2024 Articles

Dentate Gyrus Microstructure Is Associated With Resilience After Exposure to Maternal Stress Across Two Human Cohorts

Van Dijk, Milenna T.; Talati, Ardesheer; Kashyap, Pratik; Desai, Karan; Kelsall, Nora C.; Gameroff, Marc J.; Aw, Natalie; Abraham, Eyal; Cullen, Breda; Cha, Jiook; Anacker, Christoph; Weissman, Myrna M.; Posner, Jonathan

Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we test across two independent cohorts whether MS is associated with depressive symptoms and with DG micro- and macro-structural alterations in offspring. Methods: We analyzed DG DTI mean diffusivity (DG-MD) and volume in a 3-Generation Family Risk for Depression study (TGS; n=69, mean age 35.0) and the Adolescent Brain Cognitive Development Study (ABCD; n=5196, mean age 9.9) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (in TGS) and a measure compiled from the Adult Response Survey (ABCD). PHQ-9 and rumination scales (TGS) and Child Behavior Checklist (ABCD) measured offspring depressive symptoms at follow-up. Schedule for Affective Disorders and Schizophrenia–Lifetime interview measured depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (TGS) and 1-year (ABCD) after MRI. In ABCD, DG-MD is increased in high-MS offspring who have depressive symptoms at follow-up, but not in offspring who remain resilient or whose mother had low MS. Conclusions: Converging results across two independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.