age of onset of drug use and its association with DSM-IV drug abuse and dependence: Results from the national
longitudinal alcohol epidemiologic survey. Journal of Substance Abuse, 10(2), 163e173.
Grant, A., Fathalli, F., Rouleau, G., Joober, R., & Flores, C. (2012). Association between schizophrenia and genetic variation in DCC: A case-control
study. Schizophrenia Research, 137(1e3), 26e31.
Grissom, N. M., & Reyes, T. M. (2018). Let’s call the whole thing off: Evaluating gender and sex differences in executive function. Neuropsychopharmacology, 44(1), 1.
Gulley, J. M., & Juraska, J. M. (2013). The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior. Neuroscience, 249.
Hallfors, D. D., Waller, M. W., Bauer, D., Ford, C. A., & Halpern, C. T. (2005). Which comes first in adolescencedsex and drugs or depression?
American Journal of Preventive Medicine, 29(3), 163e170.
Hammelrath, L., Skoki
c, S., Khmelinskii, A., Hess, A., van der Knaap, N., Staring, M., … Hoehn, M. (2016). Morphological maturation of the mouse
brain: An in vivo MRI and histology investigation. NeuroImage, 125, 144e152.
Hollins, S. L., & Cairns, M. J. (2016). MicroRNA: Small RNA mediators of the brains genomic response to environmental stress. Progress in Neurobiology, 143, 61e81 (Dev. Biol. 283 2005).
Hoops, D., & Flores, C. (2017). Making dopamine connections in adolescence. Trends in Neurosciences, 40(12).
Horn, K. E., Glasgow, S. D., Gobert, D., Bull, S.-J., Luk, T., Girgis, J., … Kennedy, T. E. (2013). DCC expression by neurons regulates synaptic plasticity
in the adult brain. Cell Reports, 3(1), 173e185.
Ingalhalikar, M., Smith, A., Parker, D., Satterthwaite, T. D., Elliott, M. A., Ruparel, K., … Verma, R. (2014). Sex differences in the structural connectome
of the human brain. Proceedings of the National Academy of Sciences of the United States of America, 111(2), 823e828.
Jordan, C. J., & Andersen, S. L. (2017). Sensitive periods of substance abuse: Early risk for the transition to dependence. Developmental Cognitive
Neuroscience, 25, 29e44.
Juraska, J. M., & Willing, J. (2017). Pubertal onset as a critical transition for neural development and cognition. Brain Research, 1654(Pt B), 87e94.
Kessler, R. C., Amminger, P. G., Aguilar-Gaxiola, S., Alonso, J., Lee, S., & Üstün, B. T. (2007). Age of onset of mental disorders: A review of recent
literature. Current Opinion in Psychiatry, 20(4), 359e364.
Kim, J.-M., Park, S. K., Yang, J., Shin, E.-S., Lee, J.-Y., Yun, J., … Jeon, B. S. (2011). SNPs in axon guidance pathway genes and susceptibility for
Parkinson’s disease in the Korean population. Journal of Human Genetics, 56(2), 125e129.
Kolb, B., Mychasiuk, R., Muhammad, A., Li, Y., Frost, D. O., & Gibb, R. (2012). Experience and the developing prefrontal cortex. Proceedings of the
National Academy of Sciences of the United States of America, 109(Suppl. 2), 17186e17193.
Kritzer, M. F., & Creutz, L. M. (2008). Region and sex differences in constituent dopamine neurons and immunoreactivity for intracellular estrogen and
androgen receptors in mesocortical projections in rats. Journal of Neuroscience, 28(38), 9525e9535.
Lambe, E. K., Krimer, L. S., & Goldman-Rakic, P. S. (2000). Differential postnatal development of catecholamine and serotonin inputs to identified
neurons in prefrontal cortex of Rhesus monkey. Journal of Neuroscience, 20(23), 8780e8787.
Larsen, B., & Luna, B. (2018). Adolescence as a neurobiological critical period for the development of higher-order cognition. Neuroscience and
Biobehavioral Reviews, 94. Behav.Neurosci. 112 1998.
Lee, F. S., Heimer, H., Giedd, J. N., Lein, E. S., Sestan,
N., Weinberger, D. R., & Casey, B. (2014). Mental health. Adolescent mental health–opportunity
and obligation. Science, 346(6209), 547e549.
Lenroot, R. K., & Giedd, J. N. (2010). Sex differences in the adolescent brain. Brain and Cognition, 72(1), 46e55.
Li, Y., Qiao, X., Yin, F., Guo, H., Huang, X., Lai, J., & Wei, S. (2016). A population-based study of four genes associated with heroin addiction in han
Chinese. PLoS One, 11(9), e0163668.
Liston, C., Watts, R., Tottenham, N., Davidson, M. C., Niogi, S., Ulug, A. M., & Casey, B. (2006). Frontostriatal microstructure modulates efficient
recruitment of cognitive control. Cerebral Cortex, 16(4), 553e560.
Luciana, M., Wahlstrom, D., Porter, J. N., & Collins, P. F. (2012). Dopaminergic modulation of incentive motivation in adolescence: Age-related changes
in signaling, individual differences, and implications for the development of self-regulation. Developmental Psychology, 48(3), 844e861.
Mahmood, O., Goldenberg, D., Thayer, R., Migliorini, R., Simmons, A., & Tapert, S. (2013). Adolescents’ fMRI activation to a response inhibition task
predicts future substance use. Addictive Behaviors, 38(1), 1435e1441.
Manitt, C., Eng, C., Pokinko, M., Ryan, R., Torres-Berrío, A., Lopez, J., … Flores, C. (2013). Dcc orchestrates the development of the prefrontal cortex
during adolescence and is altered in psychiatric patients. Translational Psychiatry, 3(12), e338.
Adolescence, dopamine, and mental health Chapter | 26
303
Manitt, C., Labelle-Dumais, C., Eng, C., Grant, A., Mimee, A., Stroh, T., & Flores, C. (2010). Peri-pubertal emergence of UNC-5 homologue expression
by dopamine neurons in rodents. PLoS One, 5(7), e11463.
Manitt, C., Mimee, A., Eng, C., Pokinko, M., Stroh, T., Cooper, H. M., … Flores, C. (2011). The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. Journal of Neuroscience, 31(23), 8381e8394.
McCabe, S. E., West, B. T., Morales, M., Cranford, J. A., & Boyd, C. J. (2007). Does early onset of non-medical use of prescription drugs predict
subsequent prescription drug abuse and dependence? Results from a national study. Addiction, 102(12), 1920e1930.
Mengler, L., Khmelinskii, A., Diedenhofen, M., Po, C., Staring, M., Lelieveldt, B. P., & Hoehn, M. (2014). Brain maturation of the adolescent rat cortex
and striatum: Changes in volume and myelination. NeuroImage, 84, 35e44.
Naneix, F., Marchand, A. R., Scala, G., Pape, J.-R., & Coutureau, E. (2012). Parallel maturation of goal-directed behavior and dopaminergic systems
during adolescence. Journal of Neuroscience, 32(46), 16223e16232.
Nelson, J. C., & Colón-Ramos, D. A. (2013). Serotonergic neurosecretory synapse targeting is controlled by netrin-releasing guidepost neurons in
Caenorhabditis elegans. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33(4), 1366e1376.
Paus, T., Keshavan, M., & Giedd, J. N. (2008). Why do many psychiatric disorders emerge during adolescence? Nature Reviews Neuroscience, 9(12),
947e957.
Petanjek, Z., Judas, M., Simic,
G., Rasin, M., Uylings, H. B., Rakic, P., & Kostovic, I. (2011). Extraordinary neoteny of synaptic spines in the human
prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America, 108(32), 13281e13286.
Pokinko, M., Grant, A., Shahabi, F., Dumont, Y., Manitt, C., & Flores, C. (2017). Dcc haploinsufficiency regulates dopamine receptor expression across
postnatal lifespan. Neuroscience, 346, 182e189.
Pokinko, M., Moquin, L., Torres-Berrío, A., Gratton, A., & Flores, C. (2015). Resilience to amphetamine in mouse models of netrin-1 haploinsufficiency:
Role of mesocortical dopamine. Psychopharmacology, 232(20).
Reynolds, L. M., & Flores, C. (2019). Guidance cues: Linking drug use in adolescence with psychiatric disorders. Neuropsychopharmacology, 44(1),
225e226.
Reynolds, L. M., Makowski, C. S., Yogendran, S. V., Kiessling, S., Cermakian, N., & Flores, C. (2015). Amphetamine in adolescence disrupts the
development of medial prefrontal cortex dopamine connectivity in a Dcc-dependent manner. Neuropsychopharmacology, 40(5), 1101e1112.
Reynolds, L. M., Pokinko, M., Torres-Berrío, A., Cuesta, S., Lambert, L. C., Cid-Pellitero, E., … Flores, C. (2018). DCC receptors drive prefrontal cortex
maturation by determining dopamine axon targeting in adolescence. Biological Psychiatry, 83(2), 181e192.
Reynolds, L. M., Yetnikoff, L., Pokinko, M., Wodzinski, M., Epelbaum, J. G., Lambert, L. C., … Flores, C. (2018). Early adolescence is a critical period
for the maturation of inhibitory behavior. Cerebral Cortex, 11(2), 214.
Rice, F., Riglin, L., Thapar, A. K., Heron, J., Anney, R., O’Donovan, M. C., & Thapar, A. (2019). Characterizing developmental trajectories and the role
of neuropsychiatric genetic risk variants in early-onset depression. JAMA Psychiatry, 76(3), 306e313.
Robins, L. N., & Przybeck, T. R. (1985). Age of onset of drug use as a factor in drug and other disorders. NIDA Research Monograph, 56, 178e192.
Rosenberg, D., & Lewis, D. (1995). Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: A tyrosine hydroxylase immunohistochemical analysis. The Journal of Comparative Neurology, 358(3), 383e400.
Rothmond, D. A., Weickert, C. S., & Webster, M. J. (2012). Developmental changes in human dopamine neurotransmission: Cortical receptors and
terminators. BMC Neuroscience, 13(1), 18.
SAMHSA. (2012). Results from the 2011 national survey on drug use and health: Summary of national findings. NSDUH series H-44, HHS publication
No. (SMA) 12-4713. Rockville, MD: Substance Abuse and Mental Health Services Administration.
Schneider, M. (2013). Adolescence as a vulnerable period to alter rodent behavior. Cell and Tissue Research, 354(1).
Smeland, O. B., Wang, Y., Frei, O., Li, W., Hibar, D. P., Franke, B., … Andreassen, O. A. (2017). Genetic overlap between schizophrenia and volumes of
hippocampus, putamen, and intracranial volume indicates shared molecular genetic mechanisms. Schizophrenia Bulletin, 44(4).
Somerville, L. H., Hare, T., & Casey, B. (2011). Frontostriatal maturation predicts cognitive control failure to appetitive cues in adolescents. Journal of
Cognitive Neuroscience, 23(9), 2123e2134.
Soto, P. L., Wilcox, K. M., Zhou, Y., Ator, N. A., Riddle, M. A., Wong, D. F., & Weed, M. R. (2012). Long-term exposure to oral methylphenidate or dlamphetamine mixture in peri-adolescent Rhesus monkeys: Effects on physiology, behavior, and dopamine system development. Neuropsychopharmacology, 37(12), 2566e2579.
Sowell, E. R., Peterson, B. S., Kan, E., Woods, R. P., Yoshii, J., Bansal, R., … Toga, A. W. (2007). Sex differences in cortical thickness mapped in 176
healthy individuals between 7 and 87 years of age. Cerebral Cortex, 17(7), 1550e1560.
Sowell, E. R., Peterson, B. S., Thompson, P. M., Welcome, S. E., Henkenius, A. L., & Toga, A. W. (2003). Mapping cortical change across the human life
span. Nature Neuroscience, 6(3), 309e315.
Spear, L. (2000). The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews, 24(4), 417e463.
Swendsen, J., Burstein, M., Case, B., Conway, K. P., Dierker, L., He, J., & Merikangas, K. R. (2012). Use and abuse of alcohol and illicit drugs in US
adolescents: Results of the national comorbidity survey-adolescent supplement. Archives of General Psychiatry, 69(4), 390e398.
Tan, H.-Y., Callicott, J. H., & Weinberger, D. R. (2009). Prefrontal cognitive systems in schizophrenia: Towards human genetic brain mechanisms.
Cognitive Neuropsychiatry, 14(4e5), 277e298.
Tirelli, E., Laviola, G., & Adriani, W. (2003). Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in
laboratory rodents. Neuroscience and Biobehavioral Reviews, 27(1e2), 163e178.
Torres-Berrío, A., Lopez, J., Bagot, R. C., Nouel, D., Bo, G., Cuesta, S., … Flores, C. (2017). DCC confers susceptibility to depression-like behaviors in
humans and mice and is regulated by miR-218. Biological Psychiatry, 81(4), 306e315.
304 PART | II Impairments and diseases
Torres-Berrío, A., Nouel, D., Cuesta, S., Parise, E. M., Restrepo-Lozano, J., Larochelle, P., … Flores, C. (2019). MiR-218: A molecular switch and
potential biomarker of susceptibility to stress. Molecular Psychiatry, 1.
Vosberg, D. E., Leyton, M., & Flores, C. (2019). The netrin-1/DCC guidance system: Dopamine pathway maturation and psychiatric disorders emerging
in adolescence. Molecular Psychiatry.
Vosberg, D. E., Zhang, Y., Menegaux, A., Chalupa, A., Manitt, C., Zehntner, S., … Leyton, M. (2018). Mesocorticolimbic connectivity and volumetric
alterations in DCC mutation carriers. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 38(20), 4655e4665.
Wahlstrom, D., White, T., & Luciana, M. (2010). Neurobehavioral evidence for changes in dopamine system activity during adolescence. Neuroscience
and Biobehavioral Reviews, 34(5), 631e648.
Walker, D. M., Bell, M. R., Flores, C., Gulley, J. M., Willing, J., & Paul, M. J. (2017). Adolescence and reward: Making sense of neural and behavioral
changes amid the chaos. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 37(45), 10855e10866.
Weickert, C., Webster, M., Gondipalli, P., Rothmond, D., Fatula, R., Herman, M., … Akil, M. (2007). Postnatal alterations in dopaminergic markers in the
human prefrontal cortex. Neuroscience, 144(3), 1109e1119.
Weiser, M., Knobler, H. Y., Noy, S., & Kaplan, Z. (2002). Clinical characteristics of adolescents later hospitalized for schizophrenia. American Journal of
Medical Genetics, 114(8), 949e955.
Willing, J., Cortes, L. R., Brodsky, J. M., Kim, T., & Juraska, J. M. (2017). Innervation of the medial prefrontal cortex by tyrosine hydroxylase
immunoreactive fibers during adolescence in male and female rats. Developmental Psychobiology, 59(5).
Yetnikoff, L., Almey, A., Arvanitogiannis, A., & Flores, C. (2011). Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by
exposure to amphetamine during the juvenile period. Psychopharmacology, 217(4), 505e514.
Yetnikoff, L., Labelle-Dumais, C., & Flores, C. (2007). Regulation of netrin-1 receptors by amphetamine in the adult brain. Neuroscience, 150(4),
764e773.
Yetnikoff, L., Pokinko, M., Arvanitogiannis, A., & Flores, C. (2014). Adolescence: A time of transition for the phenotype of dcc heterozygous mice.
Psychopharmacology, 231(8), 1705e1714.
Yetnikoff, L., Reichard, R. A., Schwartz, Z., Parsely, K. P., & Zahm, D. S. (2014). Protracted maturation of forebrain afferent connections of the ventral
tegmental area in the rat. The Journal of Comparative Neurology, 522(5), 1031e1047.