Emotional Stability Interacts with Cortisol Levels Before fMRI on Brain Processing of Fearful Faces.

Functional-Magnetic-Imaging (fMRI) is widely adopted to investigate neurophysiological correlates of emotion processing (EP). However, studies have reported that scanning procedures in neuroimaging protocols may increase or cause anxiety and psychological distress related with the scanning, thus inducing peripheral cortisol release. These phenomena may in turn impact on brain EP. Additionally, previous findings have indicated that inter-individual differences in stress-response intensity are mediated by levels of Emotional Stability (ES), a personality trait that has been associated with brain activity during EP, especially in amygdala and prefrontal cortex (PFC). The aim of this study was to investigate the interaction between indices of stress related to anticipation of fMRI scanning and levels of ES on amygdala and PFC activity during EP. With this aim, 55 healthy volunteers were characterized for trait ES. Furthermore, salivary cortisol levels at baseline and soon before fMRI scanning were measured as an index of stress related to scanning anticipation. During fMRI, participants performed an explicit EP task. We found that variation in salivary cortisol (Δc) interacts with ES on left amygdala and PFC activity during EP. More in details, in the context of a higher ES, the greater the Δc, the lower the activity in left amygdala and PFC. In the context of lower ES, the opposite Δc-brain activity relationship was found. Our results suggest that the stressful potential of fMRI interacts with personality traits in modulating brain activity during EP. These findings should be taken into account when interpreting neuroimaging studies especially exploring brain physiology during EP.

Genetic variation is associated with RTN4R expression and working memory processing in healthy humans.

The Nogo receptor (NgR) is implicated in neurodevelopmental processes and it participates in inhibiting axonal growth. Consistent with its high levels of expression in the prefrontal cortex, animal studies indicate that NgR is relevant for prefrontal-related cognitive processing. Given that genetic variation may alter mechanisms of gene expression impacting molecular and systems-level phenotypes, we investigated the association of genetic variation with the expression of the NgR coding gene (RTN4R), as well as with prefrontal correlates at progressively greater biological distance from gene effects. First, we studied the association of single nucleotide polymorphisms (SNPs) with RTN4R mRNA expression in postmortem prefrontal cortex of humans without psychiatric illnesses. Then, we probed in peripheral blood mononuclear cells (PBMCs) the association that we found in prefrontal tissue. Thus, we investigated whether functional genetic variation affecting RTN4R expression is also associated with prefrontal activity during working memory. We found that rs696884 (A/G) predicted these phenotypes. Specifically, the AA genotype was associated with lower RTN4R mRNA expression levels in the prefrontal cortex and PBMCs and inefficient prefrontal activity during working memory compared to the GG genotype. These results suggest that genetic variation associated with RTN4R mRNA expression influences prefrontal physiology in healthy individuals. Furthermore, they highlight the need for further investigations of the role of NgR in the pathophysiology of brain disorders associated with prefrontal dysfunction.

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.

Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.

Association of GSK-3ß genetic variation with GSK-3ß expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia.

OBJECTIVE Glycogen synthase kinase 3ß (GSK-3ß) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3ß gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3ß functional variation with 1) GSK-3ß mRNA expression from postmortem prefrontal cortex, 2) GSK-3ß and ß-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3ß (rs12630592) was associated with reduced GSK-3ß mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3ß protein expression and kinase activity, as well as with downstream effects on ß-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3ß variation is implicated in multiple phenotypes relevant to schizophrenia.