Interrogating dynamics of whole-brain volumes with cell type-specific pharmacology

Duke University, Durham NC

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Abstract

Abstract Animal behavior depends on diverse neuronal cell types whose dynamic activity is shaped by many receptors. However, because receptors are often broadly expressed, it has been difficult to manipulate a specific receptor on a defined cell type. The resulting knowledge gap has significant implications for understanding normal and aberrant behaviors. As a preliminary step to address this gap, we recently developed DART (Drugs Acutely Restricted by Tethering), a genetically encoded drug-targeting technology that offers the first opportunity to establish behavioral roles of a specific receptor on a defined cell type. This proposal aims to expand applicability of DART to diverse neurobiological preparations and promote widespread adoption of the technology. The proposal will: (1) minimize barriers to entry with a universal and easy to use whole-brain DART delivery platform; (2) maximize payoff by enabling bidirectional control of key excitatory, inhibitory, and neuromodulatory receptors; and (3) demonstrate conceptual utility of the approach as applied to a previously intractable neuro-dynamics debate of broad interest. If successful, the resulting innovations may impact the hypotheses that drive the upcoming decade of neurobiology.