Tamura Yasuhisa, Takahashi Kayo, Takata Kumi, Eguchi Asami, Yamato Masanori, Kume Satoshi, Nakano Masayuki, Watanabe Yasuyoshi, Kataoka Yosky
Cellular Function Imaging Team, Multi-Modal Microstructure Analysis Unit, and
Pathophysiological and Health Science Team, Center for Life Science Technologies, RIKEN, Kobe 650-0047, Japan.
J Neurosci. 2016 Aug 3;36(31):8123-31. doi: 10.1523/JNEUROSCI.0220-16.2016.
Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment.
Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.
两个神经发生区域，即脑室下区和海马齿状回的颗粒下区（SGZ）中的神经干细胞，在整个生命过程中都能分裂并产生新的神经元。海马神经发生与包括抑郁/焦虑在内的情绪、抗抑郁药的治疗效果以及学习和记忆有关。建立用于SGZ中神经干细胞增殖活性的体内成像，可能用于诊断抑郁症并监测抗抑郁药的治疗效果。使用3'-脱氧-3'-[(18)F]氟-L-胸腺嘧啶核苷([(18)F]FLT)进行正电子发射断层扫描（PET）成像，已被用于可视化成年哺乳动物两个神经发生区域的增殖活性；然而，由于[(18)F]FLT的积累较低，PET成像尚未得到广泛应用，这使得在抑郁症状态下无法对SGZ中细胞增殖活性的下降进行定量评估。我们报告了一种增强的PET成像方法，该方法将[(18)F]FLT与丙磺舒（一种血脑屏障处药物转运体的抑制剂）相结合，可实现对大鼠神经发生活性的定量可视化。增强的PET成像使我们能够评估皮质酮诱导的抑郁症大鼠SGZ中细胞增殖的减少，以及进一步评估抗抑郁药治疗大鼠增殖活性的恢复情况。这种与丙磺舒结合的增强型[(18)F]FLT-PET成像技术可用于评估成年哺乳动物大脑中神经发生活性的动态变化，也可能为抑郁症的客观诊断和抗抑郁治疗效果的监测提供一种手段。
成年海马神经发生可能在重度抑郁症和抗抑郁治疗中起作用。建立海马神经发生活性的体内成像可能有助于诊断抑郁症并监测抗抑郁药的治疗效果。正电子发射断层扫描（PET）成像已被用于可视化神经发生活性；然而，由于PET示踪剂在神经发生区域的积累较低，PET成像尚未得到广泛应用。在此，我们成功地建立了一种使用药物转运体抑制剂对成年大脑神经发生活性进行高度定量的PET成像方法。这种增强的PET成像能够评估抑郁症大鼠海马中神经发生活性的下降以及抗抑郁治疗后神经发生活性的恢复情况。
