PROJECT SUMMARY The goal of this project is to understand the neurobiological underpinnings of the effects of ultrasound (US) on neural activity. US can modify action potential activity in neurons in vitro and in vivo without damaging neural tissue. This phenomenon can be applied in powerful new tools for basic and clinical neuroscience, with broad impact on public health issues related to mental and neurological disorders. To guide use of this new tool, our research will provide insight into the physical, biophysical and neural mechanisms underlying US neuromodulation. Our approach is unique in applying and integrating mechanistic studies of US neuromodulation at levels of complexity ranging from the single cell to the whole animal. We aim to understand the relationship between US 1) the physical processes that transform acoustic energy to effects on biological systems and the resulting measurable physical variables (Aim 1), 2) the biophysical transduction processes together with the resulting measurable biophysical effects (Aim 2) 3) the subsequent neural integration processes that lead to the final output of the neural system or behavior (Aim 3). We will address these questions in experiments across three model systems (the in vivo mouse model, in vitro salamander and mouse retina, and single hippocampal pyramidal cells in acute and cultured brain slices), focusing on hypotheses guided by our results thus far. US neuromodulation is likely to have significant impact on public health. Brain stimulation therapies are used to treat Parkinson's disease, dystonia, and epilepsy and hold promise for many others. Compared to current brain stimulation techniques that rely on invasive implanted electrodes or have limited spatial resolution and depth penetration (e.g., transcranial magnetic stimulation), US offers an ideal combination of spatial resolution, depth penetration, and non-invasiveness. US neuromodulation can also be implemented in prosthetic devices; for example, to stimulate retinal circuitry to restore vision. In addition, US neuromodulation promises to become an enormously useful research tool in basic neuroscience, and it is therefore relevant to all mental and neurological disorders of public health concern. However, all these outcomes depend on the ability to apply US neuromodulation with well-controlled, predictable results. Achieving this goal requires a detailed mechanistic understanding of US neuromodulation that our multidisciplinary research project will provide.