Molecular imaging of dopaminergic signaling in rodent brain

啮齿动物大脑中多巴胺能信号的分子成像

• 批准号: 9120356
• 负责人: Alan Jasanoff
• 金额: $ 55.7万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120356
• 关键词: Address; Amphetamines; Animal Model; Animals; BRAIN initiative; Behavior; Behavioral; Binding; Biological Markers; Brain; Brain imaging; Chemicals; Contrast Media; Corpus striatum structure; Data; Dependence; Detection; Development; Diagnosis; Disease; Dopa; Dopamine; Dopamine Receptor; Electric Stimulation; Electrical Stimulation of the Brain; Electrochemistry; Functional Magnetic Resonance Imaging; Future; Goals; Health; Human; Image; Imaging Techniques; Laboratories; Lead; Learning; Life; Ligands; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Measures; Mining; Modality; Molecular; Neurons; Neurotransmitters; Pathway interactions; Pattern; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Rattus; Reading; Reporting; Research; Research Personnel; Resolution; Rewards; Rodent; Series; Signal Transduction; Spatial Distribution; Specificity; Stimulus; Structure; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Ventral Striatum; Work; addiction; awake; blood oxygen level dependent; design; hemodynamics; imaging modality; imaging probe; improved; microstimulation; molecular imaging; nanoprobe; nanoscale; nanosensors; neural circuit; novel; particle; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; reward processing; sensor; spatiotemporal; Address; Amphetamines; Animal Model; Animals; BRAIN initiative; Behavior; Behavioral; Binding; Biological Markers; Brain; Brain imaging; Chemicals; Contrast Media; Corpus striatum structure; Data; Dependence; Detection; Development; Diagnosis; Disease; Dopa; Dopamine; Dopamine Receptor; Electric Stimulation; Electrical Stimulation of the Brain; Electrochemistry; Functional Magnetic Resonance Imaging; Future; Goals; Health; Human; Image; Imaging Techniques; Laboratories; Lead; Learning; Life; Ligands; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Measures; Mining; Modality; Molecular; Neurons; Neurotransmitters; Pathway interactions; Pattern; Pharmaceutical Preparations; Population; Positron-Emission Tomography; Rattus; Reading; Reporting; Research; Research Personnel; Resolution; Rewards; Rodent; Series; Signal Transduction; Spatial Distribution; Specificity; Stimulus; Structure; System; Techniques; Technology; Testing; Therapeutic Intervention; Time; Ventral Striatum; Work; addiction; awake; blood oxygen level dependent; design; hemodynamics; imaging modality; imaging probe; improved; microstimulation; molecular imaging; nanoprobe; nanoscale; nanosensors; neural circuit; novel; particle; postsynaptic; presynaptic; receptor; relating to nervous system; research study; response; reward processing; sensor; spatiotemporal

 DESCRIPTION (provided by applicant): An improved understanding of dopamine signaling patterns in the brain's reward processing systems will lead to mechanistic descriptions of reward-related behavior, and also to the discovery of new biomarkers and therapeutic intervention points for treatment of addiction. Here we propose to use a unique new molecular-level functional brain imaging technique to characterize dopamine signaling evoked by some of the most widely studied and broadly significant stimuli in addiction research. The technique uses magnetic resonance imaging (MRI) in conjunction with contrast agents that bind and report dopamine concentrations, reversibly, as a function of time. In Specific Aim 1, we will use this "molecular fMRI" technique to map the structure and dynamics of dopamine release patterns in the striatum, a key target of dopamine signaling related to reward and addiction. We will measure dopamine release in response to an important addictive drug, amphetamine, as well as to reward-related brain stimulation. We will also push the spatial coverage and resolution of the imaging itself in order to characterize details of the dopamine response, such as specificity to anatomically and neurochemically defined striatal subregions, and we will for the first time conduct dopamine MRI studies in awake animals. Data will be obtained at a spatial resolution of 100-200 µm and over temporal scales ranging from seconds to minutes, sufficient for resolving both phasic and longer-lasting dopamine changes. In Specific Aim 2, we will establish a quantitative, spatially-resolved correspondence between molecular fMRI readings and conventional hemodynamic fMRI signals, which broadly reflect neuronal population activi- ty. These experiments will provide an empirical description of the relationship between BOLD signal and dopamine release, and also facilitate circuit level description of dopaminergic function at a neural population level across the striatum and beyond. In Specific Aim 3, we propose to develop an alternative MRI sensor that will detect dopamine concentrations of 0.1-1 µM, 10-100 times better than our current sensors, and in the range of levels evoked by naturalistic rewarding stimuli. The improved sensors will be formed from na- noscale arrays of magnetic particles that change configuration in the presence of target ligands, bringing about MRI contrast changes. In additional to enabling sensitive dopamine detection, the new design will in the future be generalizable to other neural targets. These Aims will have broad impact on the study of do- paminergic neural systems important in addiction, and will also address goals of the federal BRAIN Initiative.

 描述（由适用提供）：对大脑奖励处理系统中多巴胺信号传导模式的了解，将导致对奖励相关行为的机械描述，还可以发现新的生物标志物和成瘾治疗的治疗干预点。在这里，我们建议使用独特的新分子功能性脑成像技术来表征成瘾研究中一些研究最广泛和广泛的刺激引起的多巴胺信号传导。该技术将磁共振成像（MRI）与对比剂结合并报告多巴胺浓度随时间的函数而结合和报告多巴胺浓度。在特定的目标1中，我们将使用这种“分子fMRI”技术来绘制纹状体中多巴胺释放模式的结构和动力学，这是与奖励和成瘾有关的多巴胺信号传导的关键目标。我们将根据重要的添加剂苯丙胺以及奖励相关的大脑刺激来测量多巴胺释放。我们还将推动成像本身的空间覆盖范围和分辨率，以表征多巴胺反应的细节，例如对解剖和神经化学上定义的纹状体区域的特异性，我们将首次在清醒动物中进行多巴胺MRI研究。数据将以100-200 µm的空间分辨率以及从秒到几分钟的临时尺度（特定的目标2）获得，我们将建立一个定量的，空间分辨的对应关系，分子FMRI读数与常规血液动力学FMRI信号之间，这广泛反映了神经元人群活动ty。这些实验将提供对大胆信号和多巴胺释放之间关系的经验描述，并促进电路水平的描述在整个纹状体及以后的神经体形水平上的多巴胺能功能。在特定的目标3中，我们建议开发一种替代的MRI传感器，该传感器将检测到多巴胺浓度为0.1-1 µm，比目前的传感器好10-100倍，并且在自然主义奖励刺激中引起的水平范围内。改进的传感器将由磁性颗粒的Na-Noscale阵列形成，这些磁性颗粒在存在目标配体的情况下会改变构型，从而导致MRI对比度变化。除了启用敏感的多巴胺检测外，将来新设计还可以推广到其他神经靶标。这些目标将对对成瘾重要的DO-Pamin能神经元系统的研究产生广泛的影响，并将解决联邦大脑倡议的目标。