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

Jormay Lim,Wei-Hao Liao,Ya-Cherng Chu,Hsiao-Hsin Tai,Cheng-Han Lee,Chen-Ming Hao,Sherry Hsu,Ya-Chih Chien,Shao-Shien Lin,Dar-Ming Lai,Chih-Cheng Chen,Jaw-Lin Wang,Yueh-Chun Huang,Wen-Shiang Chen

doi:10.7554/elife.61660

Abstract

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 and 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 cytoskeletal proteins 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 repress the ultrasound-mediated neuronal activation as efficiently. The ASIC1a-mediated ultrasound effects in mouse brain such as immediate response of ERK phosphorylation and DCX marked neurogenesis were statistically significantly compromised by ASIC1a gene deletion. Collated data suggest that ASIC1a is the molecular determinant involved in the mechano-signaling of low-intensity ultrasound that modulates neural activation in mouse brain.

Highlights

Transcranial ultrasound such as opening blood-brain barrier (BBB) (1) for localized drug release and modulating neural activity (2-4) has been used for therapeutic treatments of various brain diseases
The central amygdala nucleus showed the strongest phosphorylation of extracellular-signal-regulated kinase (p-ERK) signals, while medial and basolateral obviously increased in p-ERK signals (Figure 1-figure supplement 1, 2)
To examine whether endoplasmic reticulum calcium was involved in calcium signaling, we found the calcium surge of cells treated with the RyR inhibitor, JTV519 fumarate (10 M) (Figure 3-figure supplement 1G and I) was partially inhibited, while as the IP3R inhibitor, (-)[182] Xestonspongin C (1 M) was most inhibited (Figure 3 B). 183 ASIC1a mechano-response required cytoskeletal dynamics

Summary

Introduction

Transcranial ultrasound such as opening blood-brain barrier (BBB) (1) for localized drug release and modulating neural activity (2-4) has been used for therapeutic treatments of various brain diseases. Many in vivo animal experiments and human clinical trials (Supplementary file 1A) proved the clinical potential of transcranial ultrasound stimulation. With the increased interest of this technique, the mechanisms underlying ultrasound-mediated neural modulation has recently been learned. A study showed high-intensity transcranial ultrasound can elicit a startle-like motor response via an indirect auditory mechanism (5). The energy intensity or acoustic pressure of most clinical trials or basic researches used for BBB opening or neuromodulation are both high, and safety issue of this technique in clinical application remains a concern

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