Whole brain, PET-based molecular neuroimaging of fos expression – a new tool for imaging neurocircuitry involved in complex behavior - Abstract: The brain is the most complex organ in the body, controlling a wide range of conscious and unconscious functions through a complex network of neural circuits that communicate with each other. Despite significant neuroscience advancements, we lack a full understanding of which neural circuits work together to produce specific functions or behaviors, or how these circuits process information into complex cognitive and behavioral functions. Non-invasively and repeatedly measuring the location and activity of neuronal circuits throughout the entire brain in response to stimuli or complex tasks is crucial to improving our comprehension of how the brain dynamically processes neural information in both normal and abnormal conditions. We propose an innovative PET molecular neuroimaging technique for non-invasively imaging whole brain neurocircuitry in awake mammals, identifying neuronal circuits involved in complex behaviors and cognitive tasks that can be performed outside the confines of an MRI or a PET. The premise of this technology is the paired use of a clinical positron emission tomography (PET) imageable molecular probe that is intrinsically brain-penetrant, 18F-fluoroethyl-tyrosine (18F-FET), with neuronal activity-dependent expression of LAT1, a transporter that influxes 18F-FET, as reporter protein. LAT1, expressed downstream of fos in activated neurons in genetically engineered animals, will accumulate brain penetrant 18F-FET and trap it intracellularly. Accumulated 18F-FET is then imaged by PET to unambiguously map the expression of the transporter, enabling activity-dependent imaging of cells and elucidating activity of the underlying circuits. Neural activity is encoded in fully awake animals during a complex task one day and read out in the scanner the next day. This is, in essence, the first method for serially and non-invasively imaging fos expression, and hence activated neurons in vivo, over whole mammalian brains. This paradigm will enable a wide-ranging set of novel measurements in preclinical and translational sciences, currently only observable and/or measurable by histology or inferred by a surrogate test. For instance, this technology could be used in research to uncover neurocircuitry activated differentially over time during longitudinal experiments like chronic exposure to drugs or stress, or during different stages of brain development, or throughout the progression of neurological diseases like Parkinson’s disease. Successful demonstration in mice will rationalize the translation of this paradigm to pigs. Indeed, the significance of this tool in studying adaptations of neural circuitry becomes more prominent in larger brains and in animals capable of higher-level behaviors in more complex environments. This application is a crucial first step in that direction.
