Genetically encoded anatomical probes for neuronal activity and plasticity

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A major challenge in neuroscience research is to identify the precise functional neural circuits that are responsible for diverse nervous system processes such as sensory perception, learning and memory, as well as the aberrant circuits that underline the pathological conditions such as chronic pain, depression, addiction, and epilepsy. Previous work in this area has focused on designing molecular sensors that detect transient voltage change or calcium influx using optical methods. However, the use of these sensors for studying in vivo complex neural physiology, and pathophysiology processes of the mammalian nervous system have been extremely limited. Moreover, these sensors do not allow for anatomical re-construction of the activated circuits. In this EUREKA application, we propose to develop novel genetically encoded anatomical probes for visualizing neuronal activity and plasticity directly. These probes will label activated neurons and synapses (and those most likely undergo plasticity) with a marker (e.g. a fluorescent protein) for easy histological detection and anatomical tracing. The chief principle underlying this unconventional design of probes is to use activity (strong calcium influx) to induce the translation of an otherwise un-translated marker protein. Successful development of the activity-induced anatomical probes will greatly advance our understanding of the functions and dysfunctions of the nervous system.