23.2 NETRIN-1 RECEPTORS CONTROL MESOCORTICAL DOPAMINE CONNECTIVITY IN ADOLESCENCE
Bibliographic record
Abstract
Adolescence is an age of heightened vulnerability to develop psychiatric disorders that involve alterations in prefrontal cortex circuitry and cognitive dysfunction. The maturation of prefrontal cortex function is linked to the establishment of dopamine connectivity in this region. Development of mesocortical dopamine is a gradual process that continues until early adulthood. Because of its extended maturational course, this system is particularly susceptible to environmental influences. Yet there is a significant gap in our knowledge about the cellular and molecular mechanisms underlying adolescent prefrontal cortex dopamine development and how they are influenced by experience. We examined the role of the Netrin-1 guidance cue receptor, DCC, and its microRNA repressor, miR-218, on adolescent mouse prefrontal cortex development. We used axon-initiated recombination and cell-specific knock-down techniques to characterize the spatiotemporal growth of mesocortical dopamine axons and the role that DCC and miR-218 play in this process. Next, we assessed whether stimulant drugs in adolescence alter miR-218/DCC signaling, thereby disrupting mesocortical dopamine axon growth. Finally, we determined whether altered dopamine axon growth influences prefrontal cortex development by quantifying pyramidal neuron morphology and cognitive performance in adulthood. Here we show, for the first time, that dopamine axons continue to grow from the nucleus accumbens to the prefrontal cortex during adolescence. We discovered that DCC receptors control the extent of this protracted growth by determining where and when dopamine axons recognize their innervation target. Exposure to stimulant drugs or to stress leads to disruption of DCC-dependent adolescent targeting events, causing dopamine axons that should innervate the nucleus accumbens, to grow ectopically to the prefrontal cortex. This effect profoundly changes prefrontal cortex structural and functional development, producing alterations in cognitive processes known to be impaired across psychiatric conditions, including schizophrenia. Importantly, miR-218 controls DCC receptor expression in dopamine neurons across postnatal development and acts as a molecular mediator of the effects of stimulant drugs on prefrontal cortex development. The prolonged growth of dopamine axons during adolescence represents an extraordinary period for experience to influence their growth and predispose to or protect against psychopathology. MicroRNA control of DCC receptor in dopamine neurons is a molecular link where genetic and environmental factors seem to interact in adolescence to influence the development and function of the prefrontal cortex.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".