ASIC1a is required for neuronal activation via low-intensity ultrasound stimulation in mouse brain

Accumulating evidence has shown transcranial low-intensity ultrasound can be potentially a non-invasive neural modulation tool to treat brain diseases. However, the underlying mechanism remains elusive, because the majority of studies on animal models applying rather high-intensity ultrasound that cannot be safely used in humans. Here we showed low-intensity ultrasound was able to activate neurons in the mouse brain and repeated ultrasound stimulation resulted in adult neurogenesis in specific brain regions. In vitro calcium imaging studies showed that a specific ultrasound stimulation mode, which combined with both ultrasound-induced pressure and acoustic streaming mechanotransduction, is required to activate cultured cortical neurons. ASIC1a and the tether-mode mechanotransduction were involved in the low-intensity ultrasound-mediated mechanotransduction and cultured neuron activation, which was inhibited by ASIC1a blockade and cytoskeleton-modified agents. In contrast, the inhibition of mechanical sensitive channels involved in bilayer-model mechanotransduction like Piezo or TRP proteins did not affect the ultrasound-mediated neuronal activation. SIGNIFICANCECNS neurons have no sensory function, protected by the skull. For this reason, brain neuromodulation by ultrasound were either done at a high intensity or through auditory nerves. We demonstrate in this study CNS neurons react to ultrasound stimulation at an intensity (5 mW/cm2) far lower than typical therapeutic ultrasound (>30 mW/cm2). Using micropipette ultrasound in calcium imaging, we show the reactions of CNS neurons to ultrasound is through ASIC1a channels, pointing to the molecular basis for direct ultrasound neuromodulation at low intensity. Furthermore, we also show evidence of neurogenesis with the same ultrasound stimulation, suggesting potential therapeutic translation.