Summary: A family with a rare genetic mutation are helping researchers answer important questions about how the human brain is wired. The family, who share an altered copy of the DCC gene, have less connectivity between areas where dopamine neurons originate and their target sites.
Source: McGill Univeristy.
The study of a Quebec family with an unusual gene provides novel insight into how our brain is built and, according to the McGill led team of scientists, offers a better understanding of psychiatric disorders such as depression, addictions and schizophrenia.
Very little is known about how the human brain wires itself. Mouse studies conducted by Cecilia Flores, Professor in McGill’s Department of Psychiatry, have previously shown that the gene, DCC, helps dopamine producing cells in the developing adolescent brain make specific connections.
Building upon this work, a new study published in the Journal of Neuroscience by Professor Flores and Marco Leyton, who is also a professor in the Department of Psychiatry, shows that DCC seems to have the same effects in humans.
By scanning the brain of 20 family members who share an altered copy of DCC, the researchers found less connectivity between the areas where dopamine neurons originate (the substantia nigra and ventral tegmental area) and their target sites, such as the striatum and frontal cortex. One of these target sites – the striatum – was also smaller.
“It’s very interesting because we were able to show that this DCC gene alteration induces similar changes to the brain in both mice and humans,” says Cecilia Flores.
Because the brain systems affected by the gene influence responses to rewards, it was not surprising to see that the family members with the DCC mutation also have lower impulsivity traits and are less likely to smoke cigarettes. Indeed, an increasing number of studies, including those by Professor Flores’ team, link DCC to psychiatric conditions.
“Because the gene affects the brain’s dopamine pathways, which are implicated in schizophrenia, addiction and depression, our study potentially helps us understand how these disorders arise. The version of the gene inherited by the Québec family is probably protective, but other versions of the gene seem to increase risk. Our study helps us to understand why. It also provides clear evidence that a single gene has large effects on how the human nervous system is wired,” says Professor Leyton, senior author of the study.
Funding: This research was funded by the Canadian Institutes of Health Research and the National Institute on Drug Abuse.
Source: Katherine Gombay – McGill Univeristy
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract for “Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers” by Daniel E. Vosberg, Yu Zhang, Aurore Menegaux, Amanda Chalupa, Colleen Manitt, Simone Zehntner, Conrad Eng, Kristina DeDuck, Dominique Allard, France Durand, Alain Dagher, Chawki Benkelfat, Myriam Srour, Ridha Joober, Franco Lepore, Guy Rouleau, Hugo Théoret, Barry J. Bedell, Cecilia Flores and Marco Leyton in Journal of Neuroscience. Published May 16 2018
Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers
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.