Prenatal Maternal Stress From a Natural Disaster and Hippocampal Volumes: Gene-by-Environment Interactions in Young Adolescents From Project Ice Storm.

Gene-by-environment interactions influence brain development from conception to adulthood. In particular, the prenatal period is a window of vulnerability for the interplay between environmental and genetic factors to influence brain development. Rodent and human research demonstrates that prenatal maternal stress (PNMS) alters hippocampal volumes. Although PNMS affects hippocampal size on average, similar degrees of PNMS lead to different effects in different individuals. This differential susceptibility to the effects of PNMS may be due to genetic variants. Hence, we investigated the role of genetic variants of two SNPs that are candidates to moderate the effects of PNMS on hippocampal volume: COMT (rs4680) and BDNF (rs6265). To investigate this, we assessed 53 children who were in utero during the January 1998 Quebec ice storm. In June 1998 their mothers responded to questionnaires about their objective, cognitive, and subjective levels of stress from the ice storm. When children were 11 1/2 years old, T1-weighted structural magnetic resonance imaging (MRI) scans were obtained using a 3T scanner and analyzed to determine hippocampal volumes. We collected and genotyped the children's saliva DNA. Moderation analyses were conducted to determine whether either or both of the SNPs moderate the effect of PNMS on hippocampal volumes. We found that objective hardship was associated with right hippocampal volume in girls, and that the BDNF and COMT genotypes were associated with left hippocampal volume in boys and girls. In addition, SNPs located on COMT moderated the effect of maternal objective distress in boys, and subjective distress in girls, on both right hippocampal volume. Thus, we conclude that an individual's genotype alters their susceptibility to the effects of PNMS.

Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a DCC-dependent manner.

Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.