耳蝸核與海馬迴的神經細胞對低強度超音波之反應

Abstract

近年來，許多研究團隊開始將低強度超音波作為一種非侵入性的腦刺激工具，有許多研究指出低強度超音波具有神經調節特性，並且已經開始應用於治療腦部疾病上，而神經性聽力損失目前並無有效治療方法。既然低強度超音波能夠調節神經活性，或許具有成為治療神經性聽力損失方法的潛力，因此本研究試圖探討低強度超音波對於聽覺系統的影響，特別是中樞聽覺路徑。研究對象其一為中樞聽覺路徑起始的耳蝸核，而由於多項證據顯示超音波能夠影響海馬迴的神經活性，並且過往實驗室也針對海馬迴進行了許多研究，因此研究對象其二為海馬迴。超音波調節神經的機制被認為是透過機械力敏感通道調控，根據過往實驗室研究結果，我們認為N-甲基-D-天門冬胺酸受體(NMDAR)具有受超音波調控的潛力，因此本研究還會針對海馬迴中的NMDAR進行探討。 本研究使用c-Fos作為神經活性標記，並且利用c-Fos TRAP2小鼠來探討活體內神經活化的現象。研究結果顯示，低強度超音波會促進耳蝸核與海馬迴的c-Fos表現量上升，影響其神經活化，也會影響耳蝸核的音調排列結構，但不會使耳蝸核與海馬迴在兩次同樣刺激下產生的神經網路重疊率提升，推斷沒有長期影響；針對超音波與NMDAR的關係性，研究結果指出低強度超音波會促進海馬迴NMDAR磷酸化，並且超音波促進的神經活化會受NMDAR抑制而降低。綜上所述，本研究結果顯示低強度超音波可影響神經活性，且具備對NMDAR潛在的調節性。

In recent years, many research teams have explored using low-intensity ultrasound as a non-invasive brain stimulation tool. Numerous studies have investigated its applications in treating brain diseases. Sensorineural hearing loss (SNHL), which may result from central nervous system (CNS) damage, currently lack effective treatments. Given that low-intensity ultrasound can regulate neuronal activity, it may have the potential to treat SNHL. Therefore, this study aims to investigate the effects of low-intensity ultrasound on CNS, especially on the central auditory pathway. One focus of this study is the cochlear nucleus, the starting point of the central auditory pathway. Additionally, previous laboratory studies have extensively examined the ultrasound effects on the hippocampus, thus another focus will be the hippocampus. The mechanism by which ultrasound modulates neuronal activity is believed to involve regulating mechanosensitive channels. Based on previous laboratory findings, we hypothesize that N-Methyl-D-Aspartate Receptors (NMDAR) may be regulated by ultrasound. Thus, this study also investigates the response of NMDAR under ultrasound stimulation. We use c-Fos as a neuronal activity marker, and utilize c-Fos TRAP2 mice to study neural activation in vivo. The results showed a significant immediate increase in c-Fos expression in both the cochlear nucleus and the hippocampus under ultrasound stimulation; however, no significant difference was observed in the overlap ratio of neural networks generated by the same stimulus. This indicates that ultrasound stimulation can immediately increase neuronal activity but with limitations in repeatedly activating the same group of neurons. Moreover, the 12kHz band pattern labeled by c-Fos in the cochlear nucleus was consistently wider under ultrasound stimulation. Regarding the relationship between ultrasound and NMDAR, the results showed that low-intensity ultrasound could promote NMDAR phosphorylation in the hippocampus, and the neuronal activation induced by ultrasound was reduced by NMDAR inhibition. In conclusion, these findings suggest that low-intensity ultrasound may affect neuronal activation and demonstrate the potential regulatory effect of ultrasound on NMDAR.