The development of minimally invasive direct readouts of neural activity is one of the greatest challenges facing neuroscience today. Our laboratory is leading efforts to enable high resolution functional magnetic reso- nance imaging (fMRI) of molecular-level phenomena using MRI contrast agents sensitive to hallmarks of neu- ral activity. Calcium-sensitive fMRI is of outstanding interest. Functional imaging performed with MRI calcium sensors would combine the noninvasiveness and whole-brain coverage of MRI with the molecular specificity and broad applicability of established optical calcium neuroimaging techniques. Calcium-dependent fMRI will be a breakthrough technique for analysis of neural circuits in animals, with potential longer term applications in humans. The technique could achieve near-cellular resolution and specificity to genetically-targeted cell popu- lations in conjunction with ultrahigh field MRI scanners and labeling techniques. In preliminary work funded by a first-cycle BRAIN Initiative grant, we successfully created a set of membrane permeable MRI contrast agents that interact with intracellular targets and can be selectively or nonselectively trapped inside cells using ester- ase cleavage-based mechanisms. By chemically fusing these agents to calcium chelating moieties, we were able recently to create the first MRI-detectable calcium sensors that accumulate inside cells and respond to modulation of intracellular calcium concentration in a manner that parallels behavior of optical sensors such as Fura-2. With these results in hand, we are now on the threshold of in vivo experiments to validate the sensors in animals and begin applying them for basic research. To tackle the next steps in this trajectory, we propose three Aims that address in vivo validation, improvements to calcium sensitivity and potency of the sensors, and integration of cell specific targeting capability into the probe designs. This work will bring calcium-dependent molecular fMRI technology from its current state of intermediate development to a form that will be broadly disseminable and applicable to many facets of neuroscience research. The likely impact of this work and our achievements to date make this next-generation neuroimaging project particularly suitable for BRAIN Initiative funding under RFA-NS-17-003.
Cellular-level noninvasive imaging of brain activity could be of immense utility to the study and diagnosis of neurological diseases. This proposal describes novel approaches to noninvasive neuroimaging that allow direct measures of cellular activity to be obtained using chemical contrast agents detectable by magnetic resonance imaging.
