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.

多巴胺能信号的功能障碍是药物滥用障碍的共同特征。基于