Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.

中文翻译：

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哺乳动物大脑深层神经回路 PET 成像的基因靶向报告基因

正电子发射断层扫描 (PET) 允许生物分子跟踪，但由于缺乏合适的记者，PET 对大脑网络的监测受到阻碍。在这里，我们利用细菌二氢叶酸还原酶 ecDHFR 及其独特的拮抗剂 TMP，促进体内大脑中的成像。放射性氟化和荧光 TMP 类似物的外周给药分别使小鼠神经元 ecDHFR 表达的 PET 和活体显微镜检查成为可能。该技术可用于可视化小鼠海马体中化学遗传学操作引起的神经元回路活动。值得注意的是，ecDHFR-PET 允许映射非人类灵长类动物大脑中的神经元投射，证明了基于 ecDHFR 的跟踪技术在网络监测中的适用性。最后，我们展示了 TMP 类似物在 PET 研究中对标记有 ecDHFR 突变体的蛋白质的周转和自组装的效用。这些结果为以前无法​​在分子水平上对哺乳动物大脑回路进行广泛的 PET 分析创造了机会。