Project Summary: The inability to distribute gene products broadly throughout the CNS is a major limitation of current gene delivery methods for brain disease. Employing white matter connectivity to map brain networks is a powerful, well- established method in laboratory studies, but has not been exploited clinically for therapeutic delivery. The central goal of this proposal is to advance a focused ultrasound (FUS)-based gene therapy delivery strategy – “circuit focused ultrasound” (CIFUS) – that utilizes brain connectivity to widely target interconnected brain regions. Our approach overcomes several longstanding obstacles that have thwarted the tremendous promise of gene therapy for central nervous system (CNS) diseases. This proposal will advance the development of CIFUS and test the hypothesis that this approach can functionally rescue key phenotypes in models of a degenerative and a circuit-based brain disease. We will use a mouse model of Alzheimer disease with tau pathology that spreads across multiple interconnected brain regions during maturation and aging.6,7 We will use mouse models of dystonia that recapitulates motor circuit dysfunction8,9 and neurodevelopmental neurodegeneration8,10. Successful completion of this proposal will advance development of a novel method of widespread, targeted gene delivery that will empower basic neuroscience research and lay the groundwork for human trials.