Hippocampal subfields volumes, endocrine stress axis and early life stress in major depressive disorder

Introduction Hippocampus (HC) volume reductions have been a consistent finding in major depression (MDD). One possible mechanism that contribute to these reductions might be the inhibition of hippocampal neurogenesis through increased glucocorticoid stimulation following the chronic activation of the hypothalamo-pituitary stress axis (HPA) [1,2]. This is also supported by the fact that the resulting volume reductions can be partially reversed with antidepressant treatment [1,2] Furthermore, preclinical studies suggest that the effect of HPA dysregulation on hippocampal volume reduction, neurogenesis and their reversal by antidepressant response vary across hippocampal regions and are especially present in CA1, CA3 (atrophy of dendrites) and dentate gyrus (neurogenesis) [2]. Compatibly with this hypothesis, genetic variants influencing the endocrine stress axis in MDD, such as the FKBP5 glucocorticoid receptor regulator, were shown to be associated with brain structural changes, especially in the presence of environmental stressors such as early life stress (ELS) [3,4]. In accordance with the above mentioned findings we hypothesized that there might be a differential effect of early life stress on hippocampal subfields volumes in MDD patients with different allelic variants of FKBP5. To answer this question, we investigated whether patients exposed to childhood adversity and carrying the high-risk T allele of the rs1360780 polymorphism of FKBP5 showed smaller hippocampal volumes compared to C homozygous patients. Since CA1, CA3 and the dentate gyrus are especially affected by HPA axis alterations, we decided to focus on these hippocampal subfields. Methods We processed structural MRI data from 65 healthy controls (HC) and 91 MDD patients with automated hippocampal subfields segmentation using Freesurfer 5.3 for whole brain segmentation, followed by hippocampal subfields segmentation using Freesurfer 6 developer version. A quality check was performed using the ENIGMA hippocampal subfield protocols. We selected the following subfields for analysis: granule cells/molecular layer/dentate gyrus (GCMLDG), CA1, CA3, whole hippocampus (WH). ELS was evaluated with the Childhood Trauma Questionnaire Short Form. At least one mild expression of sexual abuse (subscale score > 7), emotional abuse (subscale score > 12) or physical abuse (subscale score > 9) was seen as having had a history of childhood abuse. We predicted the volume of each subfield using generalized linear scale response models, testing for the significance of between-group (diagnosis, ELS, allele status, age, sex, site, total intractranial volume) and within-group (side) factors. Results MDD patients showed reduced volume in all the subfields and in the total HC (p Conclusion In MDD, volume of CA1, CA3, DG and total HC was reduced. Patients with a high-risk variant in a glucocorticoid receptor regulator gene display smaller CA1 volumes in presence of ELS.