The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation

Abstract

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of non-invasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1, was studied through a conditional knockout mouse model as a major molecule for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement and muscle EMG responses. We also detected higher Piezo1 in the central amygdala (CEA) which were found more sensitive to ultrasound stimulation than that of cortex. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation while knocking out astrocytic Piezo1 showed no obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions, and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

Low‐Frequency Ultrasound Sensitive Piezo1 Channels Regulate Keloid‐Related Characteristics of Fibroblasts

“…Previous studies have concluded that regions exhibiting higher Piezo1 expression demonstrate an increased response to ultrasound. [35] We also observed the targeted effects of LFS on PKF. The LFS-induced inhibition of migration induced by LFS is more significant in PKF cells than in NIH 3T3 or HFF-1 cells.…”

Sonogenetics for Monitoring and Modulating Biomolecular Function by Ultrasound

“…[67] Recent investigation of the underlying biological mechanisms of ultrasonic neuromodulation's demonstrated the functional expression of Piezo1 channel in different regions of the brain, including both the right motor cortex and central amygdala with the latter exhibiting greater sensitivity to US. [68] In the same context of ultrasonic neuromodulation, Yoo et al investigated the biomolecular and cellular mechanisms by which FUS excites primary cortical neurons. Their results established that US excites neurons via direct mechanical force leading to extracellular calcium influx.…”

Ultrasound pulse repetition frequency preferentially activates different neuron populations independent of cell type

“…Though the exact physical interactions between US and cellular membranes remain unknown, mechanosensitive channels are generally thought to be critical in mediating cellular signaling changes during US neuromodulation [14][15][16][17][18][19] . Many mechanosensitive channels are widely expressed in the brain 20 , such as the two-pore potassium K2P family [20][21][22] , hyperosmolality-gated calcium-permeable TMEM63 family 20,23 , mechanosensitive cation channel Piezo family 20,24,25 , and the transient receptor potential TRP families 19,20,[26][27][28][29][30] . Among the large number of mechanosensitive channels, several members of the K2P, TRP and Piezo1 families have been implicated in ultrasound neuromodulation 19,[24][25][26]31,32 (Supplemental Table 1).…”

“…Many mechanosensitive channels are widely expressed in the brain 20 , such as the two-pore potassium K2P family [20][21][22] , hyperosmolality-gated calcium-permeable TMEM63 family 20,23 , mechanosensitive cation channel Piezo family 20,24,25 , and the transient receptor potential TRP families 19,20,[26][27][28][29][30] . Among the large number of mechanosensitive channels, several members of the K2P, TRP and Piezo1 families have been implicated in ultrasound neuromodulation 19,[24][25][26]31,32 (Supplemental Table 1). For example, genetic knockout of Piezo1 25 or knockdown of Trpm2 26 reduced US-mediated neural and behavioral responses in mice.…”

“…Among the large number of mechanosensitive channels, several members of the K2P, TRP and Piezo1 families have been implicated in ultrasound neuromodulation 19,[24][25][26]31,32 (Supplemental Table 1). For example, genetic knockout of Piezo1 25 or knockdown of Trpm2 26 reduced US-mediated neural and behavioral responses in mice. Similarly, genetic knockdown of TRPC1, TRPP1, and TRPP2 attenuated cellular calcium responses in cultured neurons in vitro 19 .…”