Longitudinal MRI imaging of clock gene expression in mice brains

PROJECT SUMMARY/ABSTRACT The ability to precisely track gene expression is fundamental to unraveling the complexities of brain function, elucidating the mechanisms underpinning neurological disorders, and devising targeted diagnostic and therapeutic interventions. While bioluminescent imaging (BLI) has traditionally been the primary method for monitoring gene expression in living animal models, it has inherent limitations such as limited optical signal penetration and reliance on external detectors. In contrast, magnetic resonance imaging (MRI) offers exceptional capabilities for deep tissue imaging and full-brain coverage. However, existing molecular MRI-based methods have been hampered by low signal-to-noise ratios or potential cell toxicity when sensor overexpressed. In this proposed project, we introduce an innovative optical MRI (oMRI) technique for the time-resolved visualization of gene expression patterns within living brains. This novel imaging approach harnesses the strengths of bioluminescent imaging for molecular specificity and sensitivity, in conjunction with MRI's capacity for 3- dimensional imaging and high spatiotemporal resolution. We achieve this by directly associating bioluminescent signals with hemodynamic MRI signals using optogenetic tools, allowing us to map the expression of target genes across both space and time. In Aim 1, we will implement the oMRI strategy to image rhythmic clock gene expression in living mouse brains, building on our already validated luciferase-opsin pair design. We expect the oMRI technique to detect differential Per2 expression levels in mice brains exposed to 12-hour light and dark cycles. This pioneering imaging strategy will establish a foundation for tracking Per2 and other core clock genes in the brain and significantly advance Alzheimer's disease research. In Aim 2, we will advance the oMRI toolkit and develop dual-channel gene expression imaging. This will allow us to study the longitudinal interactions of multiple molecular events during AD progression, particularly the relationship between clock gene disruptions and other AD pathological events. We anticipate that this novel MRI technique will revolutionize our understanding of the circadian system's role in AD development, paving the way for discovering biomarkers for early AD diagnosis and intervention.