Insulin modulates the effects of early life adversity on executive functioning skills
Bibliographic record
Abstract
While the co-morbidity between metabolic and psychiatric disorders is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. Here, we demonstrate that individual differences in insulin functioning interact with ELA to modulate mesocorticolimbic dopaminergic-related executive functioning behavior in children and adults. First, we showed that the genetic background linked to fasting insulin (FI) interacts with postnatal adversity to predict impulsivity in childhood, which is a DA-related behavior. Second, since impulsivity is an endophenotype linked to the development of substance use disorders (SUDs), we also demonstrated that the same FI genetic background interacted with adversity to predict SUD and addiction related behaviors in adulthood. Third, using the sex-specific FI genome wide association studies, we established that the FI genetic background interacts with ELA to predict executive function psychopathology throughout development in a sex-specific manner. Furthermore, using mendelian randomization, we were able to establish a causal association between FI and impulsive behavior in females exposed to adversity. Lastly, we performed an exploratory mechanistic study in rodents to investigate the effect of early adversity and insulin on dopaminergic axonal growth pathways. Since the Netrin-1 guidance cue system participates in the maturation of the dopamine circuitry via its interaction with its DCC receptor, we showed that insulin action on miR-218, which is a negative DCC regulator, could be mediating the metabolic effects of early adversity on DCC expression in the medial prefrontal cortex of male rodents, which could potentially explain the resulting altered executive functioning behaviors. This work may contribute to the early identification of vulnerability to chronic adult diseases associated with early adversity, as well as inform on the mechanisms involved
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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 | 0.001 |
| 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) | 0.005 | 0.000 |
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".