Dysfunction of dopaminergic signaling is a common denominator of substance abuse disorders. Based on this premise, specific modulation of mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) has been at the focus of interventions to treat substance abuse. However, a non- invasive, precise and reliable method that targets dopaminergic neurons has not been developed yet as an alternative to pharmacological treatment. Focused ultrasound is emerging as an alternative non- invasive method to transcranial magnetic stimulation and deep brain stimulation. Ultrasound is able to penetrate the skull and transducers may be designed to steer sound waves to any area of the brain. However, a major limitation of focused ultrasound has been the inability to determine the effect of pressure waves on the activity of specific cell types in behaving animals. We have developed a new device that combines a lightweight piezoelectric ring transducer that can be mounted on the mouse’s skull, and an optical fiber to monitor neuronal activity by means of fluorescent signals from a calcium biosensor (e.g. GCamp7). Preliminary studies in the hippocampus and in the VTA indicate that there are combinations of parameters of ultrasound (i.e. intensity, carrier frequency, pulse frequency and duration) that result in differential stimulation or inhibition of excitatory and inhibitory neurons. Here we plan to use this new device to interrogate the effect of ultrasound on dopaminergic neuronal activity in the VTA. We will determine an optimal set of parameters that differentially stimulate dopaminergic VTA neurons compared to adjacent GABA neurons. In parallel, we will validate conditions that result in ultrasound-elicited conditioned place preference or aversion. The result of these experiments will dramatically advance our understanding of the effect of ultrasound on brain reward circuits, and may lead the path for intervention of the dopaminergic system in patients suffering from substance abuse disorders.