Abstract
Background
Dysregulation of GABAergic system was shown in anxiety, and inhibitory/excitatory homeostasis in cortico-limbic structures such as anterior cingulate cortex (ACC) was depicted crucial for affective regulation. Factors contributing to development and higher prevalence in women are however not known. Thus, we investigated effects of GAD65 polymorphism, a GABA synthetizing enzyme and sex on intrinsic brain activity and inhibition/ excitation balance in pregenual (pgACC) and mid cingulate (aMCC). Furthermore, we explored relationship to harm avoidance (HA), behavioral phenotype of anxiety.
Methods
105 healthy subjects (45 females, 40 G-carriers, age= 27.07±6.75) completed resting state fMRI, magnetic resonance spectroscopy (MRS) in 7T scanner, where GABA and glutamate (Glu) were measured, and HA questionnaire. Gene and sex interaction were analyzed with ANOVA for both local ACC brain activity and GABA/Glu levels. Further mediating effects of the regional GABA/Glu on a gene-HA relationship was explored with relevance to sex. Statistics was set at p<0.05, when appropriate corrected for multiple comparisons.
Results
We found increased intrinsic activity and decreased inhibition/ excitation balance for the AA variant in pgACC, which, for GABA/Glu was driven by genotype difference in females. Furthermore, pgACC GABA/Glu in females was negatively associated with HA. Lastly, there was an effect of sex on the mediation model, with again significance in women.
Conclusions
Our results show that gene and sex are factors contributing to region specific functional and metabolic associates of circuits of affect regulation. The observed interaction could be the basis of female- bias of anxiety disorders.
