THE ROLE OF LIPID-ASSOCIATED CIRCULATING MIRNAS IN THE INTERGENERATIONAL TRANSMISSION OF THE EFFECTS OF PARENTAL ADVERSE CHILDHOOD EXPERIENCES

Adverse childhood experiences (ACE) have lasting negative effects on adult physical and mental health, and growing evidence suggests that ACE-related behavioral and metabolic alterations can be transmitted across generations. This study investigates the role of lipid-associated circulating microRNAs (miRNAs) in mediating ACE effects to the germline for intergenerational transmission of behavioral and metabolic perturbations. ACE was modelled in mice using the well-established unpredictable maternal separation and stress (MSUS) paradigm with parallel modeling of lipid-modifying interventions; high fat diet (HFD) and voluntary exercise (VE). Intergenerational behavioral and metabolic phenotyping was performed across all cohorts of mice along with unbiased characterization of serum and sperm miRNAs through small RNA sequencing and RT-qPCR assays. Both MSUS and HFD were associated with robust intergenerational behavioral and metabolic effects, including impaired glucose tolerance, and increased despair and anxiety-like behaviors in the offspring. Cross-injection studies confirmed the contribution of lipid-associated circulating miRNAs in germline embedding and intergenerational transmission of phenotypes. Specifically, injecting lipid-associated miRNA carriers from MSUS into control male mice recapitulated anxiety-like phenotypes, as well as impaired glucose tolerance in their offspring. On the contrary, cross-injections of lipid-associated miRNA carriers from VE mice into MSUS partially mitigated the metabolic perturbations associated with MSUS. Together, these results provide 'proof-of-concept' evidence for the contribution of lipid-associated circulating miRNAs in the intergenerational transmission of ACE-related phenotypes. Ongoing studies are using conditional knock-out approaches in mice to further define the causal role of lipid-associated miRNAs in the intergenerational transmission of ACE effects.