DART.3-Revolutionizing Neuropsychiatric Treatment through Noninvasive, Programmable Cell-Type-Specific Neuropharmacology

DART.3―Revolutionizing Neuropsychiatric Treatment through Noninvasive, Programmable Cell-Type-Specific Neuropharmacology ABSTRACT Neuropharmacology is central to the treatment of brain disorders, and new tools are needed to untangle how canonical drug-receptor interactions are transformed by brain circuits to impact complex behavioral

states. DART (drugs acutely restricted by tethering) offers a new path forward, by making it possible to deliver clinical drugs to one cell type at a time, observe ensuing behaviors and cellular dynamics, and reconstruct mechanisms from parts to the whole. Since its debut, we have worked closely with a growing

user base to refine and deploy the technology. In particular, the second-generation DART.2 offers thousandfold cellular specificity, histology tracers of target engagement, and a catalog of antagonists, agonists, and allosteric modulators of several receptors. Here, we propose to advance the technology in

three new domains of innovation with DART.3. Aim 1 enables noninvasive, whole-body delivery for precise drug engagement. Aim 2 broadens the therapeutic range to Nicotinic and 5-HT2A receptors and cellular locales. Aim 3 provides two kinds of programmable rapid reversibility. Our priorities in technical innovation

reflect the most pressing gaps identified by our community of collaborators. Understanding complex animal behavior is our standard. Thus, we characterize tools in behaving animals, develop robust systems of rigor and reproducibility, and invest in our user base by providing reagent distribution, training and support

through frequent interactions. These priorities are empowering a thriving and intellectually diverse neuroscience community to transform how we study the brain.