Fetal neuronal extracellular vesicle biomarkers of in-utero effects of maternal cannabinoid use and human fetal brain development and neurobehavioral outcomes

This proposal aims to determine whether biomarkers in fetal central nervous system-derived extracellular vesicles (CNSEVs) are useful predictors of derangements in fetal neurodevelopment in women using cannabinoids during pregnancy compared to controls. NOT- DA-20-039: Notice of Special Interest (NOSI): Effects of Cannabis Use and Cannabinoids on the Developing Brain specifically requests translational projects that will enhance our understanding of the how cannabinoids affect both cellular and molecular events specific to neural plasticity and the impact of these alterations on subsequent cognition and behavior. Purification of CNSEVs from maternal blood allows noninvasive evaluation of fetal CNS cannabinoid targets without significant contamination from each other or non-CNS sources. The surface protein used to isolate fetal CNSEVs, Contactin-2/Tag-1 specifically targets neurons undergoing synaptic plasticity and has been validated with respects to its ability to specifically target fetal neurons with little contamination from maternal neurons or other organs. To achieve these goals pragmatically we have partnered with an ongoing NIH funded clinical cohort of 450 subjects (5RO1DA054722) that includes clinically relevant neurobehavioral outcomes including fetal fMRI between 35 and 37 weeks gestational age, Finnegan score at birth and measures of executive function at 12 and 24 months (Lab-TAB and Minnesota EF Task). The proposed project with focus on the identification of novel protein and miRNA biomarkers of these outcomes and sex differences in these biomarkers. The completion of this project with result in improved counseling of pregnant women regarding the safety of cannabis use in pregnancy, effective clinical/research tools for the ongoing non-invasive monitoring of the fetal brain over the course of pregnancy, and identify changes at the molecular/cellular level associated with cannabis use that may reveal novel targets for neuroprotection.