Brainmap: Molecular fMRI
Alan Jasanoff, Ph.D.
Department of Biological Engineering
Massachusetts Institute of Technology, USA
Comprehensive analysis of brain function depends on understanding the dynamics of diverse neural signaling processes over large tissue volumes in intact animals and humans. Most existing approaches to measuring brain signaling suffer from limited tissue penetration, poor resolution, or lack of specificity for well-defined neural events. Here we describe our efforts to establish a new approach to brain activity mapping that achieves a combination of molecular specificity and comprehensiveness using a novel functional imaging technique, “molecular fMRI,” in which neural processes are studied using MRI-detectable sensors for signaling molecules in the brain. I focus particularly on contrast agents designed to detect neurotransmitters and on genetically encodable sensors for intracellular signalling. In our neurotransmitter imaging approaches, we used protein engineering to generate contrast agents that allow the monoamines dopamine and serotonin to be measured by MRI. We combined the dopamine sensor with brain stimulation techniques to map signalling patterns in the ventral striatum of rats, and are trying to understand how these patterns relate to stimulus properties and to readouts obtained using conventional functional MRI. Using the serotonin sensor, we are mapping neurotransmitter reuptake processes and studying their modulation by pharmacological agents. Ongoing research aims at producing analogous neurotransmitter sensors with greater target sensitivity. Our work on genetically encodable sensors revolves largely around variants of endogenous iron storage proteins, which we have modified to produce MRI changes in response to kinase activity or calcium ion concentration changes. We demonstrate results with magnetically-enhanced proteins expressed in cells. I discuss limitations of current techniques and foreshadow attempts to create improved forms of molecular fMRI.