Interrogation of dopaminergic activity using non-invasive ultrasound

多巴胺能信号转导功能障碍是物质滥用障碍的共同特征。基座 在此前提下，腹侧中皮质边缘多巴胺能神经元的特异性调制 被盖区(VTA)一直是治疗药物滥用干预的重点。然而，一个非 以多巴胺能神经元为靶点的侵入性、精确和可靠的方法尚未开发出来 作为药物治疗的替代方案。聚焦超声正在成为一种替代的非 经颅磁刺激和脑深部刺激的侵入性方法。超声波能够 穿透头骨，换能器可能被设计成将声波引导到大脑的任何区域。 然而，聚焦超声的一个主要局限性是无法确定 压力波对行为动物特定细胞类型活动的影响。我们开发了一种新的 一种结合了轻量级压电环传感器的装置，可以安装在鼠标的 以及一根光纤，通过钙离子的荧光信号监测神经元的活动 生物传感器(如GCamp7)。对海马体和VTA的初步研究表明， 是超声参数(即强度、载波频率、脉冲频率和 持续时间)，导致兴奋性和抑制性神经元的不同刺激或抑制。在这里我们 计划使用这一新设备来询问超声波对脑内多巴胺能神经元活动的影响 VTA。我们将确定一组不同刺激多巴胺能VTA的最佳参数 与邻近的GABA神经元相比。同时，我们将验证导致 超声波引起的条件性位置偏爱或厌恶。这些实验的结果将 极大地提高了我们对超声波对大脑奖赏回路的影响的理解，并可能 引领药物滥用患者多巴胺能系统的干预途径 精神错乱。

Dysfunction of dopaminergic signaling is a common denominator of substance abuse disorders. Based on this premise, specific modulation of mesocorticolimbic dopaminergic neurons in the ventral tegmental area (VTA) has been at the focus of interventions to treat substance abuse. However, a non- invasive, precise and reliable method that targets dopaminergic neurons has not been developed yet as an alternative to pharmacological treatment. Focused ultrasound is emerging as an alternative non- invasive method to transcranial magnetic stimulation and deep brain stimulation. Ultrasound is able to penetrate the skull and transducers may be designed to steer sound waves to any area of the brain. However, a major limitation of focused ultrasound has been the inability to determine the effect of pressure waves on the activity of specific cell types in behaving animals. We have developed a new device that combines a lightweight piezoelectric ring transducer that can be mounted on the mouse’s skull, and an optical fiber to monitor neuronal activity by means of fluorescent signals from a calcium biosensor (e.g. GCamp7). Preliminary studies in the hippocampus and in the VTA indicate that there are combinations of parameters of ultrasound (i.e. intensity, carrier frequency, pulse frequency and duration) that result in differential stimulation or inhibition of excitatory and inhibitory neurons. Here we plan to use this new device to interrogate the effect of ultrasound on dopaminergic neuronal activity in the VTA. We will determine an optimal set of parameters that differentially stimulate dopaminergic VTA neurons compared to adjacent GABA neurons. In parallel, we will validate conditions that result in ultrasound-elicited conditioned place preference or aversion. The result of these experiments will dramatically advance our understanding of the effect of ultrasound on brain reward circuits, and may lead the path for intervention of the dopaminergic system in patients suffering from substance abuse disorders.