UC San Diego

Neuromodulatory tools are important for understanding how the brain functions in health and disease and for treating disorders whose pathology is primarily neurological. Clinical techniques such as deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and pharmacological interventions have all been used thus far to neuromodulate various pathologies. Each has benefits and drawbacks—TMS is minimally invasive but DBS gives more precise targeting, while pharmacology is non-invasive but hard to control temporally. Genetic techniques such as optogenetics and chemogenetics offer more targeted control, but are not yet used clinically, and optogenetics will likely require implantation of a fiber optic cannula to deliver light to target tissue. To overcome these limitations, ultrasound-based neuromodulation is being explored to non-invasively control specific populations of neurons in a spatially and temporally precise way. Ultrasound transducers can be focused to millimeter resolution, and research in several animal models including human studies have shown neuromodulatory effects of transcranial ultrasound stimulation. While these studies are promising, they do not account for the heterogeneity of neuronal subtypes in the brain. Additionally, the mechanisms of ultrasound-based neuromodulation are speculated but not fully understood—these include thermal effects, cavitation effects, membrane permeabilization, and mechanosensitive protein channel-mediated effects. To make ultrasound a more reliable and useful neuromodulatory tool, a sonogenetics approach is proposed to sensitize ultrasound-insensitive neurons by expressing mechanosensitive proteins in populations of interest and targeting them with ultrasound. This approach requires a biological component, the candidate mechanosensitive protein channels, and a technological component, the ultrasound transducers capable of delivering the neuromodulatory stimulus. Each of these components is explored in this dissertation: Chapter 1 focuses on ultrasound mechanosensitivity in the nematode C. elegans, elucidating novel findings about multiple ultrasound-sensitive pathways and their underlying protein channels. Chapter 2 explores the development of a novel transducer that is small enough to be worn by an awake, freely moving mouse yet powerful enough to trigger endogenous neuronal activity measured by fiber photometry. Together, these findings advance the quest to build a single-component sonogenetics toolbox capable of dissecting neural circuitry and ultimately treating neurological disorders by precisely controlling neuronal activity with ultrasound.