Metabolic Basis of Vulnerability to Adverse Childhood Experiences – MUSEACE

Adverse childhood experiences (ACEs) are a major risk factor for neuropsychiatric disorders later in life. Emerging evidence suggests that environmental factors—such as diet and physical activity—modify the long-term outcomes of ACEs. This project explores the role of peripheral lipids and associated non-coding RNAs in shaping vulnerability to the long-term consequences of ACEs through microglial modifications in the brain.

Our preliminary studies indicate that ACEs induce changes in serum lipid profiles and associated microRNAs in children who have recently experienced paternal loss and maternal separation (PLMS). Notably, children with PLMS who developed moderate to severe depressive symptoms (vulnerable to PLMS effects) exhibit reduced levels of high-density lipoproteins (HDL) as well as increased serum expression of miR-142-3p compared with PLMS children with no or mild depressive symptoms (resilient to PLMS effects).

Furthermore, in vitro studies have revealed that microglial function depends on lipid availability, particularly in the context of inflammatory and phagocytic responses. Additional differences in microglial phagocytic capacity were observed after stimulation with serum derived from PLMS-vulnerable children, with a sex-dependent effect. Building on these preliminary findings, the project will investigate the contribution of lipids and microglia to vulnerability and resilience mechanisms associated with ACEs. In mice exposed to ACEs in the form of maternal separation and unpredictable maternal stress (MSUS), dyslipidemia will be induced through a high-fat diet (HFD).

Microglial transcriptomics, lipidomics, and metabolomics will be performed in juvenile and adult mice, along with behavioural assessments in adulthood. The role of microglia in vulnerability to ACEs will be evaluated by repeating the MSUS and HFD paradigms in mice with genetically ablated microglial cells. Molecular pathways identified in these experiments will then be validated in a mouse model.

Translational validation will be carried out by stimulating human brain organoids containing microglia (MC-HBOs) with previously collected serum samples from three ethnically diverse human ACE cohorts. In the final phase of the project, preclinical studies in mice will assess the potential of lipid-modulating dietary supplements and miRNA-targeted interventions to enhance resilience against the long-term consequences of ACEs.