DART2.0: comprehensive cell type-specific behavioral neuropharmacology

Duke University, Durham NC

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Abstract

ABSTRACT. DART2.0: comprehensive cell type-specific behavioral neuropharmacology Neuro-active drugs have provided hope to millions. However, a major gap in identification of novel therapeutic targets can be attributed to a poor understanding of how neuropharmaceuticals work at the circuit level; in particular, how behavioral effects of drugs are mediated by individual neuron types in the brain. As a preliminary step to address this gap, we developed DART (drugs acutely restricted by tethering), the first and only method to date that enables behavioral effects of clinically relevant drugs to be deconstructed with cellular specificity. This proposal aims to substantially expand the chemical diversity of DART ligands, enabling cell type specific and bi-directional control of key ionotropic receptors, neuromodulatory receptors, reuptake transporters, and voltage-gated ion channels. In a parallel effort, the genetic components of DART will be engineered to afford subcellular drug localization and to improve ease- of-use for multiplexing with recording devices and interrogation of large brain volumes. The overarching objective is to maximize adoption by empowering the neurobiology community to address previously intractable questions of broad public-health relevance. Reagents will be characterized in vitro and in vivo, and a robust system of authentication and distribution will be implemented. The decision to prioritize ease- of-use and commitment to the free dissemination of reagents are likely to pay dividends in overall impact.