PROJECT SUMMARY/ABSTRACT Critical advances in the treatment of human brain disorders are hindered by our inability to specifically target dysfunctional circuitry in a safe and noninvasive manner. Existing noninvasive techniques (e.g., transcranial magnetic, electrical, and ultrasound neuromodulation) activate many brain circuit components within the targeted region, and their efficacies are difficult to control. Genetic approaches (e.g., optogenetics and chemogenetics) modulate defined neural populations, but commonly require invasive surgical procedures for intracranial injection of viral vectors encoding stimulus-sensitive ion channels and/or implantation of long-term hardware for stimulus delivery. The objective of this application is to develop and validate a next-generation neuromodulation tool, incisionless sonogenetics (iSonogenetics), for noninvasive and cell-type-specific manipulation of neuronal activity in non-human primate (NHP) brains. Our ultimate goal is to use iSonogenetics for the modulation of the NHP and human brain to identify the neuronal bases of cognitive behavior and to progress toward the targeted treatment of human brain disorders. iSonogenetics involves a dual approach. (1) Sonodelivery uses focused ultrasound (FUS) to noninvasively deliver intranasally administered adeno-associated viruses (AAVs) encoding a thermosensitive ion channel, transient receptor potential vanilloid 1 (TRPV1), to genetically defined populations of neurons. (2) Sonoactivation uses FUS to induce mild warming, which opens TRPV1 channels and thereby activates the AAV-transduced neurons. Guided by strong preliminary data obtained in rodents, our objective will be accomplished by pursuing three specific aims: (1) Develop sonodelivery for noninvasive and efficient AAV delivery to a targeted brain region with minimal systemic exposure in anesthetized NHPs; (2) Develop sonoactivation for safe and reliable activation of AAV-transduced neurons in anesthetized NHPs; (3) Validate iSonogenetics in awake NHPs by conducting behavior testing. The proposed iSonogenetics is innovative because it can achieve noninvasive and cell-type-specific neuromodulation at deep brain targets with a high spatiotemporal resolution. The proposed research is significant because it directly addresses the central goal of RFA-MH-19-135 by providing the neuroscience community with a first-in-class neuromodulation tool that has the potential to transform our approaches for probing cell-specific processes and uncover new ways to understand and treat human brain disorders.