Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons towards the prefrontal cortex and shape behaviour. We demonstrate in mice (Mus musculus) that dopamine axons reach the cortex through a transient gradient of Netrin-1 expressing cells – disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; Phodopus sungorus) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner – delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.
This study addresses an important question using approaches that link molecular, circuit, and behavioral changes. The findings that Netrin-1 and UNC5c can guide dopaminergic innervation from the nucleus accumbens to the cortex during adolescence are solid. The data showing that the onset of Unc5 expression is sexually dimorphic in mice, and that in Siberian hamsters, environmental effects on development are also sexually dimorphic are solid. While this work is novel and on an interesting, understudied topic, the reviewers also identified significant gaps in experimental data and agree that support for the main claims is incomplete.
Adolescence is a critical developmental period involving dramatic changes in behaviour and brain anatomy. The prefrontal cortex, the brain region responsible for our most complex cognitive functions, is still establishing connections during this time (Gogtay et al., 2004; Petanjek et al., 2011; Sowell et al., 2004). The trajectory of prefrontal cortex development in adolescence determines the vulnerability or resilience of individuals to adolescent-onset psychiatric diseases (Fuhrmann et al., 2015; Keshavan et al., 2014; Kessler et al., 2007, 2005; Lee et al., 2014). The age at which this adolescent development occurs therefore represents a critical window during which the brain is particularly susceptible to environmental influences. Traditionally, the onset of adolescence is thought to coincide with puberty (Hollenstein and Lougheed, 2013). In humans, the age of pubertal onset has been advancing throughout the 19th, 20th and 21st centuries, and environmental influences, such as nutrition, can pathologically alter the age of puberty (Wolf and Long, 2016). However, it remains entirely unknown whether the neural and cognitive maturational processes of adolescence can also be plastic. Here, for the first time, we examine how the timing of adolescence is programmed in the brain, and whether this timing can be plastic in response to a natural environmental cue, in parallel with pubertal plasticity.
Dopamine innervation to the prefrontal cortex increases substantially across adolescence and psychopathologies of adolescent origin prominently feature dopamine dysfunction. Evidence continues to emerge that protracted dopamine innervation is a key neural process underlying the cognitive and behavioural changes that characterize adolescence (Larsen and Luna, 2018). The mesocorticolimbic dopamine system – which includes the prefrontal cortex – is unique because not only are connections being formed and lost during adolescence, but there is also long-distance displacement of dopamine axons between brain regions. At the onset of adolescence, both mesolimbic and mesocortical dopamine axons innervate the nucleus accumbens in rodents, but the mesocortical axons leave the accumbens and grow towards the prefrontal cortex during adolescence and early adulthood (Hoops et al., 2018; Reynolds et al., 2018a). This is the only known case of axons growing from one brain region to another so late during development (Hoops and Flores, 2017).
The prolonged growth trajectory renders mesocortical dopamine axons particularly vulnerable to disruption. Environmental insults during adolescence (e.g. drug abuse) alter the extent and organization of dopamine innervation in the prefrontal cortex, leading to behavioural and cognitive changes in mice throughout adulthood (Drzewiecki and Juraska, 2020; Hoops and Flores, 2017; Reynolds and Flores, 2021). These changes often involve cognitive control, a prefrontal function that develops in parallel with dopamine innervation to the cortex in adolescence (Luna et al., 2015). Disruption of dopamine innervation frequently seems to result in “immature” cognitive control persisting through adulthood (Larsen and Luna, 2018).
Here, we examine the guidance of growing dopamine axons to the prefrontal cortex, and its timing. The guidance cue molecule Netrin-1, upon interacting with its receptor DCC, determines which dopamine axons establish connections in the nucleus accumbens and which ones leave this region to grow to the prefrontal cortex (Hoops and Flores, 2017; Reynolds and Flores, 2021). We hypothesized that the answers to how and when this extraordinary developmental feat is achieved may also lie in the Netrin-1 signalling system.
Part 1: Netrin-1 “paves the way” for dopamine axons in adolescence
To identify the route by which dopamine axons grow from the nucleus accumbens to the medial prefrontal cortex we visualized dopamine axons in the adult mouse forebrain. We observed that dopamine axons medial to the nucleus accumbens form a distinct bundle oriented dorsally towards the cortex (Figure 1A,B). Individual fibres can be seen crossing the boundary between the nucleus accumbens shell and this bundle (Figure 1C). We hypothesized that these are the fibres that grow to the prefrontal cortex during adolescence. If this is correct, the number of dopamine axons in the bundle should continue to increase until adulthood. To test this, we used a modified unbiased stereological approach (Kim et al., 2011) where axons are counted only if they crossed the upper and lower bounds of a counting probe. We also measured the average width of the dopamine axon bundle. We found, in both male and female mice, that the density of dopamine axons does not change between adolescence (21 days old) and adulthood (75 days old; Figure 1D). However, the width of the dopamine axon bundle does change, increasing between adolescence and adulthood (Figure 1E). These results indicate that the total number of dopamine axons passing through this bundle increases over adolescence and that dopamine axons grow to the medial prefrontal cortex via this route.
Next, we focussed on Netrin-1, a secreted protein that acts as a guidance cue to growing axons and is important for dopamine axon targeting in the nucleus accumbens in adolescence (Cuesta et al., 2020). Using unbiased stereology, we quantified the number of Netrin-1 expressing cell bodies along the dopamine axon route, and in an adjacent medial region as a control (Figure 1 F, G). We found that in adolescence there are more Netrin-1 positive neurons within the dopamine axon route than adjacent to it. Furthermore, along the axon route the density of Netrin-1 positive cells increases towards the medial prefrontal cortex, forming a dorsoventral gradient (Figure 1H). In adulthood, there remains a higher density of Netrin-1 positive cells along the dopamine route compared to the adjacent region, however the dorsoventral gradient is no longer present (Figure 1I).
To determine if Netrin-1 along the dopamine axon route is necessary for axon navigation, we silenced Netrin-1 expression in the dorsal peduncular cortex, the transition region between the septum and the medial prefrontal cortex, at the onset of adolescence (Figure 1J,K). In adulthood we quantified the number of dopamine axon terminals in the regions below and above the injection site. Silencing Netrin-1 did not alter dopamine terminal density below the injection, in the lateral septum (Figure 1L). In the infralimbic cortex, which is the first prefrontal cortical region the axons reach after the injection site, terminal density was reduced in the Netrin-1 knock-down group compared to controls (Figure 1L). The knock-down appears to erase the Netrin-1 path to the prefrontal cortex, resulting in dopamine axons losing their way and failing to reach their correct innervation target. We conclude that Netrin-1 expressing cells “pave the way” for the mesocortical dopamine axons.
We next examined how the Netrin-1 path may be important for behaviour. The dopamine input to the prefrontal cortex is a key factor in the transition from juvenile to adult behaviours that occurs in adolescence. We hypothesized that cognitive processes involving mesocortical dopamine function would be altered when these axons are misrouted in adolescence. To test our hypothesis we used the Go/No-Go behavioural paradigm. This test quantifies inhibitory control, which matures in parallel with the innervation of dopamine axons to the prefrontal cortex in adolescence (Casey et al., 2008; Klune et al., 2021; Luna et al., 2015; Paus, 2005; Reynolds and Flores, 2021; Spear, 2000) and it is impaired in adolescent-onset disorders like depression and schizophrenia (Catts et al., 2013; Clementz et al., 2016; McTeague et al., 2016; Millan et al., 2012).
At the onset of adolescence, we injected the Netrin-1 silencing, or a scrambled control virus, bilaterally into the dorsal peduncular cortex; in adulthood we tested the mice in the Go/No-Go task. This paradigm first involves discrimination learning and reaction time training (Supplementary Figure 1), followed by a Go/No-Go test consisting of “Go” trials where mice respond to a cue as previously trained and “No-Go” trials where mice must abstain from responding to the cue (Figure 1M). Correct responses to both trial types are reinforced with a food reward. We quantified the percent of “No-Go” trials where the mice incorrectly responded to the cue (“Commission Errors”) and the percent of “Go” trials where the mice correctly responded (“Rewards” or “Hits”; Supplementary Figure 2). The ability of mice to respond correctly overall to both trial types is quantified as the Correct Response Rate (Supplementary Figure 3) (Cuesta et al., 2019; Reynolds et al., 2018a, 2018b; Vassilev et al., 2021).
Mice injected with the Netrin-1 silencing virus differed from controls in their performance during “No-Go” trials. As the mice learn to withhold their responses over the course of the test, the number of commission errors they made in No-Go trials decreased in a sigmoidal fashion (Figure 1N). The upper and lower asymptotes of the sigmoidal curve quantify the number of commission errors committed during early and late test days, respectively, while the inflection point (ED50) indicates when mice start improving their ability to inhibit their behavior. Already at the start of the Go/No part of the task, the Netrin-1 silencing group make slightly fewer commission errors (Figure 1O) than control groups, although both groups begin to improve in the No-Go task at around the same time. However, the Netrin-1 silencing group achieved a substantially higher level of behavioural inhibition, quantified as a lower percentage of commission errors in the last test days (Figure 1Q), indicating an improved ability to withhold their behaviour on cue. These behavioural results demonstrate that the maturation of action impulsivity is sensitive to the organization of the ventro-dorsal Netrin-1 path that guides mesocortical dopamine axon growth. Deviations in this route lead to striking changes in the cognitive development that is characteristic of adolescence.
Part 2: UNC5C expression coincides with the onset of adolescence
When axons leave the nucleus accumbens during adolescence, they follow a Netrin-1 “path” through intermediate brain regions to reach their intended innervation target. However, only a small subset of the dopamine axons that have reached the nucleus accumbens by early adolescence leave; the vast majority stay and form connections in the accumbens throughout life (Reynolds et al., 2018a). The “decision making” process of whether to “stay” (in the accumbens) or “go” (to the cortex via the Netrin-1 path) happens during a narrow developmental window at the onset of adolescence (Reynolds et al., 2018b). It remains unknown how the timing of this process is determined.
In adolescence, dopamine neurons begin to express the repulsive Netrin-1 receptor UNC5C, and reduction in UNC5C expression appears to cause growth of mesolimbic dopamine axons to the prefrontal cortex (Auger et al., 2013; Manitt et al., 2010; Pokinko et al., 2015). Using immunohistochemistry, we assessed the expression of UNC5C on nucleus accumbens dopamine axons across development. In male mice, we found little expression of UNC5C on dopamine axons at the onset of adolescence (Figure 2A), while we did find UNC5C expression on dopamine axons in adults (Figure 2B). Remarkably, when we assessed this in females, we found dopamine axons already expressing UNC5C in the nucleus accumbens at the onset of adolescence (Figure 2D), similar to adult females (figure 2E), indicating that the onset of UNC5C expression on dopamine axons in the nucleus accumbens is sexually dimorphic, with an earlier emergence in females. We examined the nucleus accumbens in pre-adolescent female mice and indeed found little UNC5C expression on dopamine axons (Figure 2C). The onset of UNC5C expression in mesocorticolimbic dopamine axons is therefore peri-adolescent but occurs earlier in females than in males, consistent with the earlier emergence of adolescence in female rodents and the earlier onset of adolescence and puberty in humans (Wolf and Long, 2016).
Part 3: Environmental control of the timing of adolescence
We hypothesize that at the emergence of adolescence, UNC5C expression by dopamine axons in the nucleus accumbens signals the initiation of the growth of dopamine axons to the prefrontal cortex. We therefore examined whether the developmental timings of UNC5C expression and dopamine innervation of the prefrontal cortex are similarly affected by an environmental cue known to delay pubertal development in seasonal species.
Siberian hamsters (Phodopus sungorus) regulate many aspects of their behavior and physiology to meet the changing environmental demands of seasonality (Paul et al., 2008; Stevenson et al., 2017). In winter, they increase the thickness of their fur, exchange their brown summer coats for white winter ones, and undergo a daily torpor to conserve energy (Scherbarth and Steinlechner, 2010). In addition, adults suppress reproduction and juveniles delay puberty (Pevet, 1988; Yellon and Goldman, 1984), including developmental changes in gonadotropin releasing hormone neurons in the hypothalamus (Buchanan and Yellon, 1991; Heywood and Yellon, 1997). This seasonal plasticity is regulated by long or short periods of daylight (Heldmaier and Steinlechner, 1981; Hoffmann, 1978) and raises the possibility that aspects of adolescent development are sensitive to these environmental cues. To our knowledge, adaptive variation in the timing of adolescent neural development has never been recorded in any animal.
Here, we tested whether day length regulates when dopamine axons grow to the cortex, and whether the timing of UNC5C expression in the nucleus accumbens and adolescent changes in exploratory behavior are similarly affected.
3.i The seasonality of adolescence
Male hamsters were examined at three ages: 15 days old (±1), 80 days old (±10), and 215 days old (±20). We compared the density of the dopamine innervation to the medial prefrontal cortex in male hamsters housed under lighting conditions that replicate summer daylengths (long days, short nights) or winter daylengths (short days, long nights) (Figure 3A,B). We will refer to these two groups as “summer hamsters” and “winter hamsters” to emphasize the natural stimulus we are replicating in the laboratory environment. We confirmed that puberty is delayed in male winter hamsters compared to summer hamsters in the present experiment by measuring their gonadal weights across ages (Supplementary Figure 4).
In male summer hamsters, dopamine input density to the prefrontal cortex increases during adolescence, after 15 days old and before 80 days old (Figure 3C), consistent with dopamine axon growth in mice (Manitt et al., 2013, 2011; Reynolds et al., 2018a). Prefrontal cortex dopamine innervation in summer hamsters continues to increase after 80 days old (Figure 3C).
In male winter hamsters, dopamine innervation to the prefrontal cortex is delayed until after 80 days, which coincides with their delayed pubertal onset (Figure 3D, Supplementary Figure 2B). This is the first demonstration of an environmental cue shaping adolescent brain development.
We then examined UNC5C expression by dopamine axons in the nucleus accumbens in male summer and winter hamsters across age classes. UNC5C expression was apparent only after the onset of adolescence in summer hamsters (Figure 3E,F,G), as observed in male mice. However, UNC5C expression was delayed in male winter hamsters – this group did not show UNC5C expression in dopamine axons in the nucleus accumbens until after 80 days old (Figure 3H,I,J). This aligns with the delayed timing of mesocortical dopamine axon growth and pubertal onset in male winter hamsters and demonstrates that the emergence of UNC5C is a marker of adolescent onset in male mice.
A behaviour characteristic of adolescence is increased willingness to enter a novel environment, called exploratory behaviour (Arrant et al., 2013; Lynn and Brown, 2009); to measure this we used the light/dark test (Bourin and Hascoёt, 2003). Time spent in the light compartment is dopamine-dependent (Bahi and Dreyer, 2019; Gao and Cutler, 1993) and peaks in adolescence (Arrant et al., 2013). We assessed the developmental profile of exploratory behavior in the light/dark box test in summer and winter hamsters across adolescence. In male summer hamsters, the exploratory behavior increases across adolescence, peaks around 50 days, then subsequently declines (Figure 3K). However, the adolescent increase in exploratory behavior is protracted in winter hamsters: across the age range examined we observe a gradual, consistent increase in exploratory behaviour rather than a peak and decline.
We next assessed a cohort of 215-day old hamsters, for which both summer and winter male hamsters have undergone puberty and exhibit high levels of dopamine innervation of the prefrontal cortex (Figure 3C,D,G,J, Supplementary Figure 2B). In these hamsters, we find no difference in exploratory behaviour between the male summer and winter groups (Figure 3L), demonstrating that, after 80 days, exploratory behaviour begins to decline in male winter hamsters and that by 215 days it has declined to the same level as in summer hamsters. Male hamsters raised under summer-mimicking long days and winter-mimicking short days both ultimately make the transition to the adult behavioral phenotype.
3.ii An extraordinary case of decoupling puberty and adolescence
In parallel with males, we conducted equivalent experiments in female hamsters (Figure 4A,B). Under a summer-mimicking daylength, dopamine innervation to the medial prefrontal cortex increases between 15 and 80 days old, similar to male summer hamsters (Figure 4C). There is no further increase in innervation density after 80 days old, consistent with earlier adolescent development in females observed in other rodent species (Juraska and Willing, 2017; Kopec et al., 2018; Reynolds and Flores, 2021; Spear, 2000; Westbrook et al., 2018). We confirmed that puberty is delayed in female winter hamsters compared to summer hamsters by measuring their uterine weights across ages (Supplementary Figure 2A).
When housed under a winter-mimicking daylength, dopamine input density in the prefrontal cortex of female hamsters is not delayed as in males, but rather reaches adult levels prior to 15 days old (Figure 4D). We replicated this unexpected finding in a separate, independent cohort of female winter hamsters (Figure 4E). To our knowledge, this is the first time an intervention is shown to accelerate adolescent cortical development.
We then measured dopamine axon density in female winter hamsters at two earlier ages: 10 and 15 days old. Dopamine innervation increases during this period (figure 4F), well before normal adolescence and long before pubertal development. This is an extraordinary phenomenon: a key marker of adolescent neurodevelopment is accelerated and dissociated from puberty in female hamsters raised under winter-mimicking short days (Supplementary Figure 2A).
The early increase in prefrontal cortex dopamine terminals in winter females is followed by a dramatic reduction between 80 and 215 days old (Figure 4D,E). This overlaps with the delayed timing of puberty in these females (Butler et al., 2007; Supplementary Figure 2A). Synaptic pruning in the cortex is a well-known component of adolescent neural development across species (Huttenlocher, 1984; Koss et al., 2013; Petanjek et al., 2011). Under normal conditions, the effect of pruning on dopamine synapses is likely masked by the growth of new dopamine axons to the prefrontal cortex (Manitt et al., 2013, 2011; Reynolds et al., 2018a). In the case of female winter hamsters, we hypothesize that the growth of dopamine axons to the prefrontal cortex occurs early while synaptic pruning, including of dopamine synapses, appears to occur later. This leads to a remarkable dissociation between two cortical developmental processes that are normally simultaneous, the behavioural implications of which are unclear.
If the developmental onset of UNC5C expression determines the timing of dopamine innervation of the prefrontal cortex, then onset of UNC5C expression should also be advanced in female winter hamsters. Hence, we examined UNC5C expression at the same ages as we examined dopamine axon growth in female hamsters. At 10 and 15 days old, UNC5C expression is present only in the winter hamsters (Figure 4G,H,K,L), but at 80 and 215 days old, UNC5C expression is apparent in both summer and winter hamsters (Figure 4I,J,M,N).
We used the light/dark box test to examine potential exploratory behavioural implications of the extraordinary developmental trajectory we observed in the prefrontal cortex of female hamsters. In female summer and winter hamsters the adolescent increase and peak in exploratory behaviour occurs between the ages of 15 and 80 days, as it does in summer daylength males (Figure 4O). However, contrary to what we would expect, the peak in winter females is delayed compared to summer females. When we assessed an independent cohort of 215-day-old female hamsters, we found no difference in exploratory behaviour between groups (Figure 4R), indicating that, like males, female summer and winter hamsters both eventually reach the same adult level of exploratory behaviour.
In both sexes, hamsters housed under a summer-mimicking daylength showed an adolescent peak in exploratory behaviour at an age that we would predict based on results from other rodents (Arrant et al., 2013; Pietropaolo et al., 2004; Tanaka, 2015). When raised under a winter-mimicking daylength, hamsters of either sex show a protracted exploratory peak. In males, it is delayed beyond 80 days old, but the delay is substantially less in females. For dopamine and UNC5C neural markers, males delayed, whereas females advanced, adolescent neural development. Based on the delayed developmental profile in exploratory behavior, we predict that other adolescent neural changes are delayed in female winter hamsters. We hypothesize that the advanced dopamine/UNC5C neural development lessens the delay in peak exploratory behaviour of female winter hamsters compared to that of males.
Here we describe how the gradual growth of mesocortical dopamine axons marks adolescent development, and how this process uses guidance cues and is sensitive to sex and environment. Netrin-1 signalling provides the “stay-or-go” “decision making” conducted by dopamine axons that innervate the nucleus accumbens at the onset of adolescence (Cuesta et al., 2020). UNC5C expression by these dopamine axons marks the timing at which this decision is made. In mice, UNC5C expression coincides with sex differences in both adolescent and pubertal development. Females, which develop earlier, show earlier UNC5C expression in dopamine axons compared to males.
In hamsters, behavioural and developmental shifts in response to environmental cues occur in parallel with alterations in the timing of dopamine axon growth. As we show here, male hamsters raised under a winter-mimicking daylength delay not only puberty, but also adolescent dopamine and behavioural maturation. In contrast, female hamsters under identical conditions delay puberty but accelerate dopamine axon growth, a key marker of adolescent brain development. Behavioural shifts during adolescence appear to be delayed in these females, but less substantially than in male hamsters. Notably, under all conditions, the developmental timing of UNC5C expression corresponds to the timing of dopamine innervation of the prefrontal cortex.
In both mice and hamsters, the emergence of UNC5C expression coincides with the onset of dopamine axon growth to the prefrontal cortex, a key characteristic of the adolescent transition period. While previously we have shown that the Netrin-1 signalling in the nucleus accumbens is responsible for coordinating whether dopamine axons grow in adolescence (Reynolds and Flores, 2021), here we propose that Netrin-1 signalling is also key to determining how and when this marker of adolescence occurs.
We are grateful for the technical assistance of the Pathology Core, Centre for Phenogenomics, Toronto, Canada, and in particular Milan Ganguly and Gregory Ossetchkine, for their excellent histological assistance. Furthermore, we are grateful to Helen Cooper and Philip Vassilev for their critical and insightful readings of our manuscript.
Conceptualization: DH, MJP, CF
Data Curation: DH
Formal Analysis: DH
Investigation: DH, RFK, SS, EE, AH, TO, AD, MG, CP, JZ, KCS, LPL, QEC
Methodology: DH, MJP, CF
Resources: GL, MJP, CF
Supervision: DH, MJP, CF
Writing—original draft: DH
Writing—review & editing: DH, MJP, CF
National Institute on Drug Abuse grant R01DA037911 (CF)
Canadian Institutes of Health Research FRN: 156272 (CF)
Canadian Institutes of Health Research FRN: 170130 (CF)
National Science and Engineering Research Council of Canada RGPIN-2020-04703 (CF)
National Science Foundation IOS-1754878 (MJP)
National Science and Engineering Research Council of Canada PGSD3-415253-2012 (DH)
Quebec Nature and Technology Research Fund 208332 (DH)
National Science and Engineering Research Council of Canada PDF5171462018 (DH)
Authors declare that they have no competing interests.
Data and code availability
All data and code use in these analyses are available through the Open Science Framework (DIO 10.17605/OSF.IO/DU3H4).
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