AVATar · Engineering vasoactive probes for brain-wide imaging of molecular signaling

Brain function depends on spatiotemporally defined brain-wide signaling via molecules such as neurotransmitters. No current technology can measure signaling molecules throughout the brain with sufficient spatial and temporal resolution in living mammals. This poses a major roadblock for understanding how molecular neuronal communication coordinates whole-brain function.Magnetic resonance imaging (MRI) currently provides the highest brain-wide resolution. Dynamic imaging of blood flow and oxygenation in the finely arborized vasculature, so-called functional MRI (fMRI), is the only method that can visualize whole-brain function in mammals and humans. However, MRI is inherently insensitive, which precludes it from accessing molecular signaling that occurs at (sub)micromolar concentrations and fMRI cannot resolve neurotransmitter signaling underlying measured hemodynamic signals.I previously designed protein-based vasoactive sensors, named AVATar, that directly cause hemodynamic signals in fMRI in response to target molecules at low nanomolar doses, without using radioactive or metallic components. They can be genetically encoded and also pave the way for noninvasive brain delivery through the vasculature, critical for translational applications in primates and humans.Here, I will combine my expertise in synthetic biology and in vivo molecular imaging to develop my proof-of-concept work into a robust preclinical neuroimaging method along three objectives:1) Engineering AVATars that convert neurotransmitter signaling into hemodynamic signals.2) Brain delivery via non-invasive routes.3) Application for fMRI of brain-wide neurotransmitter signaling in rodents.My project will provide neurotransmitter-sensing AVATars to turn fMRI into molecular fMRI and bridge the long-standing gap between molecular nuclear imaging and functional hemodynamic imaging. AVATars will visualize how brain-wide molecular signaling dynamics shape healthy and pathological brain function.