As an emerging technology, transcranial focused ultrasound has been demonstrated to successfully evoke motor responses in mice, rabbits, and sensory/motor responses in humans. Yet, the spatial resolution of ultrasound does not allow for high-precision stimulation. Here, we developed a tapered fiber optoacoustic emitter (TFOE) for optoacoustic stimulation of neurons with an unprecedented spatial resolution of 20 microns, enabling selective activation of single neurons or subcellular structures, such as axons and dendrites. A single acoustic pulse of 1 microsecond converted by the TFOE from a single laser pulse of 3 nanoseconds is shown as the shortest acoustic stimuli so far for successful neuron activation. The highly localized ultrasound generated by the TFOE made it possible to integrate the optoacoustic stimulation and highly stable patch clamp recording on single neurons. Direct measurements of electrical response of single neurons to acoustic stimulation, which is difficult for conventional ultrasound stimulation, have been demonstrated for the first time. By coupling TFOE with ex vivo brain slice electrophysiology, we unveil cell-type-specific response of excitatory and inhibitory neurons to acoustic stimulation. These results demonstrate that TFOE is a non-genetic single-cell and sub-cellular modulation technology, which could shed new insights into the mechanism of neurostimulation.
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