Project 3. Circular RNAs that underlie neuroimmune dysregulation and cognitive deficits from prenatal alcohol exposure

Emerging evidence from both preclinical and clinical studies supports that the biological vulnerability to chronic central nervous system (CNS) dysfunction in FASD populations is driven by aberrant CNS-immune interactions, rendering them particularly susceptible to developing cognitive disabilities during the period of adolescence, often manifesting after secondary challenges such as stress or immune challenges. While the underlying mechanism of adolescent cognitive deficits from prenatal alcohol exposure (PAE) is unknown, the proposed research will identify whether non-coding circular RNAs underlie sensitized CNS-inflammatory immune signaling pathways, potentially inclusive of TLR4-associated factors from PAE that lead to cognitive deficits. Exploring these novel molecular targets in preclinical models, along with leveraging clinical data from adolescent children with FASD, will provide a foundation to develop future therapeutic targets to treat adolescent cognitive deficits as well as identify biomarkers of adolescent cognitive dysfunction for early intervention to mitigate the impact PAE exerts on cognitive function.

Circular RNAs and Immune Factors in Adolescents​

• Investigating circRNAs and associated immune factors in the brain and blood of adolescent mice.​
• Extending the study to saliva or blood samples from human adolescents with FASD.​
• Focusing on the action of the toll-like 4 (TLR4) immune receptor and its role in cognitive deficits triggered by stressors.​

Cognitive Impact of Stress and Immune Activation​

• Assessing visuospatial memory deficits induced by acute isolation or direct immune activation.​
• Characterizing multiple brain regions, including the prefrontal cortex and thalamus.​

Hypotheses and Objectives​

• Hypothesizing that circular RNAs could serve as regulators and biomarkers of immune-brain dysregulation due to prenatal alcohol exposure.​
• Evaluating the impact of prenatal alcohol exposure on circular RNAs associated with TLR4-related mRNAs and proteins in adolescent mouse blood and brain, and in human adolescent saliva and blood during cognitive tasks and magnetoencephalography evaluations.​

Cross-Species and Cross-Component Correlation​

• Complementing other projects by evaluating cognitive function in early and middle adolescence, predicting deficits in later stages.​
• Correlating circular RNA, mRNA, and protein analyses in adolescent mice with data from young adult mice and human adolescents.​
• Identifying potential biomarkers for FASD by linking newly identified circular RNAs with mRNA/protein immune factors and cognitive function​