Mesocorticolimbic Connectivity and Volumetric Alterations in Mutation Carriers.

TitleMesocorticolimbic Connectivity and Volumetric Alterations in Mutation Carriers.
Publication TypeJournal Article
Year of Publication2018
AuthorsVosberg DE, Zhang Y, Menegaux A, Chalupa A, Manitt C, Zehntner S, Eng C, DeDuck K, Allard D, Durand F, Dagher A, Benkelfat C, Srour M, Joober R, Lepore F, Rouleau G, Théoret H, Bedell BJ, Flores C, Leyton M
JournalJ Neurosci
Date Published2018 May 16

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 -haploinsufficient mice. The human volunteers were 20 mutation carriers, 16 relatives, and 20 unrelated healthy volunteers (UHVs; 28 females). The mice were 11 and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [: = 0.0005, () = 0.60; UHV: = 0.0029, = 0.48] and ventral medial prefrontal cortex (: = 0.0031, = 0.53; UHV: = 0.034, = 0.35); (2) lower novelty-seeking scores (: = 0.034, = 0.82; UHV: = 0.019, = 0.84); and (3) reduced striatal volume (: = 0.0009, = 1.37; UHV: = 0.0054, = 0.93). Striatal volumetric reductions were also present in mice, and these were seen during adolescence ( = 0.0058, = 1.09) and adulthood ( = 0.003, = 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 mutations might affect susceptibility to diverse neuropsychiatric disorders. Opportunities 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, , enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in -haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

Alternate JournalJ. Neurosci.
PubMed ID29712788
PubMed Central IDPMC5956985
Grant ListR01 DA037911 / DA / NIDA NIH HHS / United States