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: 10467409
• 负责人: Luis De Lecea
• 金额: $ 23.8万
• 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/10467409
• 关键词: Affect; Amygdaloid structure; Anatomy; Animals; Area; Behavior; Behavioral; Biological Assay; Biosensor; Brain; Brain region; Calcium; Cell Nucleus; Coupled; Deep Brain Stimulation; Development; Devices; Disease; Drug abuse; Fiber; Focused Ultrasound; Frequencies; Functional disorder; Genetic; Habenula; Head; Hippocampus (Brain); Human; Image; Intervention; Lead; Light; Magnetism; Methods; Midbrain structure; Molecular; Monitor; Mus; Neurons; Nucleus Accumbens; Operative Surgical Procedures; Patients; 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; base; 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; 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.

多巴胺能信号传导功能障碍是物质滥用障碍的共同特征。基于 在此前提下，腹侧中脑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的干预措施的重点。然而，一个非- 尚未开发出靶向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案。聚焦超声正在成为一种替代性的非- 经颅磁刺激和脑深部电刺激。超声波能够 穿透颅骨，并且换能器可以被设计成将声波引导到大脑的任何区域。 然而，聚焦超声的主要局限性是无法确定 压力波对行为正常的动物体内特定细胞类型的活动的影响。我们已经开发出一种新 该设备结合了一个轻便的压电环形传感器，可以安装在鼠标的 头骨，和一个光纤，以监测神经元的活动，通过荧光信号从钙 生物传感器（例如GCamp 7）。对海马体和腹侧被盖区的初步研究表明， 是超声参数（即强度、载波频率、脉冲频率和 持续时间），其导致兴奋性和抑制性神经元的不同刺激或抑制。这里我们 计划使用这种新设备来询问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的参数，差异刺激多巴胺能腹侧被盖区 与相邻的GABA神经元相比。与此同时，我们将验证导致 超声波引发的条件性位置偏好或厌恶。这些实验的结果将 极大地推进了我们对超声波对大脑奖励回路影响的理解， 为药物滥用患者的多巴胺能系统干预开辟道路 紊乱