Noninvasive focal gene transfer of chemogenetic proteins in the primate brain

We leverage our recent development of transcranial focused ultrasound (tFUS) for noninvasive, focal delivery of adeno-associated viruses (AAVs)-encoding excitatory designer receptors exclusively activated by designer drugs (DREADDs)-to marmoset frontal cortex. Using FDG positron emission tomography, we demonstrate significant increases in glucose metabolism at the site of viral delivery after administering the DREADD-specific agonist deschloroclozapine (DCZ), as compared to vehicle control. Focal neuronal DREADD expression was confirmed by immunohistochemistry at the site of opening. Through a comparison of awake resting-state functional connectivity and structural connectivity from the sites of delivery, we demonstrate that increases in glucose metabolism occur within both mono- and polysynaptically connected brain regions. Taken together, these results demonstrate the ability to focally deliver excitatory chemogenetics without the need for surgery, allowing for activation of long-range frontal cortex circuits of the primate brain.