Molecular imaging of dopaminergic signaling in rodent brain

 描述(申请人提供)：对大脑奖赏处理系统中的多巴胺信号模式的更好理解将导致对奖赏相关行为的机械性描述，并将发现新的生物标记物和治疗成瘾的干预点。在这里，我们建议使用一种独特的新的分子水平功能脑成像技术来表征由成瘾研究中一些最广泛研究和广泛意义的刺激所引起的多巴胺信号。这项技术使用磁共振成像(MRI)结合造影剂，可逆地结合和报告多巴胺浓度作为时间的函数。在具体目标1中，我们将使用这种“分子功能磁共振成像”技术来绘制纹状体中多巴胺释放模式的结构和动力学图，纹状体是与奖赏和成瘾相关的多巴胺信号的关键目标。我们将测量多巴胺对一种重要的成瘾药物苯丙胺的反应，以及对与奖励相关的大脑刺激的反应。我们还将提高成像本身的空间覆盖率和分辨率，以表征多巴胺反应的细节，例如对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身上进行多巴胺磁共振研究。数据将以100-200微米的空间分辨率和从几秒到几分钟的时间尺度获得，足以分辨阶段性和更持久的多巴胺变化。在具体目标2中，我们将在分子fMRI读数和常规血流动力学fMRI信号之间建立定量的、空间分辨的对应关系，这广泛地反映了神经元群体的活动。这些实验将为BOLD信号和多巴胺释放之间的关系提供经验性的描述，并促进在整个纹状体和纹状体以外的神经种群水平上对多巴胺能功能的电路水平的描述。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微米的多巴胺浓度，比我们目前的传感器好10-100倍，并且在自然奖励刺激引起的水平范围内。改进后的传感器将由纳米尺度的磁性颗粒阵列组成，这些磁性颗粒在靶标配体存在的情况下改变构型，带来磁共振成像对比度的变化。除了能够进行灵敏的多巴胺检测外，新的设计在未来还将推广到其他神经靶标。这些目标将对在成瘾中起重要作用的多巴胺能神经系统的研究产生广泛影响，也将解决联邦大脑倡议的目标。

 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.