PROJECT SUMMARY To understand the cellular basis of cognition, behavior and pathology, it is necessary to map the different participating brain regions and circuits that participate during the different biological processes and do so I the same animals. I propose to reach this goal by establishing a novel genetic method for full brain scale recording of integrated cellular activity in living mammals. The aim of my research proposal is to apply a novel Genetic Activity-induced Tagging of cell Ensembles (GATE) to express Genetically Encoded Magnetic Indicators (GEMIs) for full brain scale integrated activity mapping by magnetic resonance Imaging (MRI). We will screen different GEMIs and their combinations for high-resolution mapping of brain activity with high signal-to-noise ratio, first in brain slices and then in vivo, both using viruses and transgenic mice. The successful implementation of this method would make a transformational impact on systems neuroscience as it would allow mapping of activated brain circuits in learning and memory consolidation and retrieval processes in the same animals. Importantly, the proposed method would help to reveal the brain activity maps in the different psychiatric and neurological disease and also track changes in brain maps after therapeutic interventions, again in the same animals. We will perform 2 Specific Aims: Specific Aim 1– A combinatorial screen to identify an optimal vGATE-GEMI(s) for integrated activity mapping by MRI in cultured rat brain slices. 1A– Viral vectors with vGATE-GEMIs and expression analyses. 1B– Chemically-induced vGATE-GEMI assisted integrated activity mapping by MRI. 2C– Correlate GEMI expression and number of labeled cells to MRI signal detection. Specific Aim 2– In vivo validation of GEMI by vGATE-assisted integrated activity mapping by MRI. 2A– Chemically-induced and sensory experience evoked MRI activity maps. 2B– Transgenic mice for integrated full brain scale activity mapping by MRI. 2C– Correlate GEMI expression and number of labelled cells for MRI signal detection.

PROJECT NARRATIVE Our brain senses the outside world, enabling us to feel, think, decide and act. One of the greatest challenges in systems neuroscience is to understand the interrelationship between the different brain circuits for sensory perception, decision-making, motor response, cognition and behavior, and also under disease conditions. This challenge would require the large-scale recording of neuronal activity in vivo. Here, I propose to develop a novel genetic method, Genetic Activity-induced Tagging of cell Ensembles” (GATE), to deliver Genetically Encoded Magnetic Indicators (GEMIs) in the brain using viruses and transgenic animals for full brain scale integrated- activity maps by magnetic resonance imaging (MRI), with a powerful possibility to reveal multiple integrated activity maps over time under the different biological processes in the same animals.