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

 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（由申请人提供）：对大脑奖励处理系统中多巴胺信号模式的更好理解将导致奖励相关行为的机械描述，以及发现新的生物标志物和治疗成瘾的治疗干预点。在这里，我们建议使用一种独特的新的分子水平的功能性脑成像技术来表征多巴胺信号诱发的一些最广泛的研究和广泛重要的刺激成瘾研究。该技术使用磁共振成像（MRI）结合造影剂，结合并报告多巴胺浓度，可逆地，作为时间的函数。在具体目标1中，我们将使用这种“分子功能磁共振成像”技术来绘制纹状体多巴胺释放模式的结构和动力学，纹状体是与奖励和成瘾相关的多巴胺信号传导的关键目标。我们将测量多巴胺的释放，以响应一个重要的成瘾药物，安非他明，以及奖励相关的大脑刺激。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，例如解剖学和神经化学定义的纹状体亚区的特异性，我们将首次在清醒动物中进行多巴胺MRI研究。将以100-200 µm的空间分辨率和秒至分钟的时间尺度获得数据，足以解决阶段性和持久的多巴胺变化。在特定目标2中，我们将建立分子fMRI读数和常规血流动力学fMRI信号之间的定量、空间分辨对应关系，这广泛反映了神经元群体的活动。这些实验将提供BOLD信号和多巴胺释放之间的关系的经验描述，也有利于电路水平的描述多巴胺能功能在整个纹状体和超越神经群体水平。在具体目标3中，我们建议开发一种替代的MRI传感器，它将检测0.1-1 µM的多巴胺浓度，比我们目前的传感器好10-100倍，并且在自然奖励刺激诱发的水平范围内。改进的传感器将由磁性颗粒的纳米级阵列形成，所述纳米级阵列在靶配体的存在下改变构型，从而引起MRI对比度变化。除了实现灵敏的多巴胺检测外，新设计未来还将推广到其他神经靶点。这些目标将对成瘾中重要的多巴胺能神经系统的研究产生广泛的影响，也将解决联邦脑倡议的目标。