DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence
Open accessAbstract
Background Dopaminergic input to the prefrontal cortex (PFC) increases throughout adolescence and, by establishing precisely localized synapses, calibrates cognitive function. However, why and how mesocortical dopamine axon density increases across adolescence remains unknown. Methods We used a developmental application of axon-initiated recombination to label and track the growth of dopamine axons across adolescence in mice. We then paired this recombination with cell-specific knockdown of the netrin-1 receptor DCC to determine its role in adolescent dopamine axon growth. We then assessed how altering adolescent PFC dopamine axon growth changes the structural and functional development of the PFC by quantifying pyramidal neuron morphology and cognitive performance. Results We show, for the first time, that dopamine axons continue to grow from the striatum to the PFC during adolescence. Importantly, we discover that DCC, a guidance cue receptor, controls the extent of this protracted growth by determining where and when dopamine axons recognize their final target. When DCC-dependent adolescent targeting events are disrupted, dopamine axons continue to grow ectopically from the nucleus accumbens to the PFC and profoundly change PFC structural and functional development. This leads to alterations in cognitive processes known to be impaired across psychiatric conditions. Conclusions The prolonged growth of dopamine axons represents an extraordinary period for experience to influ…
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DA terminals in the PFC develop throughout adolescence, and their development shapes the maturation of local circuits and calibrates adult cognitive function.
“DA terminals in the PFC are known to develop throughout adolescence, and their development shapes the maturation of local circuits and calibrates adult cognitive function [83, 145].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [83]
A highly pleiotropic effect of variation in DCC on diverse psychiatric disorders with childhood and adolescent onset would be consistent with its role in early organization of neuronal circuits and maturation of mesolimbic dopaminergic connections to the prefrontal cortex during adolescence.
“A highly pleiotropic effect of variation in DCC on diverse psychiatric disorders with childhood and adolescent onset would be consistent with its role in both early organization of neuronal circuits and the maturation of mesolimbic dopaminergic connections to the prefrontal cortex during adolescence (Hoops and Flores, 2017; Reynolds et al., 2018; Vosberg et al., 2018).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Reynolds et al., 2018
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- Authors
- Reynolds, L. M., Pokinko, M., Torres-Berrío, A., Cuesta, S., Lambert, L. C., Del Cid Pellitero, E., Wodzinski, M., Manitt, C., Krimpenfort, P., Kolb, B., & Flores, C.
- Affiliations
- Douglas Mental Health University Institute (CA)
- The Netherlands Cancer Institute (NL)
- University of Lethbridge (CA)
- Corresponding author
- Flores, Cecilia
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 83
- Issue
- 2
- Pages
- 181-192
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5723533
- OpenAlex
- W2626957219
- Cited by
- 129
- References
- 13
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 20 · 2023: 18 · 2022: 14 · 2021: 15 · 2020: 14 · 2019: 9 · 2018: 10 · 2017: 4
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-74709)
- Natural Sciences and Engineering Research Council of Canada (2982226)
- National Institute on Drug Abuse (R01DA037911, F31DA041188)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- DCC receptor, netrin-1, prefrontal cortex maturation, mesocortical dopamine pathway, axon guidance, adolescence, striatum, nucleus accumbens, axon growth, cognitive function, psychopathology risk
- MeSH terms
- DCC Receptor, Animals, Attention, Axons, Behavior, Animal, Inhibition, Psychological, Male, Nucleus Accumbens, Set, Psychology, Prefrontal Cortex, Maze Learning, Mice, Gene Knockdown Techniques, Dopaminergic Neurons
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