Interrogation of dopaminergic activity using non-invasive ultrasound

多巴胺能信号功能障碍是药物滥用障碍的共同特征。基于 在此前提下，腹侧中皮质边缘多巴胺能神经元的特异性调节 被盖区（VTA）一直是治疗药物滥用干预措施的重点。然而，一个非 尚未开发出针对多巴胺能神经元的侵入性、精确且可靠的方法 作为药物治疗的替代方案。聚焦超声波正在作为一种替代的非 侵入性方法有经颅磁刺激和深部脑刺激。超声波能够 穿透头骨，传感器可以被设计用于将声波引导到大脑的任何区域。 然而，聚焦超声的一个主要限制是无法确定聚焦超声的效果。 压力波对行为动物中特定细胞类型活动的影响。我们开发了一种新的 该设备结合了可安装在鼠标上的轻型压电环传感器 头骨和光纤，通过钙的荧光信号监测神经元活动 生物传感器（例如 GCamp7）。海马体和 VTA 的初步研究表明， 是超声波参数的组合（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差异刺激或抑制。在这里我们 计划使用这种新设备来研究超声波对多巴胺能神经元活动的影响 VTA。我们将确定一组最佳参数，以差异化刺激多巴胺能 VTA 神经元与邻近的 GABA 神经元相比。同时，我们将验证导致以下结果的条件： 超声波引起的条件性位置偏好或厌恶。这些实验的结果将 极大地增进了我们对超声波对大脑奖励回路影响的理解，并且可能 为药物滥用患者的多巴胺能系统干预开辟道路 失调。

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.