Mesocorticolimbic Connectivity and Volumetric Alterations in<i>DCC</i>Mutation Carriers
Bibliographic record
Abstract
The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected inDcc-haploinsufficient mice. The human volunteers were 20DCC+/−mutation carriers, 16DCC+/+relatives, and 20DCC+/+unrelated healthy volunteers (UHVs; 28 females). The mice were 11Dcc+/−and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the humanDCC+/−carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+:p= 0.0005,r(effect size) = 0.60; UHV:p= 0.0029,r= 0.48] and ventral medial prefrontal cortex (DCC+/+:p= 0.0031,r= 0.53; UHV:p= 0.034,r= 0.35); (2) lower novelty-seeking scores (DCC+/+:p= 0.034,d= 0.82; UHV:p= 0.019,d= 0.84); and (3) reduced striatal volume (DCC+/+:p= 0.0009,d= 1.37; UHV:p= 0.0054,d= 0.93). Striatal volumetric reductions were also present inDcc+/−mice, and these were seen during adolescence (p= 0.0058,d= 1.09) and adulthood (p= 0.003,d= 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through whichDCCmutations might affect susceptibility to diverse neuropsychiatric disorders. SIGNIFICANCE STATEMENTOpportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene,DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated inDCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".