Neural Engineering Tailored by Molecular Motors With Self-Reporting for Neuron Activation and Depression Treatment

The discovery of mechanical regulation to neuronal behavior offers a novel perspective for understanding nervous system function and advancing neural engineering. A key challenge lies in achieving precise mechanical control of neurons while simultaneously monitoring their activity in real time. Here, we engineered a novel molecular machine equipped with self-reporting capability, MM-VSD1, enabling stable anchoring into the plasma membrane. This integrated molecular tool comprises a light-driven rotary molecular motor (MM), which delivers localized mechanical force to neuronal membranes. Concurrently, a tethered near-infrared voltage-sensitive dye (VSD1) module provides real-time fluorescent feedback on changes in membrane potentials with millisecond temporal and subcellular spatial resolution. Utilizing this bifunctional molecular device, we demonstrate that MM-VSD1 effectively activates mechanosensitive TRPV1 ion channels in hippocampal neurons, triggering calcium influx and action potential (AP) firing. This mechanical modulation induced by MM-VSD1 is persistent and can be evoked in vivo up to one week, providing the potential of MM-VSD1 for alleviating depression-like behaviors in mice. By bridging mechanical manipulation with functional readouts at high spatiotemporal resolution, our work opens an avenue for mechano-based therapeutic interventions in neurological disorders.