Medical & Biological Engineering & Computing ( IF 2.6 ) Pub Date : 2021-04-21 , DOI: 10.1007/s11517-021-02351-9 Huining Guo 1 , Glen Baker 1, 2 , Kelly Hartle 1, 2 , Esther Fujiwara 1, 2 , Junhui Wang 1 , Yanbo Zhang 1, 2 , Jida Xing 3 , Haiyan Lyu 4 , Xin-Min Li 1, 2 , Jie Chen 3, 5
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There is now a relatively large body of evidence suggesting a relationship between dysfunction of myelin and oligodendrocytes and the etiology of several neuropsychiatric disorders, including depression and schizophrenia, and also suggesting that ultrasound methods may alleviate some of the symptoms of depression. We have applied low-intensity pulsed ultrasound (LIPUS) to the brains of mice treated with the demyelinating drug cuprizone, a drug that has been used as the basis for a rodent model relevant to a number of psychiatric and neurologic disorders including depression, schizophrenia, and multiple sclerosis. Prior to conducting the studies in mice, preliminary studies were carried out on the effects of LIPUS in vitro in neuron-like SH-SY5Y cells and primary glial cells. In subsequent studies in mice, female C57BL/6 mice were restrained in plastic tubes for 20 min daily with the ultrasound transducer near the end of the tube directly above the mouse’s head. LIPUS was used at an intensity of 25 mW/cm2 once daily for 22 days in control mice and in mice undergoing daily repetitive restraint stress (RRS). Behavioral or neurochemical studies were done on the mice or the brain tissue obtained from them. The studies in vitro indicated that LIPUS stimulation at an intensity of 15 mW/cm2 delivered for 5 min daily for 3 days in an enclosed sterile cell culture plate in an incubator increased the viability of SH-SY5Y and primary glial cells. In the studies in mice, LIPUS elevated levels of doublecortin, a marker for neurogenesis, in the cortex compared to levels in the RRS mice and caused a trend in elevation of brain levels of brain-derived neurotrophic factor in the hippocampus relative to control levels. LIPUS also increased sucrose preference (a measure of the attenuation of anhedonia, a common symptom of several psychiatric disorders) in the RRS model in mice. The ability of LIPUS administered daily to rescue damaged myelin and oligodendrocytes was studied in mice treated chronically with cuprizone for 35 days. LIPUS increased cortex and corpus callosum levels of myelin basic protein, a protein marker for mature oligodendrocytes, and neural/glial antigen 2, a protein marker for oligodendrocyte precursor cells, relative to levels in the cuprizone + sham animals. These results of this exploratory study suggest that future comprehensive time-related studies with LIPUS on brain chemistry and behavior related to neuropsychiatric disorders are warranted.
Graphical abstract
中文翻译：
低强度脉冲超声对小鼠脑神经化学作用的探索性研究
现在有相对大量的证据表明髓鞘和少突胶质细胞的功能障碍与包括抑郁症和精神分裂症在内的几种神经精神疾病的病因之间存在关系，并且还表明超声方法可以减轻抑郁症的一些症状。我们已将低强度脉冲超声 (LIPUS) 应用于接受脱髓鞘药物 Cuprizone 治疗的小鼠的大脑，该药物已被用作与许多精神和神经系统疾病相关的啮齿动物模型的基础，包括抑郁症、精神分裂症、和多发性硬化症。在对小鼠进行研究之前，对 LIPUS 在体外对神经元样 SH-SY5Y 细胞和原代神经胶质细胞的影响进行了初步研究。在随后的小鼠研究中，雌性 C57BL/6 小鼠每天被限制在塑料管中 20 分钟，超声换能器位于小鼠头部正上方的管末端附近。LIPUS 的使用强度为 25 mW/cm2每天一次，持续 22 天，用于对照小鼠和每天重复性束缚应激 (RRS) 的小鼠。对小鼠或从它们获得的脑组织进行了行为或神经化学研究。体外研究表明，LIPUS 刺激强度为 15 mW/cm 2在培养箱中封闭的无菌细胞培养板中每天递送 5 分钟，持续 3 天，增加了 SH-SY5Y 和原代神经胶质细胞的活力。在小鼠研究中，与 RRS 小鼠的水平相比，LIPUS 提高了皮层中双皮质素（神经发生的标志物）的水平，并导致海马中脑源性神经营养因子的大脑水平相对于对照水平升高。在小鼠的 RRS 模型中，LIPUS 还增加了蔗糖偏好（一种衡量快感缺乏症的减弱，这是几种精神疾病的常见症状）。在用铜宗长期治疗 35 天的小鼠中研究了每天施用 LIPUS 以挽救受损髓鞘和少突胶质细胞的能力。LIPUS 增加皮质和胼胝体髓鞘碱性蛋白的水平，成熟少突胶质细胞的蛋白质标记物和神经/神经胶质抗原 2，少突胶质细胞前体细胞的蛋白质标记物，相对于铜宗 + 假动物中的水平。这项探索性研究的这些结果表明，未来需要使用 LIPUS 对与神经精神疾病相关的大脑化学和行为进行全面的时间相关研究。
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