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Cited by 137Neurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology StudiesNeuroscience and Neuropharmacology Research

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Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

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Reynolds, Lauren M., Flores, Cecilia·2021·Frontiers in Neural Circuits
DOI 10.3389/fncir.2021.735625PMC PMC8456011
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Abstract

Mesocorticolimbic dopamine circuity undergoes a protracted maturation during adolescent life. Stable adult levels of behavioral functioning in reward, motivational, and cognitive domains are established as these pathways are refined, however, their extended developmental window also leaves them vulnerable to perturbation by environmental factors. In this review, we highlight recent advances in understanding the mechanisms underlying dopamine pathway development in the adolescent brain, and how the environment influences these processes to establish or disrupt neurocircuit diversity. We further integrate these recent studies into the larger historical framework of anatomical and neurochemical changes occurring during adolescence in the mesocorticolimbic dopamine system. While dopamine neuron heterogeneity is increasingly appreciated at molecular, physiological, and anatomical levels, we suggest that a developmental facet may play a key role in establishing vulnerability or resilience to environmental stimuli and experience in distinct dopamine circuits, shifting the balance between healthy brain development and susceptibility to psychiatric disease.

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Figure 1 Adolescence and Puberty timing in humans and rodents. (A) Timeline of adolescence (shaded lines) and puberty (darker portions of the lines) in girls (♀) and boys (♂), adapted from Hollenstein and Lougheed (2013); Sawyer et al. (2018); and Brix et al. (2019). (B) Adolescence (shaded lines) and puberty (darker portions of the lines) timing in female (♀) and male (♂) rodents, adapted from Vetter-O’Hagen and Spear (2012) and Schneider (2013).
Figure 1 Adolescence and Puberty timing in humans and rodents. (A) Timeline of adolescence (shaded lines) and puberty (darker portions of the lines) in girls (♀) and boys (♂), adapted from Hollenstein and Lougheed (2013); Sawyer et al. (2018); and Brix et al. (2019). (B) Adolescence (shaded lines) and puberty (darker portions of the lines) timing in female (♀) and male (♂) rodents, adapted from Vetter-O’Hagen and Spear (2012) and Schneider (2013).CC BY · PubMed Central
Figure 2 Mesocorticolimbic dopamine system organization. (A) Two-dimensional rendering of the mesocorticolimbic DA pathway (black) and the major nuclei of interest in the horizontal plane. (B) Sagittal view of the mesocorticolimbic DA pathway (black) and the major nuclei, with the STR semi-transparent in the foreground. Two-dimensional representations were adapted from the three-dimensional regions of interest in the Allen brain atlas (Wang et al., 2020). PFC, prefrontal cortex; NAc, nucleus accumbens; STR, dorsal striatum; MFB, medial forebrain bundle; VTA, ventral tegmental area.
Figure 2 Mesocorticolimbic dopamine system organization. (A) Two-dimensional rendering of the mesocorticolimbic DA pathway (black) and the major nuclei of interest in the horizontal plane. (B) Sagittal view of the mesocorticolimbic DA pathway (black) and the major nuclei, with the STR semi-transparent in the foreground. Two-dimensional representations were adapted from the three-dimensional regions of interest in the Allen brain atlas (Wang et al., 2020). PFC, prefrontal cortex; NAc, nucleus accumbens; STR, dorsal striatum; MFB, medial forebrain bundle; VTA, ventral tegmental area.CC BY · PubMed Central
Figure 3 Adolescent maturation of dopamine connectivity and function in the prefrontal cortex. (A) Summary of maturational changes in DA connectivity in the PFC across adolescence. (B) Early in adolescence DA signaling through D1 receptors is excitatory onto both classes of neurons, with DA signaling through D2 receptors inhibiting pyramidal neurons and weakly inhibiting GABAergic interneurons. In mid-adolescence DA signaling through D2 receptors becomes excitatory onto GABAergic interneurons. DA signaling through D1 receptors is now able to interact with glutamatergic NMDA receptors on pyramidal neurons, increasing the activating effect of DA. In adulthood D1 and D2 receptor populations attain their mature function.
Figure 3 Adolescent maturation of dopamine connectivity and function in the prefrontal cortex. (A) Summary of maturational changes in DA connectivity in the PFC across adolescence. (B) Early in adolescence DA signaling through D1 receptors is excitatory onto both classes of neurons, with DA signaling through D2 receptors inhibiting pyramidal neurons and weakly inhibiting GABAergic interneurons. In mid-adolescence DA signaling through D2 receptors becomes excitatory onto GABAergic interneurons. DA signaling through D1 receptors is now able to interact with glutamatergic NMDA receptors on pyramidal neurons, increasing the activating effect of DA. In adulthood D1 and D2 receptor populations attain their mature function.CC BY · PubMed Central
Figure 4 Mesocortical axon growth in adolescence revealed by an intersectional viral labeling technique. (A) Spatiotemporally specific labeling of DA neurons with axons present in the NAc at PND21 reveals that DA axons continue to grow to the PFC in adolescence. (B) Labeled DA axons are not found in the PFC of mice when subjected to the same manipulation in adulthood, supporting previous findings that DA neurons do not commonly send collaterals between these regions.
Figure 4 Mesocortical axon growth in adolescence revealed by an intersectional viral labeling technique. (A) Spatiotemporally specific labeling of DA neurons with axons present in the NAc at PND21 reveals that DA axons continue to grow to the PFC in adolescence. (B) Labeled DA axons are not found in the PFC of mice when subjected to the same manipulation in adulthood, supporting previous findings that DA neurons do not commonly send collaterals between these regions.CC BY · PubMed Central
Figure 5 Development of mesolimbic dopamine connectivity and function in the adolescent striatum. Summary of maturational changes in DA connectivity in the STR across adolescence. *Indicates that these findings are sex-dependent, with this pattern of receptor overexpression and pruning only seen in male rodents.
Figure 5 Development of mesolimbic dopamine connectivity and function in the adolescent striatum. Summary of maturational changes in DA connectivity in the STR across adolescence. *Indicates that these findings are sex-dependent, with this pattern of receptor overexpression and pruning only seen in male rodents.CC BY · PubMed Central
Figure 6 Dopamine as a “plasticity system”: convergent mechanistic processes shape adolescent mesocorticolimbic dopamine maturation in response to environmental cues. In this review, we identify three mechanistic processes that contribute to the adolescent establishment of DA pathways. We comment on how each of these processes may link experiential factors to alterations in DA development.
Figure 6 Dopamine as a “plasticity system”: convergent mechanistic processes shape adolescent mesocorticolimbic dopamine maturation in response to environmental cues. In this review, we identify three mechanistic processes that contribute to the adolescent establishment of DA pathways. We comment on how each of these processes may link experiential factors to alterations in DA development.CC BY · PubMed Central

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  1. Björklund, 1984, Dopamine-containing system in the CNS, 55

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Metadata

Authors
Reynolds, L. M., & Flores, C.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Douglas Mental Health University Institute (CA)
Corresponding author
  • Reynolds, Lauren M.
  • Flores, Cecilia
ORCID
Venue
Frontiers in Neural Circuits
Publisher
Frontiers Media SA
Published
2021-09-08
Volume
15
Pages
735625-735625
ISSN
1662-5110 (ISSN-L)
DOI
10.3389/fncir.2021.735625
PMC
PMC8456011
OpenAlex
W3198497866
Cited by
137
References
259
Citations by year
2026: 29 · 2025: 25 · 2024: 40 · 2023: 28 · 2022: 14 · 2021: 1
FWCI
3.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neural Circuits (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institute on Drug Abuse
  • Canadian Institutes of Health Research
  • Institut National de la Santé et de la Recherche Médicale
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
mesocorticolimbic dopamine system, adolescent brain development, environmental influences on brain development, reward processing, motivation, cognitive function, psychiatric vulnerability, resilience
MeSH terms
Adolescent, Brain, Dopamine, Humans, Reward, Dopaminergic Neurons

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