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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 in Dcc-haploinsufficient mice. The human volunteers were 20 DCC^+/− mutation carriers, 16 DCC^+/+ relatives, and 20 DCC^+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc^+/− and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC^+/− carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum …