Interrogation of dopaminergic activity using non-invasive ultrasound

使用非侵入性超声检查多巴胺能活性

• 批准号: 10618325
• 负责人: Luis De Lecea
• 金额: $ 19.87万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618325
• 关键词: Affect; Amygdaloid structure; Anatomy; Anesthesia procedures; Animals; Area; Behavior; Behavioral; Biological Assay; Biosensor; Brain; Brain region; Calcium; Cell Nucleus; Coupled; Deep Brain Stimulation; Development; Devices; Disease; Drug abuse; Fiber; Fiber Optics; Focused Ultrasound; Frequencies; Functional disorder; Habenula; Head; Hippocampus; Human; Image; Intervention; Lead; Light; Methods; Midbrain structure; Molecular; Monitor; Mus; Mutation; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Patients; Penetration; Persons; Pharmacological Treatment; Photometry; Physiologic pulse; Prefrontal Cortex; Resolution; Rewards; Rodent; Role; Signal Transduction; Source; Specificity; Stimulus; Substance abuse problem; Surface; System; Testing; Therapeutic; Tissues; Transcranial magnetic stimulation; Transducers; Translating; Ultrasonics; Ventral Tegmental Area; addiction; cell type; conditioned place preference; cranium; craving; design; dopaminergic neuron; excitatory neuron; experimental study; gamma-Aminobutyric Acid; inhibitory neuron; light weight; millimeter; neuroregulation; optical fiber; optogenetics; preference; pressure; response; sound; substance abuse treatment; transcranial direct current stimulation; ultrasound

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.

多巴胺能信号传导的功能障碍是药物滥用障碍的常见分母。基于 在此前提下，腹侧中质胶质的多巴胺能神经元的特定调节 段区域（VTA）一直处于干预措施以治疗药物滥用的重点。但是，一个非 尚未开发针对多巴胺能神经元的侵入性，精确和可靠的方法 作为药物治疗的替代方法。专注的超声正在成为替代的非 - 侵入性转颅磁刺激和深脑刺激的方法。超声可以 穿透头骨，换能器可以设计为将声波引导到大脑的任何区域。 但是，集中超声的主要局限是无法确定 在行为动物中特定细胞类型的活性上的压力波。我们已经开发了一个新的 结合了可以安装在鼠标上的轻质压电环传感器的设备 颅骨和光纤通过钙的荧光信号监测神经元活性 生物传感器（例如GCAMP7）。海马和VTA中的初步研究表明那里 是超声参数的组合（即强度，载体频率，脉冲频率和 持续时间）导致刺激或抑制性神经元的抑制作用。我们在这里 计划使用这种新设备询问超声对多巴胺能神经元活动的影响 VTA。我们将确定一组最佳的参数，这些参数刺激多巴胺能VTA 与相邻的GABA神经元相比，神经元。同时，我们将验证导致的条件 超声引诱的条件偏好或厌恶。这些实验的结果将 动态地推进我们对超声对大脑奖励电路影响的理解，并可能 领导多巴胺能系统干预患有药物滥用的患者的道路 疾病。