Effect of stress gene-by-environment interactions on hippocampal volumes and cortisol secretion in adolescent girls.

OBJECTIVE: Adolescence is a time of increased susceptibility to environmental stress and mood disorders, and girls are particularly at risk. Genes interacting with the environment (G × E) are implicated in hypothalamic-pituitary-adrenal axis dysregulation, hippocampal volume changes and risk or resilience to mood disorders. In this study, we assessed the effects of stress system G × E interactions on hippocampal volumes and cortisol secretion in adolescent girls. METHODS: We recruited 229 girls aged 12-18 years, and scans were obtained from 202 girls. Of these, 76 had been exposed to higher emotional trauma (abuse or neglect). Hippocampal volumes were measured using Freesurfer and high-resolution structural magnetic resonance imaging scans. Saliva samples were collected for measurement of cortisol levels and genotyping of stress system genes: FKBP5, NR3C1 (both N = 194) and NR3C2 ( N = 193). RESULTS: Among girls with the 'G' allelic variant of the NR3C1 gene, those who had been exposed to higher emotional trauma had significantly smaller left hippocampal volumes ( N = 44; mean = 4069.58 mm3, standard deviation = 376.99) than girls who had been exposed to minimal emotional trauma with the same allelic variant ( N = 69; mean = 4222.34 mm3, standard deviation = 366.74). CONCLUSION: In healthy adolescents, interactions between emotional trauma and the 'protective' NR3C1 'GG' variant seem to induce reductions in left hippocampal volumes. These G × E interactions suggest that vulnerability to mood disorders is perhaps driven by reduced 'protection' that may be specific to emotional trauma. This novel but preliminary evidence has implications for targeted prevention of mood disorders and prospective multimodal neuroimaging and longitudinal studies are now needed to investigate this possibility.

The association between the oxytocin receptor gene (OXTR) and hypnotizability.

Hypnosis has puzzled scientists for centuries, and particularly the reason why some people are prone to engaging in suggested experiences discordant with external reality. Absorption in internal experience is one key component of the hypnotic response. The neuropeptide oxytocin has been posited to heighten sensitivity to external cues, and it is possible that individual differences in oxytocin-related capacity to engage in external or internal experiences influences hypnotic response. To test this proposal, 185 Caucasian individuals provided saliva samples for analysis of polymorphisms in the oxytocin receptor gene, COMT, and independently completed standardized measures of hypnotizability and absorption. Participants with the GG genotype at rs53576 were characterized by lower hypnotizability and absorption scores than those with the A allele; there was no association between hyponotizability and COMT. These findings provide initial evidence that the capacity to respond to suggestions for altered internal experience is influenced by the oxytocin receptor gene, and is consistent with evidence that oxytocin plays an important role in modulating the extent to which people engage with external versus internal experiences.

Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: evidence from cognition, the P300 and fronto-hippocampal systems.

In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.