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J Neurosci. 2018 May 16;38(20):4655-4665. doi: 10.1523/JNEUROSCI.3251-17.2018. Epub 2018 Apr 30.

Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers.

Author information

1
Department of Psychiatry.
2
Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3A 0G4, Canada.
3
Department of Neurology and Neurosurgery.
4
Douglas Mental Health University Institute, Montreal, Quebec H4H 1R3, Canada.
5
Department of Psychology, General and Experimental Psychology, and.
6
Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität München, 80802 Munich, Germany.
7
Biospective, Montreal, Quebec H3B 2T9, Canada.
8
Département de psychologie, Université de Montréal, Montreal, Quebec H2V 2S9, Canada.
9
Department of Psychiatry, marco.leyton@mcgill.ca cecilia.flores@mcgill.ca.

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 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 [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 in Dcc+/- 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.SIGNIFICANCE STATEMENT 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, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

KEYWORDS:

axon guidance; brain morphometry; diffusion MRI; genetics; nicotine; personality

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