| Author: | Wu, Yong |
| Title: | Non-ion channel protein-mediated sonogenetics |
| Advisors: | Sun, Lei (BME) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | Department of Biomedical Engineering |
| Pages: | xv, 101 pages : color illustrations |
| Language: | English |
| Abstract: | The advancement of neuromodulation technologies has significantly enhanced our understanding of brain function and provided novel approaches for intervening neuronal activity in treating neurological disorders. In recent decades, various techniques including electrical stimulation, magnetic modulation, optogenetics, and chemogenetics have emerged. However, these methods present limitations in terms of invasiveness, precision, or tissue penetration depth. Ultrasound (US) neuromodulation has emerged as one of the most rapidly developing technologies due to its non-invasive nature, high spatiotemporal resolution, and deep tissue penetration capability, finding applications in both disease research and therapeutic interventions. Sonogenetics—an innovative neuromodulation approach that genetically modifies specific cells (e.g., neurons) with ultrasound-sensitive elements (e.g., mechanosensitive channels) to enable non-invasive manipulation of target cell activity through external ultrasound—has further improved its precision. Nevertheless, the expression of exogenous ion channels in neurons may potentially alter their intrinsic electrophysiological properties, necessitating the development of alternative strategies. This study proposes a novel ion channel-independent sonogenetic strategy utilizing the cell adhesion molecule E-cadherin as a new mediator for ultrasound-responsive neural modulation. Our key findings include: 1) Through systematic screening, we first identified E-cadherin as a highly efficient US sensor; 2) Mechanistic studies revealed that E-cadherin-mediated sonogenetic effects depend on Piezo1 channels; 3) Demonstrated that E-cadherin expression significantly enhances ultrasound-evoked calcium responses and c-fos induction in primary neurons; 4) In vivo experiments showed that targeted E-cadherin expression in mouse motor cortex induces ultrasound-dependent calcium transients and contralateral limb tremors; 5) Expression E-cadherin in D1 neurons of the DMS elicits robust motor behaviors; uncovering a cooperative mechanotransduction mechanism between adhesion molecules and ion channels. This work establishes the first non-ion channel protein-based sonogenetic approach, circumventing the limitations associated with neuronal exogenous expression of mechanosensitive ion channels while maintaining high spatiotemporal precision and biosafety. Our findings expand the current sonogenetics toolkit and pave the way for developing innovative neural modulation strategies. |
| Rights: | All rights reserved |
| Access: | open access |
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