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Published in final edited form as: Trends Neurosci. 2017 Oct 9;40(12):709–719. doi: 10.1016/j.tins.2017.09.004

Making Dopamine Connections in Adolescence

Daniel Hoops 1, Cecilia Flores 1,*
PMCID: PMC5705341  NIHMSID: NIHMS907829  PMID: 29032842

Abstract

A dramatic maturational process ongoing in adolescence is prefrontal cortex development, including its dopamine innervation. Dopamine axons grow from the striatum to the prefrontal cortex, the only known case of long-distance axon growth during adolescence. This is coordinated by the Netrin-1 guidance cue receptor DCC, which in turn controls the intrinsic development of the prefrontal cortex itself. Stimulant drugs in adolescence alter DCC in dopamine neurons and in turn prefrontal cortex maturation, impacting cognitive abilities. Variations in DCC expression are linked to psychiatric conditions of prefrontal cortex dysfunction, and microRNA regulation of DCC may be key to determining adolescent vulnerability or resilience. Since early interventions are proving to effectively ameliorate disease outcome, the Netrin-1 system is a promising therapeutic target.

Keywords: prefrontal cortex, Netrin, DCC, guidance cues, stimulant drugs, microRNA

Adolescence as a period of behavioural and cognitive transition

Adolescence is the time when individuals must negotiate the transition between childhood and adulthood at several levels (molecular, cellular, physical, social). This transition requires a diverse knowledge and skill set pertaining to independent living and the ability to navigate emotional, social and psychological stimuli far more varied and complex than those experienced during childhood. As such, adolescence is characterized by dramatic behavioural and cognitive changes.

Concurrent with and underlying these adolescent changes is ongoing brain development, in particular at the level of the prefrontal cortex (see Glossary). This region, heavily involved in the complex cognitive and social processes that mature during adolescence, continues to develop into early adulthood [e.g. 1]. One of the key changes to the prefrontal cortex during adolescence is that its dopamine input continues to increase [2–6]. This dopamine growth in the prefrontal cortex is unique; maximum innervation levels of other neuromodulators are typically reached prior to the onset of adolescence [7]. Furthermore, protracted dopamine innervation to the prefrontal cortex is critically important for various aspects of prefrontal function, including working memory, affective processing, reasoning, planning, attention, inhibitory control and the calibration of risk and reward [e.g. 8]. Not surprisingly, these are among the cognitive processes that are still maturing throughout adolescence [9]. In fact, adolescent changes in some cognitive functions seem to occur in parallel to mesocortical dopamine maturation [3,10,11].

As prefrontal dopamine fibres continue to increase in density during adolescence, they may be particularly vulnerable to external influences, both positive and negative. Alterations in dopamine connectivity and activity have been linked to cognitive dysfunction observed across various psychiatric conditions [12]. The delayed dopamine connectivity in the prefrontal cortex during adolescence may underlie, at least in part, the heightened risk to develop mental disorders [13]. Therefore external influences that can affect adolescent prefrontal dopamine development may have the potential either to exacerbate or protect against the risk of developing certain psychiatric conditions.

In order to understand both the cognitive changes that occur during adolescence as well as adolescent vulnerability to mental disorders, it is crucial to clarify the cellular and molecular mechanisms underlying dopamine innervation and connectivity in the prefrontal cortex. Recent studies using rodent model systems have pointed at the role of specific axon guidance cues in this context. This review examines these advances, which lead to a molecular mechanistic explanation for the protracted development of mesocortical dopamine projections. We propose that this emerging picture could explain, at least in part, the particular susceptibility of adolescents to drug addiction and other mental disorders.

The challenges of characterizing adolescence across species

Though we may think of adolescence as a characteristically human attribute, the key behavioural traits associated with the adolescent transition are remarkably consistent across diverse species. Adolescence in humans is characterised by specific, well-described behavioural changes, particularly increased sociality, increased novelty-seeking, and increased risk-taking [14], and these changes are seen in a range of other animal species. The advantage of this is that these organisms can be used to study the neural changes associated with adolescence. However, a challenge to overcome is the need to precisely characterize the developmental time period that constitutes adolescence across multiple species, while keeping in mind that adolescence is a gradual behavioural and cognitive shift that does not have a specific onset or offset.

In the scientific literature there is a specific developmental timeframe typically referred to as the “adolescent period”. This is more of an arbitrary standard that encloses adolescence rather than the ‘true’ adolescent period. In the case of mice and rats, the adolescent period is usually considered to encompass the time from when the animals are weaned until they reach their adult weight [14–19]. In humans most often it is considered to be between 12 and 19 years of age [14,20]. These adolescent periods are often further divided into three equal thirds constituting “early,” “mid,” and “late” adolescence. Standardisation of the adolescent period, with all its caveats, allows for reproducible and quantifiable comparisons across species, particularly between model organisms, in our case mice, and humans, whose development we ultimately strive to understand.

Dopamine development in the prefrontal cortex is complex and critical

In the prefrontal cortex all cortical layers are innervated by dopamine fibres, which synapse onto pyramidal cells and parvalbumin-expressing interneurons [21–25]. However, the density of fibres varies between layers: density is greater in the superficial and deep cortical layers compared to the intermediate layers [25]. In the rodent, superficial layer dopamine fibres are distinct from deep layer fibres; they are located only in the supragenual (posterior) parts of the cingulate 1 and cingulate 2 subregions and originate from the substantia nigra rather than the ventral tegmental area [2,26]. To our knowledge, studies on the function of this separate yet interesting population of dopamine fibres are lacking. Therefore, we will limit our discussion to the much better known fibres located in the deep layers in the rodent. These fibres are located in the pregenual (anterior) medial prefrontal cortex and the orbital prefrontal cortex, and originate from cell bodies located in the ventral tegmental area.

Dopamine neurons in the ventral tegmental area, in addition to projecting to cortical regions, also project to subcortical structures, including the nucleus accumbens. This mesocorticolimbic dopamine system governs key aspects of complex behaviour including motivation and reward. However, despite their common origin, mesocortical and mesolimbic projections are distinct: they originate from different ventral tegmental area neuronal populations with specific structures and physiologies [27]. Furthermore, dopamine input to the prefrontal cortex is sparse compared to the dense input to limbic structures like the nucleus accumbens [3,28]. Nonetheless, we and others have shown that mesocortical dopamine fibres appear to be strategically localized to profoundly influence prefrontal cortex function [29–31].

Dopamine connectivity is still in flux during adolescence

The vast majority of neuronal growth, maturation, and connectivity happens during the prenatal and juvenile life stages. By the onset of adolescence, most axonal innervations in the brain have reach their adult densities, including dopamine innervations to limbic regions [32,33]. Although this is true of the nucleus accumbens, there is ample evidence that adolescence is a dynamic period in terms of connectivity and receptor expression in this region in particular [34–36]. In contrast, the dopamine innervation to the prefrontal cortex continues to increase throughout adolescence, achieving final axon density levels in early adulthood [2,3,6,28]. This is accompanied by increases in dopamine synapses onto prefrontal pyramidal neurons [5].

The unknown source of the increasing mesocortical dopamine fibres

It has long been known that the dopamine fibre density in the prefrontal cortex continues to increase throughout adolescence, however the source of this increase was unknown. The most parsimonious explanation was that dopamine axons innervating the cortex continue to sprout new branches throughout adolescence. However, an alternate possibility was that additional dopamine axons continue to reach the cortex throughout this period. Such late-stage, long-distance growth would make the dopamine innervation to the prefrontal cortex all the more unusual.

To study this possibility, our group developed a strategy using dual viral injections to label and track axon growth [31]. Using this strategy, we labelled dopamine axons that innervate the nucleus accumbens at the onset of adolescence. When we tracked these axons into adulthood we found that, though the vast majority of axons remained in the nucleus accumbens, a significant subset grew to the medial prefrontal cortex [31]. We also found that, as more dopamine axons innervate the medial prefrontal cortex, there is a correlated reduction in the axons innervating the nucleus accumbens [31]. This was the first clear evidence that protracted mesocortical dopamine development is due to ongoing axonal growth. Because they grow such a long distance, mesocortical dopamine axons need to make frequent and cumulative navigational decisions at intermediate targets and likely remain particularly vulnerable to environmental influences throughout this process.

Netrin-1 and its receptors coordinate neural development throughout life

What are the molecular mechanisms guiding adolescent mesocortical axon development, and are they linked to the intrinsic maturation of the prefrontal cortex? During neural development, growing axons find their targets by responding to the coordinated actions of proteins called guidance cues. Guidance cues vary in effective concentration, both spatially across the brain and temporally throughout development, forming signalling pathways that guide growing axons to their intended targets. One family of guidance cues, found across all bilaterally symmetrical animals, is the netrins [37]. Work from our group has focused on the most characterized protein in the netrin family, Netrin-1, and its role is mesocortical axon growth and navigation.

Netrin-1 is a ~65 kDa protein with 3 domains [38]. The two N-terminal domains (domains VI and V) are homologues to domains in the laminin protein family, while the C-terminal domain appears unique to netrins and binds to cell surfaces and the extracellular matrix [38,39]. Netrin-1 acts as a guidance cue by influencing the “decision-making” processes of growing axons, effectively signalling whether, where and when to grow [39–42]. Netrin-1 also plays a critical role in the wiring events that follow axonal pathfinding, including target recognition, axon arborisation, and synapse formation, as well as in other processes like oligo-axonal adhesion and synaptic plasticity [38,43–45]. The different functions achieved by Netrin-1 appear to be specific to particular developmental periods and maturational states, including adulthood [44,46].

Netrin-1 organizes neuronal circuitries by either attracting or repelling growing axons and dendrites [37]. These opposing responses depend on the binding of Netrin-1 to different receptors or receptor complexes. Two families of Netrin-1 receptors, the DCC (deleted in colorectal cancer) and the UNC5 (uncoordinated 5) families, account for the bifunctional nature of Netrin-1. DCC receptors mediate attraction, whereas UNC5 receptors signal repulsion [47]. These opposing actions can be altered by regulating the availability of DCC and UNC5 receptors at the cell surface [48]. Therefore, the selectivity with which Netrin-1 organizes neuronal connectivity can be mediated by the balance between “attractive” and “repulsive” receptors expressed at a given time. Subtle alterations in receptor expression can result in selective changes to the organization of neuronal circuits and, in turn, significant changes to the function of these systems in adulthood. As discussed next, our group has shown that variations in DCC receptor expression during adolescence dramatically influence the development of the rodent mesocorticolimbic dopamine system.

Mapping the topography of Netrin-1 and DCC in mesocorticolimbic dopamine targets

Dopamine neurons in the ventral tegmental area highly express DCC receptors throughout life [49,50]. During embryonic rodent development, the onset of DCC receptor expression appears to coincide with dopamine axons starting to grow towards the forebrain [50–52]. DCC continues to be strongly expressed by ventral tegmental neurons throughout postnatal development and to a lesser degree in adulthood [50].

In the medial prefrontal cortex, DCC receptors are expressed by pyramidal neurons [53], but only weakly by dopamine axons [28]. Here, Netrin-1 expression is substantial and localized to pyramidal and parvalbumin-expressing GABA neurons [28], the neurons onto which dopamine axons synapse. Notably, Netrin-1 expression is particularly strong in the deep cortical layers [28], where dopamine innervation is dense. In contrast, in the nucleus accumbens DCC receptors are exclusively expressed by dopamine axons and Netrin-1 expression is much weaker [28]. These contrasting expression patterns are maintained before, during and after adolescence [28]. The high-to-low, receptor-to-ligand expression of DCC and Netrin-1 in dopamine targets suggests an important role for these proteins in the development, organization, and connectivity of mesocorticolimbic dopamine neurons (Figure 2). We hypothesize that axons expressing copious DCC are sensitive to low concentrations of Netrin-1, while axons expressing minute quantities of DCC respond only to higher concentrations of Netrin-1.

Figure 2. Schematic illustration of the complementary expression patterns of Netrin-1 and DCC in forebrain dopamine innervation targets.

Figure 2

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The figure depicts a coronal section through the anterior mouse brain (modified from Paxinos & Franklin [86]). The figure illustrates only the relative levels of DCC expressed by dopamine axons, not DCC expressed by other cell types. (a) Netrin-1 expression is substantial in the medial prefrontal cortex (mPFC) and much weaker in the nucleus accumbens (NAcc). (b) Dopamine axons in the mPFC rarely express DCC. In contrast, DCC is highly expressed in the nucleus accumbens. Note that in this figure the frontal 2 cortical region, also referred to as secondary motor cortex, is included in the mPFC. Despite its name, this region is considered part of the prefrontal cortex [87].

To uncover the actual relationship between Netrin-1 signalling and adolescent dopamine development, we have studied the consequences of varying Dcc gene expression with spatial and temporal specificity. We have used Dcc heterozygous mice as well as mice with Dcc haploinsufficiency exclusively in dopamine neurons from adolescence onwards [28,29,31,46]. As DCC regulates many processes throughout life, we used Dcc heterozygous mice to gain an initial understanding of the role of DCC in adolescence and to develop more specific, testable hypotheses. To confirm the role of the mesocorticolimbic system, all critical results we describe have been generated or replicated using mice with targeted Dcc haploinsufficiency in dopamine neurons from adolescence onwards. This strategy has uncovered a critical role for DCC signalling in shaping mesocorticolimbic dopamine circuitry. Notably, Dcc haploinsufficiency also occurs in humans [54–58].

DCC receptors control dopamine axon targeting in adolescence

As mentioned, DCC is highly expressed by mesolimbic dopamine axons [28]. By inducing Dcc haploinsufficiency specifically in dopamine neurons during adolescence and tracking the growth of their axons, the role of DCC in determining the trajectory of these axons can be studied [31]. Dopamine axons with reduced Dcc fail to recognize the nucleus accumbens as their intended innervation target and instead reroute to the inner layers of the medial prefrontal cortex [31]. This results in excess dopamine varicosities and dopamine content in the prefrontal cortex [28,29,31,49,59]. Because prefrontal dopamine varicosities are the sites at which the majority of dopamine synthesis, packaging, release and reuptake occur [60], and because in the cortex about 93% of dopamine varicosities form synapses [61], it is possible that DCC receptor signalling ultimately controls the number of dopamine synapses in the medial prefrontal cortex. In summary, DCC receptor signalling promotes target recognition of mesolimbic dopamine axons in the nucleus accumbens, thereby controlling the extent of dopamine innervation to the medial prefrontal cortex (Figure 3, Key Figure).

Figure 3, Key Figure. DCC expression in dopamine axons determines their forebrain innervation target in adulthood.

Figure 3, Key Figure

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(a) A schematic diagram of the nucleus accumbens (NAcc, light cyan) and the medial prefrontal cortex (mPFC, dark green) shows that at the onset of adolescence, both dopamine axons that express DCC (red) and ones that do not (pink) innervate the nucleus accumbens. Dopamine axons that innervate the mPFC by early adolescence do not pass through the NAcc. scale bar = approximately 500μm (a′) A zoomed-in illustration of the nucleus accumbens at the onset of adolescence showing the high density of dopamine input to this region. This level of dopamine innervation remains relatively unchanged throughout adolescence and adulthood. scale bar = approximately 10μm (b) In the adult, dopamine axons that do not express DCC have left the NAcc and now innervate the mPFC. (b′) A zoomed-in illustration of the mPFC emphasizes that the density of dopamine innervation is far lower than in the NAcc. (c) A schematic diagram representing ectopic innervation of dopamine fibres in the adult mPFC following exposure to amphetamine in adolescence. (c′) A zoomed-in illustration of the adult mPFC following exposure to amphetamine in adolescence demonstrates that although there is an increase in the number of dopamine axons innervating the mPFC, these axons differ from the ones seen in non-treated animals: they are denuded of varicosities, and some of the innervating axons, abnormally, express DCC.

DCC-mediated wiring of mesocortical dopamine circuitry determines complex cognition in adulthood

By delimiting mesocortical dopamine input, DCC receptors determine the dendritic arbour complexity, dendritic spine density, and excitability of prefrontal layer V pyramidal neurons [28,29,31,49]. Because of these developmental alterations, we hypothesized that DCC signalling in adolescence influences adult cognitive abilities associated with prefrontal cortex function, specifically cognitive inhibition and behavioural flexibility. To examine cognitive inhibition, we tested mice heterozygous for Dcc in dopamine neurons in a Go/No-Go task, in which the animals are trained to respond to a specific cue, as well as to refrain their behavioural responses according to the presence of a secondary cue in order to obtain a food reward [62]. These mice show equal performance at all training stages of the task, but during the Go/No-Go phase show a specific behavioural alteration; while they have a normal ability to respond during a go trial, they are better able to inhibit responses during a no-go trial [31], indicating that these animals are less impulsive. We also found improved cognition in Dcc heterozygous mice in the attentional set-shifting test [63], a test of cognitive flexibility. Cognitive or behavioural flexibility is the ability to make adaptive responses to a changing environment and is specifically tested by the extradimensional set-shifting component of the attentional set-shifting test [29,63,64]. Performance on this component of the test is enhanced in Dcc heterozygous mice [29]. In contrast, these mice perform normally in the other stages of the task, including intradimensional set-shifting, indicating that their ability to generate an attentional set is not altered [29,63]. By reducing DCC expression on dopamine neurons, we have been able to manipulate the adolescent development of the prefrontal cortex and selectively alter prefrontal cortex-dependent behaviours.

By organizing dopamine development, DCC receptors determine adult sensitivity to stimulant drugs

Dopamine neurotransmission in the prefrontal cortex plays an important role in regulating dopamine activity in the nucleus accumbens. In fact, prefrontal dopamine activity has been shown to attenuate accumbal dopamine release [65]. Because we found that DCC controls dopamine connectivity and activity in the prefrontal cortex, we hypothesized that it may also impact the effects of stimulant drugs that are mediated by dopamine release in the nucleus accumbens. These include effects on locomotor activity, conditioned place preference, sensorimotor gating, and sensitivity to intracranial self-stimulation. We have found that, as adults, mice with Dcc haploinsufficiency are protected against all these effects [49,59,66–68]. Furthermore, we recently demonstrated that increased input and concentration of dopamine in the medial prefrontal cortex directly causes the effects on locomotor activity [69], and we expect that the same is true for the other effects.

By inducing Dcc haploinsufficiency in dopamine neurons in adolescence, dopamine axons are rerouted to the prefrontal cortex. As noted earlier, this results in a measureable decrease in the dopamine innervation to the nucleus accumbens [31]. This reduction may also contribute to the blunted amphetamine-induced dopamine release in the nucleus accumbens and therefore the blunted behavioural responses.

Addictive drugs in adolescence alter DCC signalling and dopamine development

Adolescent exposure to factors that increase the risk of developing disorders involving prefrontal cortex dysfunction, such as addictive drugs, may cause their effects by altering DCC expression in dopamine neurons. We have shown that repeated exposure to amphetamine in adolescence, but not in adulthood, downregulates DCC receptors in ventral tegmental area dopamine neurons [70,71]. Remarkably, adult mice that received this treatment during adolescence have an increase in the dopamine input to the prefrontal cortex [72]. Importantly, the drug regimen we use results in blood plasma levels in mice comparable to those achieved by adolescent people who use amphetamine recreationally [73]. As we detailed above, reduced DCC expression in adolescence induces target-recognition errors by dopamine axons in the nucleus accumbens and their ectopic innervation in the prefrontal cortex [31]. Therefore, we believe that the increased span in mesocortical innervation observed in amphetamine-treated mice may result from drug-induced target recognition errors in the nucleus accumbens and concomitant rerouting to the prefrontal cortex (Figure 3c).

It is important to emphasize that although amphetamine in adolescence leads to an increase in the expanse of dopamine axons in the medial prefrontal cortex, it also induces a dramatic reduction in the number and density of their presynaptic sites [72]. This effect is opposite to the one observed in transgenic mouse models of Dcc haploinsufficiency [28,29]. How amphetamine denudes dopamine axons of presynaptic sites remains to be established. However, aberrant contact and adhesion between dopamine axon terminals and dendrites in the prefrontal cortex is likely to be involved [74]. This idea is consistent with evidence showing that DCC-mediated Netrin-1 signalling maintains synapses in the prefrontal cortex [75].

Variations in DCC receptor expression are linked to psychiatric disorders

Dcc haploinsufficiency has been found in several family lineages worldwide [54–58]. There has been great interest in the neuroanatomical and behavioural implications of Dcc haploinsufficiency in humans, however its implications for mesocorticolimbic development and related psychiatric disorders have so far remained unexamined. We have started to address these questions, and we predict that Dcc haploinsufficiency will alter mesocorticolimbic connectivity. We expect that this change will be associated with differences in prefrontal cortex-dependent cognitive functions such as cognitive flexibility, reasoning, planning, and reward calibration. We anticipate phenotypic changes to emerge after adolescence. Furthermore it would be interesting to determine whether subjects with Dcc haploinsufficiency show some level of protection against disorders of prefrontal cortex dysfunction.

Recently, using techniques such as genome-wide association, several studies have suggested links between DCC receptors and psychiatric conditions. One intriguing finding was an association between schizophrenia and polymorphisms in the 3′ untranslated region (UTR) of the DCC gene [76,77]. Although associations between gene polymorphisms and schizophrenia are not uncommon, this finding may be of particular significance because post-transcriptional gene expression regulators modify gene expression by binding the 3′ UTR [78], and therefore such polymorphisms could alter DCC expression levels in dopamine neurons and disrupt mesocorticolimbic system development. A second notable link between psychiatric disease and altered DCC epigenetics is an increase of about 50% in DCC gene expression in the prefrontal cortex of antidepressant-free patients with major depressive disorder who committed suicide [29], a finding later replicated [53]. In fact, there is now substantial correlational genetic evidence from human populations that variation in DCC expression is a risk factor for depression [29,53,79–82]. Although such evidence lacks a causative link, using a mouse model of depression we have recently shown that increased Dcc expression in the prefrontal cortex induces susceptibility to developing depression-like phenotypes [53]. This is the first direct evidence that DCC plays a causal role in determining vulnerability to traits that are associated with psychiatric conditions.

The increase in DCC-expression found in subjects with depression is negatively correlated with the expression of microRNA-218, a potent repressor of DCC expression in human and mouse neurons [53]. MicroRNAs are emerging as molecular links between environmental factors and changes in gene expression [78] and are commonly altered in psychiatric disorders [83]. In general, microRNAs can be relatively easily measured in blood samples [84], so it is feasible that microRNA-218 could be measure in humans. Since circulating levels of microRNAs, including microRNA-218, are known to correlate with levels of microRNAs in the brain, blood-sample measurements of microRNAs, including perhaps microRNA-218, could potentially serve as biomarkers for susceptibility to psychiatric disorders [84,85]. This is a promising strategy for identifying people, particularly at the onset of adolescence, who may be predisposed to developing psychiatric disorders, including depression. Providing interventions for these individuals prior to any prodromal symptoms could offer an effective new way to combat adolescent-emergent psychiatric disorders.

Concluding Remarks

Mesocortical dopamine axons represent the only known case of long-distance axon growth during adolescence. As these axons navigate to the prefrontal cortex they remain particularly sensitive to environmental influences. The Netrin-1/DCC signalling pathway, which mediates dopamine axon targeting decisions, is a molecular substrate linking environmental events in adolescence to changes in brain maturation and cognition. Notably, animal studies have shown that stimulant drugs acting via Netrin-1/DCC can modify the extent and the organization of the dopamine input to the prefrontal cortex. Furthermore, changes in DCC expression, including in humans, most likely involving microRNAs, are implicated in psychiatric disorders. As microRNAs can be easily measured in blood samples, this presents an opportunity to identify individuals, at a vulnerable age, who may be at risk of developing a psychiatric condition. Contrasting with the detrimental effects of changes in DCC expression, work using transgenic Dcc mouse models has also shown the potential of alterations in DCC expression to be protective. Identifying potential environmental influences that can induce these beneficial alterations is an active area of research (see Outstanding Questions). Perhaps the most intriguing of the avenues for further investigation is the possibility of preventing the development of psychiatric conditions in humans through targeted a priori interventions. Much further research would be needed to achieve this goal, both to pin down useful biomarkers and to identify effective interventions. Nonetheless, the key contributions of the Netrin-1/DCC pathway to prefrontal cortex development during adolescence, and accordingly its relevance to psychiatric disorders, are becoming clear.

Outstanding Questions.

  • To what extent does adolescent dopamine axon growth contribute to individual differences in vulnerability to psychiatric disorders? Do variations in DCC gene expression dictate susceptibility to psychiatric disorders? What is the role of microRNAs?

  • Does DCC/Netrin-1 signalling play a role in the changes to the endocrine system that coincide with adolescence? If so, is there any interaction between the roles of Netrin/DCC in dopamine and endocrine development?

  • Do fluctuations in circulating gonadal hormone levels influence the effects of DCC receptors on dopamine axon targeting in adolescence? Are these effects different between males and females?

  • Does exposure to other drugs, such as alcohol and marijuana, during adolescence influence the growth of dopamine axons? And what about exposure to amphetamine at doses used in therapeutic contexts; do they influence the growth of dopamine axons?

  • Can resilience to psychopathology be induced through changes in the Netrin-1/DCC signalling pathway? If so, what environmental experiences could trigger these processes?

  • Is there a role for the other known Netrin-1 receptors, UNC-5 (uncoordinated), Neogenin, and DSCAM (Down syndrome cell adhesion molecule), in coordinating dopamine axon growth in adolescence? UNC-5C receptors are expressed in dopamine neurons from adolescence onwards. What are the implications of this for axon targeting?

  • By controlling the extent of the dopamine input to the prefrontal cortex, DCC receptors determine the functional organization of pyramidal neurons. Does the Netrin-1/DCC system influence the adolescent maturation of GABA interneurons as well?

  • Why does late-stage axon growth exist in the brain? Does it have an evolutionary benefit?

Figure 1. The responses of growing axons to Netrin-1 gradients.

Figure 1

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The response of growing axons to Netrin-1 depends on the expression pattern of Netrin-1 receptors on the axons. In general, axons that express DCC but not UNC5 (DCC+ UNC5−) are attracted to Netrin-1, whereas axons that express both DCC and UNC5 (DCC+ UNC5+) are repelled by Netrin-1. Axons that express neither DCC nor UNC5 (DCC− UNC5−) do not respond to the Netrin-1 gradient, provided they do not express other Netrin-1 receptors.

Trends.

  • Dopamine axons grow from the nucleus accumbens to the prefrontal cortex during adolescence; this is the only known case of adolescent long-distance axon growth

  • The Netrin-1 receptor DCC is responsible for coordinating this growth

  • These axons are particularly vulnerable to environmental effects, including recreational drug use, during adolescence and are strategically localized to profoundly influence prefrontal cortex structure and function

  • Changes in DCC gene expression in humans are linked psychiatric conditions involving prefrontal cortex dysfunction, including schizophrenia and depression

  • DCC gene expression is under microRNA control, which may act as a link between environmental factors and prefrontal cortex development

Acknowledgments

CF is supported by the National Institute on Drug Abuse (R01DA037911), the Canadian Institutes of Health Research (MOP-74709), and the Natural Science and Engineering Research Council of Canada (2982226). CF is a Fonds de Recherche du Québec – Santé research scholar. DH is supported by the Quebec Nature and Technology Research Fund (208332). We are grateful to Dr. Patricia Pelufo Silveira and Daniel Vosberg for providing comments and suggestions on drafts of this manuscript. Both authors declare no conflicts of interest.

Glossary

Attentional Set

a group of related stimuli that either do or do not contain information relevant to a task, such as acquiring food. By classifying individual stimuli into sets, information processing and decision making can be performed more efficiently.

Cognitive Inhibition

the ability to ignore stimuli that do not contain information relevant to a task, even if the stimuli are relevant to a different task. The Go/No-Go Task is a commonly used test of this ability.

DCC

the acronym for the protein “deleted in colorectal cancer”; acts as a Netrin-1 receptor. It is expressed by growing axons and signals attraction to Netrin-1.

Dcc haploinsufficient mouse models

genetically modified mice that carry one non-functional allele of the Dcc gene. These mice have reduced DCC protein expression in the brain compared to wild-type mice. More refined manipulations can be used to modulate DCC expression in specific populations of neurons and/or time windows. For instance, the Cre/lox viral-mediated gene editing technique has been used to generate mice with Dcc haploinsufficiency only in ventral tegmental dopamine neurons and from adolescence onwards.

Guidance Cue

a protein which signals the appropriate path for growing neurites to follow to their intended innervation target through the developing nervous system.

Mesocorticolimbic Dopamine System

a group of brain regions consisting of the ventral tegmental area and forebrain regions that receive its dopamine projections. The “mesolimbic” component of this system refers to the limbic forebrain regions that receive these projections and includes the nucleus accumbens. The “mesocortical” component of this system refers to the cortical forebrain regions that receive these projections and consists primarily of the prefrontal cortex.

microRNA

a small RNA that prevents the translation of a specific messenger RNA into protein by binding the 3′ untranslated region. MicroRNAs are thought to be important for the “fine tuning” of protein expression.

Netrin-1

A guidance cue protein that binds to elements of the extracellular matrix and interacts with receptors expressed on the surfaces of growing axons, signalling axon growth trajectories. Netrin-1 is also heavily involved in other aspects of axon development and maintenance and is expressed in the brain throughout life.

Prefrontal Cortex

The most anterior component of the frontal lobe of the cerebral cortex; defined anatomically by the dense projection it receives from the dorsomedial thalamic nucleus. Heavily involved in the most complex components of cognition including planning, reasoning and decision making. Receives a sparse dopamine input from the ventral tegmental area that continues to increase until early adulthood.

Set-shifting

the process of learning that the information contained by different attentional sets has changed. The “dimension” of an attentional set refers to the sensory modality or property of the set, for example colour, texture, shape, or odour. Set-shifting may be intra- or extradimensional.

UNC5

the acronym for the protein “uncoordinated-5”; acts as a Netrin-1 receptor. When bound to Netrin-1 it forms a complex with DCC and signals repulsion from regions of high Netrin-1. Whether the mammalian forms of UNC5 can respond to Netrin-1 in the absence of DCC remains unknown.

Untranslated region (UTR)

messenger RNA nucleotide sequences that do not consist of codons and are not translated, but instead contain regulatory sequences. They can be located before the start codon (5′) or after the stop codon (3′).

Footnotes

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References

  • 1.Caballero A, et al. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev. 2016;70:4–12. doi: 10.1016/j.neubiorev.2016.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Kalsbeek A, et al. Development of the Dopaminergic Innervation in the Prefrontal Cortex of the Rat. J Comp Neurol. 1988;269:58–72. doi: 10.1002/cne.902690105. [DOI] [PubMed] [Google Scholar]
  • 3.Naneix F, et al. Parallel Maturation of Goal-Directed Behavior and Dopaminergic Systems during Adolescence. J Neurosci. 2012;32:16223–16232. doi: 10.1523/JNEUROSCI.3080-12.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Benes FM, et al. Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb Cortex. 2000;10:1014–1027. doi: 10.1093/cercor/10.10.1014. [DOI] [PubMed] [Google Scholar]
  • 5.Lambe EK, et al. Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey. J Neurosci. 2000;20:8780–8787. doi: 10.1523/JNEUROSCI.20-23-08780.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Rosenberg DR, Lewis DA. Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: a tyrosine hydroxylase immunohistochemical study. Biol Psych. 1994;36:272–277. doi: 10.1016/0006-3223(94)90610-6. [DOI] [PubMed] [Google Scholar]
  • 7.Lidov HGW, et al. The serotonin innervation of the cerebral cortex in the rat—an immunohistochemical analysis. Neurosci. 1980;5:207–227. doi: 10.1016/0306-4522(80)90099-8. [DOI] [PubMed] [Google Scholar]
  • 8.Floresco SB. Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions. Front Neurosci. 2013:7. doi: 10.3389/fnins.2013.00062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Luna B, et al. An integrative model of the maturation of cognitive control. Annu Rev Neurosci. 2015;38:151–170. doi: 10.1146/annurev-neuro-071714-034054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Padmanabhan A, Luna B. Developmental imaging genetics: linking dopamine function to adolescent behavior. Brain Cognit. 2014;89:27–38. doi: 10.1016/j.bandc.2013.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Sannino S, et al. Adolescence is the starting point of sex-dichotomous COMT genetic effects. Transl Psychiatry. 2017;7:e1141. doi: 10.1038/tp.2017.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2011;12:652–669. doi: 10.1038/nrn3119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Paus T, et al. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci. 2008;9:947–957. doi: 10.1038/nrn2513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24:417–463. doi: 10.1016/s0149-7634(00)00014-2. [DOI] [PubMed] [Google Scholar]
  • 15.Desbonnet L, et al. Gut microbiota depletion from early adolescence in mice: Implications for brain and behaviour. Brain, Behavior, and Immunity. 2015;48:165–173. doi: 10.1016/j.bbi.2015.04.004. [DOI] [PubMed] [Google Scholar]
  • 16.Schneider M. Adolescence as a vulnerable period to alter rodent behavior. Cell Tissue Res. 2013;354:99–106. doi: 10.1007/s00441-013-1581-2. [DOI] [PubMed] [Google Scholar]
  • 17.Yamamuro K, et al. Social Isolation During the Critical Period Reduces Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Cell in Mouse Prefrontal Cortex. Cereb Cortex. 2017 doi: 10.1093/cercor/bhx010. [DOI] [PubMed] [Google Scholar]
  • 18.Baarendse PJJ, et al. Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function. Neuropsychopharmacology. 2013;38:1485–1494. doi: 10.1038/npp.2013.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Makinodan M, et al. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science. 2012;337:1357–1360. doi: 10.1126/science.1220845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Sacks D. Age limits and adolescents. Paediatr Child Health. 2003;8:577. doi: 10.1093/pch/8.9.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Sesack SR, et al. Ultrastructural associations between dopamine terminals and local circuit neurons in the monkey prefrontal cortex: a study of calretinin-immunoreactive cells. Neurosci Lett. 1995;200:9–12. doi: 10.1016/0304-3940(95)12076-g. [DOI] [PubMed] [Google Scholar]
  • 22.Verney C, et al. Ultrastructural Double-Labelling Study of Dopamine Terminals and GABA-Containing Neurons in Rat Anteromedial Cerebral Cortex. Eur J Neurosci. 1990;2:960–972. doi: 10.1111/j.1460-9568.1990.tb00008.x. [DOI] [PubMed] [Google Scholar]
  • 23.Sesack SR, et al. Dopamine innervation of a subclass of local circuit neurons in monkey prefrontal cortex: ultrastructural analysis of tyrosine hydroxylase and parvalbumin immunoreactive structures. Cereb Cortex. 1998;8:614–622. doi: 10.1093/cercor/8.7.614. [DOI] [PubMed] [Google Scholar]
  • 24.Smiley JF, Goldman-Rakic PS. Heterogeneous Targets of Dopamine Synapses in Monkey Prefrontal Cortex Demonstrated by Serial Section Electron Microscopy: A Laminar Analysis Using the Silver-enhanced Diaminobenzidine Sulfide (SEDS) Immunolabeling Technique. Cereb Cortex. 1993;3:223–238. doi: 10.1093/cercor/3.3.223. [DOI] [PubMed] [Google Scholar]
  • 25.Goldman-Rakic PS, et al. Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. PNAS. 1989;86:9015–9019. doi: 10.1073/pnas.86.22.9015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Berger B, et al. Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci. 1991;14:21–27. doi: 10.1016/0166-2236(91)90179-x. [DOI] [PubMed] [Google Scholar]
  • 27.Roeper J. Dissecting the diversity of midbrain dopamine neurons. Trends Neurosci. 2013;36:336–342. doi: 10.1016/j.tins.2013.03.003. [DOI] [PubMed] [Google Scholar]
  • 28.Manitt C, et al. The Netrin Receptor DCC Is Required in the Pubertal Organization of Mesocortical Dopamine Circuitry. J Neurosci. 2011;31:8381–8394. doi: 10.1523/JNEUROSCI.0606-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Manitt C, et al. dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. Transl Psychiatry. 2013;3:e338–13. doi: 10.1038/tp.2013.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Verwey M, et al. Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon. eNeuro. 2016;3:1–15. doi: 10.1523/ENEURO.0009-16.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Reynolds LM, et al. DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence. Biol Psych. 2017 doi: 10.1016/j.biopsych.2017.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Brummelte S, Teuchert-Noodt G. Postnatal development of dopamine innervation in the amygdala and the entorhinal cortex of the gerbil (Meriones unguiculatus) Brain Res. 2006;1125:9–16. doi: 10.1016/j.brainres.2006.10.006. [DOI] [PubMed] [Google Scholar]
  • 33.Antonopoulos J, et al. Distribution and synaptology of dopaminergic fibers in the mature and developing lateral septum of the rat. Dev Brain Res. 1997;102:135–141. doi: 10.1016/s0165-3806(97)00088-6. [DOI] [PubMed] [Google Scholar]
  • 34.Brenhouse HC, et al. Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence. J Neurosci. 2008;28:2375–2382. doi: 10.1523/JNEUROSCI.5064-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Huppé Gourgues F, O’Donnell P. D1 NMDA receptor interactions in the rat nucleus accumbens change during adolescence. Synapse. 2012;66:584–591. doi: 10.1002/syn.21544. [DOI] [PubMed] [Google Scholar]
  • 36.Pokinko M, et al. Dcc haploinsufficiency regulates dopamine receptor expression across postnatal lifespan. Neurosci. 2017;346:182–189. doi: 10.1016/j.neuroscience.2017.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Manitt C, Kennedy TE. Where the rubber meets the road: netrin expression and function in developing and adult nervous systems. Prog Brain Res. 2002;137:425–442. doi: 10.1016/s0079-6123(02)37034-1. [DOI] [PubMed] [Google Scholar]
  • 38.Finci L, et al. Signaling mechanism of the netrin-1 receptor DCC in axon guidance. Prog Biophys Molec Biol. 2015;118:153–160. doi: 10.1016/j.pbiomolbio.2015.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Moore SW, et al. Traction on Immobilized Netrin-1 Is Sufficient to Reorient Axons. Science. 2009;325:166–166. doi: 10.1126/science.1173851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Varadarajan SG, et al. Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord. Neuron. 2017 doi: 10.1016/j.neuron.2017.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Akin O, et al. Frazzled promotes growth cone attachment at the source of a Netrin gradient in the Drosophila visual system. eLife Sciences. 2016;5:e20762. doi: 10.7554/eLife.20762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Dominici C, et al. Floor-plate-derived netrin-1 is dispensable for commissural axon guidance. Nature. 2017;78:409. doi: 10.1038/nature22331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Jarjour AA, et al. Maintenance of Axo-Oligodendroglial Paranodal Junctions Requires DCC and Netrin-1. J Neurosci. 2008;28:11003–11014. doi: 10.1523/JNEUROSCI.3285-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Horn KE, et al. DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain. Cell Reports. 2013;3:173–185. doi: 10.1016/j.celrep.2012.12.005. [DOI] [PubMed] [Google Scholar]
  • 45.Shen K, Cowan CW. Guidance Molecules in Synapse Formation and Plasticity. Cold Spring Harb Perspect Biol. 2010;2:a001842. doi: 10.1101/cshperspect.a001842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Flores C. Role of netrin-1 in the organization and function of the mesocorticolimbic dopamine system. J Psychiatry Neurosci. 2011;36:296–310. doi: 10.1503/jpn.100171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Hong K, et al. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell. 1999;97:927–941. doi: 10.1016/s0092-8674(00)80804-1. [DOI] [PubMed] [Google Scholar]
  • 48.Muramatsu R, et al. The ratio of “deleted in colorectal cancer” to ‘uncoordinated-5A’ netrin-1 receptors on the growth cone regulates mossy fibre directionality. Brain. 2010;133:60–75. doi: 10.1093/brain/awp266. [DOI] [PubMed] [Google Scholar]
  • 49.Grant A, et al. Netrin-1 receptor-deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine. Eur J Neurosci. 2007;26:3215–3228. doi: 10.1111/j.1460-9568.2007.05888.x. [DOI] [PubMed] [Google Scholar]
  • 50.Manitt C, et al. Peri-Pubertal Emergence of UNC-5 Homologue Expression by Dopamine Neurons in Rodents. PLoS ONE. 2010;5:e11463–14. doi: 10.1371/journal.pone.0011463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Gad JM, et al. The expression patterns of guidance receptors, DCC and Neogenin, are spatially and temporally distinct throughout mouse embryogenesis. Dev Biol. 1997;192:258–273. doi: 10.1006/dbio.1997.8756. [DOI] [PubMed] [Google Scholar]
  • 52.Livesey FJ, Hunt SP. Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol Cell Neurosci. 1997;8:417–429. doi: 10.1006/mcne.1997.0598. [DOI] [PubMed] [Google Scholar]
  • 53.Torres-Berrío A, et al. DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218. Biol Psych. 2017;81:306–315. doi: 10.1016/j.biopsych.2016.08.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Srour M, et al. Mutations in DCC cause congenital mirror movements. Science. 2010;328:592–592. doi: 10.1126/science.1186463. [DOI] [PubMed] [Google Scholar]
  • 55.Depienne C, et al. A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology. 2011;76:260–264. doi: 10.1212/WNL.0b013e318207b1e0. [DOI] [PubMed] [Google Scholar]
  • 56.Marsh APL, et al. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance. Nat Genet. 2017 doi: 10.1038/ng.3794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Welniarz Q, et al. Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline. Scient Rep. 2017;7:410. doi: 10.1038/s41598-017-00514-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Jamuar SS, et al. Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet. 2017;49:606–612. doi: 10.1038/ng.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Flores C, et al. Netrin receptor deficient mice exhibit functional reorganization of dopaminergic systems and do not sensitize to amphetamine. Mol Psychiatry. 2005;10:606–612. doi: 10.1038/sj.mp.4001607. [DOI] [PubMed] [Google Scholar]
  • 60.Benes FM, et al. Increased interaction of dopamine-immunoreactive varicosities with GABA neurons of rat medial prefrontal cortex occurs during the postweanling period. Synapse. 1996;23:237–245. doi: 10.1002/(SICI)1098-2396(199608)23:4<237::AID-SYN1>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  • 61.Séguéla P, et al. Ultrastructural features of dopamine axon terminals in the anteromedial and the suprarhinal cortex of adult rat. Brain Res. 1988;442:11–22. doi: 10.1016/0006-8993(88)91427-8. [DOI] [PubMed] [Google Scholar]
  • 62.Fuster JM. The Prefrontal Cortex. 5. Elsevier; 2015. [Google Scholar]
  • 63.Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20:4320–4324. doi: 10.1523/JNEUROSCI.20-11-04320.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Scheggia D, et al. The Ultimate Intra-/Extra-Dimensional Attentional Set-Shifting Task for Mice. Biol Psych. 2014;75:660–670. doi: 10.1016/j.biopsych.2013.05.021. [DOI] [PubMed] [Google Scholar]
  • 65.Ventura R, et al. Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion. Neuropsychopharmacology. 2004;29:72–80. doi: 10.1038/sj.npp.1300300. [DOI] [PubMed] [Google Scholar]
  • 66.Grant A, et al. Post-pubertal emergence of a dopamine phenotype in netrin-1 receptor-deficient mice. Eur J Neurosci. 2009;30:1318–1328. doi: 10.1111/j.1460-9568.2009.06919.x. [DOI] [PubMed] [Google Scholar]
  • 67.Yetnikoff L, et al. Adolescence: a time of transition for the phenotype of dcc heterozygous mice. Psychopharmacology. 2013;231:1705–1714. doi: 10.1007/s00213-013-3083-z. [DOI] [PubMed] [Google Scholar]
  • 68.Hoops D, et al. Netrin-1 receptor deficiency protects against psychostimulant-induced behaviours in mice. MSURJ. 2008;3:9–16. [Google Scholar]
  • 69.Pokinko M, et al. Resilience to amphetamine in mouse models of netrin-1 haploinsufficiency: role of mesocortical dopamine. Psychopharmacology. 2015;232:3719–3729. doi: 10.1007/s00213-015-4032-9. [DOI] [PubMed] [Google Scholar]
  • 70.Yetnikoff L, et al. Netrin-1 receptor in the ventral tegmental area is required for sensitization to amphetamine. Eur J Neurosci. 2010;31:1292–1302. doi: 10.1111/j.1460-9568.2010.07163.x. [DOI] [PubMed] [Google Scholar]
  • 71.Yetnikoff L, et al. Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period. Psychopharmacology. 2011;217:505–514. doi: 10.1007/s00213-011-2312-6. [DOI] [PubMed] [Google Scholar]
  • 72.Reynolds LM, et al. Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner. Neuropsychopharmacology. 2015;40:1101–1112. doi: 10.1038/npp.2014.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Gustavsen I, et al. Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers. Accid Anal Prev. 2006;38:490–495. doi: 10.1016/j.aap.2005.11.005. [DOI] [PubMed] [Google Scholar]
  • 74.Thompson-Steckel G, Kennedy TE. Maintaining and modifying connections: roles for axon guidance cues in the mature nervous system. Neuropsychopharmacology. 2014;39:246–247. doi: 10.1038/npp.2013.212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Goldman JS, et al. Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly. J Neurosci. 2013;33:17278–17289. doi: 10.1523/JNEUROSCI.1085-13.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Grant A, et al. Association between schizophrenia and genetic variation in DCC: A case control study. Schizo Res. 2012;137:26–31. doi: 10.1016/j.schres.2012.02.023. [DOI] [PubMed] [Google Scholar]
  • 77.Yan P, et al. An Association Study Between Genetic Polymorphisms in Functional Regions of Five Genes and the Risk of Schizophrenia. Journal of Molecular Neuroscience. 2016 doi: 10.1007/s12031-016-0751-6. [DOI] [PubMed] [Google Scholar]
  • 78.Wahid F, et al. MicroRNAs: Synthesis, mechanism, function, and recent clinical trials. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2010;1803:1231–1243. doi: 10.1016/j.bbamcr.2010.06.013. [DOI] [PubMed] [Google Scholar]
  • 79.Dunn EC, et al. Genome-wide association study (GWAS) and genome-wide by environment interaction study (GWEIS) of depressive symptoms in african american and hispanic/latina women. Depress Anxiety. 2016;33:265–280. doi: 10.1002/da.22484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Okbay A, et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet. 2016;48:624–633. doi: 10.1038/ng.3552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Zeng Y, et al. A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway Is Associated With Major Depressive Disorder. Biol Psych. 2016;81:1–11. doi: 10.1016/j.biopsych.2016.04.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Vértes PE, et al. Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder. Biol Psych. 2017 doi: 10.1016/j.biopsych.2017.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Lopez JP, et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat Med. 2014;20:764–768. doi: 10.1038/nm.3582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Belzeaux R, et al. Potential Use of MicroRNA for Monitoring Therapeutic Response to Antidepressants. CNS Drugs. 2017;31:253–262. doi: 10.1007/s40263-017-0418-z. [DOI] [PubMed] [Google Scholar]
  • 85.Rao P, et al. MicroRNAs as biomarkers for CNS disease. Front Mol Neurosci. 2013;6:39. doi: 10.3389/fnmol.2013.00039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. Academic Press; 2013. [Google Scholar]
  • 87.Uylings HBM, et al. Do rats have a prefrontal cortex? Behav Brain Res. 2003;146:3–17. doi: 10.1016/j.bbr.2003.09.028. [DOI] [PubMed] [Google Scholar]

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