Mesocorticolimbic Connectivity and Volumetric Alterations inDCCMutation Carriers

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 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.

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

“…The associations between DCC and psychiatric disorders might be a consequence of DCC-related alterations to mesocorticolimbic pathways. As predicted, our group revealed that DCC haploinsufficient members of the Quebec family, as compared with control groups without the mutation (i.e., both relatives and unrelated healthy volunteers) exhibit striking reductions in anatomical connectivity, assessed using diffusion MRI probabilistic tractography, from the SN/VTA to both the ventral striatum and ventral mPFC [79].…”

“…The DCC haploinsufficient Quebecers have an adult behavioral phenotype that shares two striking features with adult Dcc haploinsufficient mice [79]. First, the adult DCC haploinsufficient humans exhibit reduced novelty seeking personality traits [79]. Second, compared with their unaffected relatives, the DCC haploinsufficient humans smoke less tobacco yet use similar amounts of alcohol and cannabis [79], consistent with the evidence in mice that DCC's effects are specific to stimulant drugs.…”

“…First, the adult DCC haploinsufficient humans exhibit reduced novelty seeking personality traits [79]. Second, compared with their unaffected relatives, the DCC haploinsufficient humans smoke less tobacco yet use similar amounts of alcohol and cannabis [79], consistent with the evidence in mice that DCC's effects are specific to stimulant drugs. Notably, cigarette smoking increases dopamine transmission in humans [80] while lowered dopaminergic tone can decrease smoking [81], indicating that an altered smoking phenotype could reflect alterations to the dopamine system.…”

“…We recently reported that both DCC haploinsufficient humans and mice exhibit reduced striatal volumes. While these effects occur in the NAcc in mice, they are localized to the putamen in humans [79]. These effects were also identified in largescale GWAS investigations.…”

“…As in Dcc haploinsufficient mice, robust anatomical and behavioral phenotypes are observed as a consequence of human DCC haploinsufficiency, underscoring the sensitivity of the system. The DCC haploinsufficient Quebecers have an adult behavioral phenotype that shares two striking features with adult Dcc haploinsufficient mice [79]. First, the adult DCC haploinsufficient humans exhibit reduced novelty seeking personality traits [79].…”