|Investigating mechanosensitive ion channel piezo1’s role in in vivo ultrasonic neuromodulation
|Sun, Lei (BME)
|Ultrasonic waves --Therapeutic use
Ultrasonics in medicine
Hong Kong Polytechnic University -- Dissertations
|Department of Biomedical Engineering
|xi, 92 pages : color illustrations
|Low intensity ultrasound is an emerging technology that can noninvasively modulate neurons in deep brain regions (over 10 cm through intact skull) with fine spatial (cubic millimeter) and temporal (millisecond) resolution. It thus holes great promise as a tool probing brain function and treating brain diseases. Ultrasonic activation of human cortical, sub-cortical and the related network has been widely reported, along with various clinical trials in various stages. Importantly, these studies did not find observable side effects, even with chronic stimulation. Multiple studies have also shown that ultrasonic stimulation of specific neurons or brain regions can elicit distinct behaviors in animals. These pieces of evidence demonstrate ultrasound a credible and safe method with great clinically translational potential. However, the biological mechanism underlying the neuromodulatory effects of ultrasound remains to be elucidated. This lack of clarity poses a hurdle for future ultrasound-based therapies if they are to be applied predictably and consistently, with maximal achievable efficacy and minimal side-effects.
At present, three mechanisms are most widely considered: thermo-effect, cavitation, and acoustic radiation force (ARF). Literatures have proven negligible heating effect brought by low intensity ultrasound and a frequency dependency of the neuromodulatory effect under conditions unfavoring cavitation, leaving ARF as the most conceivable physical mechanism. Mechanosensitive ion channel thus becomes a plausible candidate as the mediator since it is a pivotal component for cellular sensation of mechanical disturbance including ARF and it enables fast ultrasonic neuromodulatory effects as observed. The significantly increased sensitivity in cells overexpressing one of various such channels further imply that ultrasonic effect in the mammalian brain could be modulated by endogenous mechanosensitive ion channels. In this context, Piezo1, the most sensitive mechanotransduction ion channel that responds to force as low as 10 pN and ultrasound sonication as low as 0.1 MPa, stands out. With its broad expression of Piezo1 RNA in mouse brain as shown in the Allen Mouse Brain Atlas database and its protein level expression reported in studies, these lead to a hypothesis that Piezo1 is one of the mediators, if not the only, responsible for ultrasonic neuromodulatory effect in vivo.
With our previous study demonstrating Piezo1 mediates the ultrasonic neuromodulation in vitro, this research continues investigating the role of Piezo1 in living animals. In this study, Piezo1 is demonstrated functionally expressed and mediating the ultrasonic neuromodulation ex vivo and in vivo. It is found that the neuronal activity induced by ultrasound in P1KO (Piezo1 conditional knockout) neurons is significantly reduced comparing with the control ones in ex vivo brain slice experiment. Similarly, P1KO neurons displayed lower sensitivity to ultrasound stimuli in vivo revealed by the reduced limb movement, muscle electromyography amplitude, local neuronal calcium signaling response and c-Fos expression. Higher sensitivity to ultrasound stimuli is also found in CEA (central amygdala), one of the brain areas found highly expressing Piezo1. From the loss-of-function and gain-of-function-like investigation, followed by the exclusion of auditory confound, the prominent role Piezo1 plays in ultrasonic neuromodulation can be confirmed.
Interestingly, in this study, Piezo1 is found specially located in certain brain areas including the bed nucleus of the stria terminalis (BNST), central amygdala (CEA), Edinger-Westphal nucleus (EW), Red nucleus (RN) and paraventricular nucleus of hypothalamus (PVH) which are all stress regulating area. With the well response of CEA neurons to ultrasound stimuli, ultrasound is a promising tool for studying and treating psychiatric disease.
To conclude, Piezo1 is demonstrated a mechanism of ultrasonic neuromodulation in vivo and thus displayed an outstanding application probability in both neuroscience research and brain disease treatment.
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