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.
