Fusion of nanomagnetic and viral tools to interrogate brain-body circuits

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Abstract The information flow between the peripheral organs and the brain is increasingly recognized as bidirectional, with activity in peripheral circuits influencing high-level behaviors including mood, motivation, and stress. To establish mechanistic links between activity of peripheral neurons and brain circuits, we will develop a species- agnostic framework for targeting and remote modulation of specific cells within the peripheral organs and the brain during behavior. Our framework will combine the homing, modulation, and contrast properties of synthetic magnetic nanomaterials with the targeting specificity of viral vectors. Magnetic nanomaterials have recently emerged as versatile transducers of remotely applied weak magnetic fields into thermal, chemical, or mechanical stimuli perceived by ion channels. We will dramatically expand the palette of magnetic nanotransducers to enable receptor-specific remote magnetic modulation of neurons (or other electrogenic cells) anywhere in the body during free behavior. Moreover, we will leverage recent advances in adeno-associated viral vectors for targeting specific cells and tissues by creating an array of fusions of nanotransducers and viral capsids. This will allow for magnetic guidance and localization of the hybrid magnetic- viral fusions to the locations of interest following systemic delivery regardless of the model organism. We will apply our framework to elucidate circuits connecting the enteric (gut) nervous system to the midbrain structures. Recent work has drawn links between gastrointestinal dysfunction and social and mood disorders as well as demonstrated vagal transmission of the enteric signals to the brain. By applying receptor-specific modulation to the enteric neurons we intend to test the hypothesis that their activity influences midbrain pathways governing reward and motivation, and possibly motor behaviors. In addition to empowering studies of gut-brain circuits, our species-agnostic framework can be extended to investigate connections between any peripheral organ and the brain thus opening opportunities to develop peripheral organ interventions for neurological and mental conditions.