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Vosberg, Daniel E.; Zhang, Yu; Menegaux, Aurore; Chalupa, Amanda; Manitt, Colleen; Zehntner, Simone; Eng, Conrad; DeDuck, Kristina; Allard, Dominique; Durand, France; Dagher, Alain; Benkelfat, Chawki; Srour, Myriam; Joober, Ridha; Lepore, Franco; Rouleau, Guy; Theoret, Hugo; Bedell, Barry J.; Flores, Cecilia and Leyton, Marco (2018): Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers. In: Journal of Neuroscience, Vol. 38, No. 20: pp. 4655-4665

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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 Dec (+ /+) 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 [DCC+/+: p = 0.0005, r(effect size) = 0.60;UHV: p = 0.0029, r = 0.48] and ventralmedial 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 in Dec (+/+) 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 which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.

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