Principal Investigator

李毓龙
荧光探针、神经成像、突触传递、信号转导、神经疾病

联系电话：62766905
通信地址： 北京市海淀区颐和园路5号金光生命科学大楼142信箱，100871
电子邮件：[email protected]

李毓龙，研究员

 

研究兴趣：

      人的大脑由数十亿的神经元组成，后者又通过数万亿的突触组成复杂的神经网络。不同种类的神经元经过或远或近的投射，通过突触与其他神经元进行信息交流，实现感知觉、决策和运动等高级神经功能。
研究大脑的最大挑战在于脑的高度复杂性。我们实验室集中在神经元通讯的基本结构突触上，从两个层面上开展研究：一是开发前沿的工具，即开发新型成像探针，用于在时间和空间尺度上解析神经系统的复杂功能；二是借助先进的工具探究突触传递的调节机制，特别是在生理及病理条件下对神经递质释放的调节。
      具体而言，对于工具开发，我们集中于：
1、结合光遗传学和荧光成像，无损伤性的研究神经元之间的电突触连接。电突触的异常可导致耳聋、癫痫、脑部肿瘤和心脏功能异常等疾病。
2、开发可遗传编码的检测神经递质/调质的荧光探针。神经递质/调质是神经元化学突触传递的关键介导分子，与感知、学习和记忆以及情绪密切相关。
      利用上述荧光探针，我们的功能性和生理性的研究集中于：
1、结合双光子成像和可遗传编码的荧光探针，使用果蝇和小鼠作为模式生物，研究嗅觉传导或睡眠过程中脑的工作机制。
2、寻找上述新型化学递质/调质小分子的对应受体，即寻找“孤儿”受体的配体。
3、结合生物信息学、分析化学、生物化学、生理学和成像学方法，系统地探索和鉴定潜在的新型小分子神经递质。

 

代表性科研论文：

主要研究论文：

  1. Zhuo, Y.#, Luo, B.#, Yi, X., Dong, H., Miao, X., Wan, J., Williams, J. T., Campbell, M. G., Cai, R., Qian, T., Li, F., Weber, S. J., Wang, L., Li, B., Wei, Y., Li, G., Wang, H., Zheng, Y., Zhao, Y., Wolf, M. E., Zhu, Y., Watabe-Uchida, M., & Li, Y.* (2023). Improved green and red GRAB sensors for monitoring dopaminergic activity in vivo. Nature Methods
  2. Wang, H.#, Qian, T.#, Zhao, Y., Zhuo, Y., Wu, C., Osakada, T., Chen, P., Chen, Z., Ren, H., Yan, Y., Geng, L., Fu, S., Mei, L., Li, G., Wu, L., Jiang, Y., Qian, W., Zhang, L., Peng, W., Xu, M., Hu, J., Jiang, M., Chen, L., Tang, C., Zhu, Y., Lin, D., Zhou, J.-N., & Li, Y.* (2023). A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors. Science
  3. Wu, Z.#, Cui, Y.#, Wang, H.#, Wu, H., Wan, Y., Li, B., Wang, L., Pan, S., Peng, W., Dong, A., Yuan, Z., Jing, M., Xu, M., Luo, M.*, & Li, Y.* (2023). Neuronal activity-induced, equilibrative nucleoside transporter-dependent, somatodendritic adenosine release revealed by a GRAB sensor. Proceedings of the National Academy of Sciences
  4. Dong, H.#, Li, M.#, Yan, Y., Qian, T., Lin, Y., Ma, X., Vischer, H. F., Liu, C., Li, G., Wang, H., Leurs, R., & Li, Y.* (2023). Genetically encoded sensors for measuring histamine release both in vitro and in vivo. Neuron
  5. Zeng, J.#*, Li, X.#, Zhang, R., Lv, M., Wang, Y., Tan, K., Xia, X., Wan, J., Jing, M., Zhang, X., Li, Y., Yang, Y., Wang, L., Chu, J., Li, Y., & Li, Y.*. (2023). Local 5-HT signaling bi-directionally regulates the coincidence time window for associative learning. Neuron
  6. Qian, T.#, Wang, H.#, Wang, P.#, Geng, L., Mei, L., Osakada, T., Wang, L., Tang, Y., Kania, A., Grinevich, V., Stoop, R., Lin, D., Luo, M., & Li, Y.* (2023). A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments. Nature Biotechnology
  7. Wu, Z.*, He, K., Chen, Y., Li, H., Pan, S., Li, B., Liu, T., Wang, H., Du, J., Jing, M., & Li, Y.* (2021). A sensitive GRAB sensor for detecting extracellular ATP in vitro and in vivo. Neuron
  8. Dong, A., He, K., Dudok, B., Farrell, J. S., Guan, W., Liput, D. J., Puhl, H. L., Cai, R., Wang, H., Duan, J., Albarran, E., Ding, J., Lovinger, D. M., Li, B., Soltesz, I., & Li, Y.*. (2021). A fluorescent sensor for spatiotemporally resolved imaging of endocannabinoid dynamics in vivo. Nature Biotechnology
  9. Wan, J., Peng, W., Li, X., Qian, T., Song, K., Zeng, J., Deng, F., Hao, S., Feng,J., Zhang, P., Zhang, Y., Zou, J., Pan, S., Shin, M., Venton, B. J., Zhu, J. J., Jing, M., Xu, M., Li, Y.*.(2021). A genetically encoded sensor for measuring serotonin dynamics. Nature Neuroscience
  10. Qian, C., Wu, Z., Sun, R., Yu, H., Zeng, J., Rao, Y., & Li, Y.* (2021). Localization, proteomics, and metabolite profiling reveal a putative vesicular transporter for UDP-glucose. eLife
  11. Sun, F.#, Zhou, J.#, Dai, B.#, Qian, T., Zeng, J., Li, X., Zhuo, Y., Zhang, Y., Wang, Y., Qian, C., Tan, K., Feng, J., Dong, H., Lin, D.*, Cui, G.*, & Li, Y.*.(2020). Next-generation GRAB sensors for monitoring dopaminergic activity in vivo. Nature Methods, https://doi.org/10.1038/s41592-020-00981-9.
  12. Jing, M.*, Li, Y., Zeng, J., Huang, P., Skirzewski, M., Kljakic, O., Peng, W., Qian, T., Tan, K., Wu, R., Zhang, S., Pan, S., Xu, M., Li, H., Saksida, L. M., Prado, V. F., Bussey, T., Prado, M. A. M., Chen, L., Cheng, H., Li, Y.*.(2020). An optimized acetylcholine sensor for monitoring in vivo cholinergic activity. Nature Methods, https://doi.org/10.1038/s41592-020-0953-2.
  13. Yu, H., Zhao, T., Liu, S., Wu, Q., Johnson, O., Wu, Z., Zhuang, Z., Shi, Y., He, R., Yang, Y., Sun, J., Wang, X., Xu, H., Zeng, Z., Lei, X., Luo, W.* & Li, Y.*. (2019). MRGPRX4 is a bile acid receptor for human cholestatic itch. eLife, 8, e48431.
  14. Feng, J., Zhang, C., Lischinsky, J. E., Jing, M., Zhou, J., Wang, H., Zhang, Y., Dong, A., Wu, Z., Wu, H., Chen, W., Zhang, P., Zou, J., Hires, S. A., Zhu, J. J., Cui, G., Lin, D., Du, J. & Li, Y.* (2019). A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo Detection of Norepinephrine. Neuron, 102(4), 745-761.
  15. Wu, Z.#, Feng, J.#, Jing, M., & Li, Y.* (2019). G protein-assisted optimization of GPCR-activation based (GRAB) sensors. Neural Imaging and Sensing 2019, vol. 10865, p. 108650N. International Society for Optics and Photonics.
  16. Wu, L., Dong, A., Dong, L., Wang, S. Q., & Li, Y*. (2019). PARIS, an optogenetic method for functionally mapping gap junctions. eLife, 8, e43366.
  17. Sun, F.#, Zeng, J.#, Jing, M.#, Zhou, J., Feng, J., Owen, S., Luo, Y., Li, F., Wang, H., Yamaguchi, T., Yong, Z., Gao, Y., Peng, W., Wang, L., Zhang, S., Du, J., Lin, D., Xu, M., Kreitzer, A. C., Cui, G. & Li, Y.* (2018). A genetically-encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice. Cell, 174(2), 481-496.
  18. Jing, M.#, Zhang, P.#, Wang, G., Feng, J., Mesik, L., Zeng, J., Jiang, H., Wang, S., Looby, J. C., Guagliardo, N. A., Langma, L. W., Lu, J., Zuo, Y., Talmage, D. A., Role, L. W., Barrett, P. Q., Zhang, L. I., Luo, M., Song, Y., Zhu, JJ* & Li, Y*. (2018). A genetically-encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. Nature Biotechnology, 36(8), 726-737.
  19. Li, Y.*, & Tsien, R. W.* (2012). pHTomato, a red, genetically encoded indicator that enables multiplex interrogation of synaptic activity. Nature neuroscience, 15(7), 1047-1053.
  20. Li, Y., Augustine, G. J., & Weninger, K.* (2007). Kinetics of complexin binding to the SNARE complex: correcting single molecule FRET measurements for hidden events. Biophysical journal, 93(6), 2178-2187.

合作发表论文：

  1. Sang, D.#, Lin, K.#, Yang, Y.#, Ran, G., Li, B., Chen, C., Li, Q., Ma, Y., Lu, L., Cui, X.-Y., Liu, Z., Lv, S.-Q., Luo, M., Liu, Q., Li, Y., & Zhang, E. E.* (2023). Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals. Cell, 186(25), 5500-5516.e5521. 
  2. Terauchi, A., Yee, P., Johnson-Venkatesh, E. M., Seiglie, M. P., Kim, L., Pitino, J. C., Kritzer, E., Zhang, Q., Zhou, J., Li, Y., Ginty, D. D., Lee, W. A., & Umemori, H.# (2023). The projection-specific signals that establish functionally segregated dopaminergic synapses. Cell, https://doi.org/10.1016/j.cell.2023.07.023.
  3. Krok, A. C., Maltese, M., Mistry, P., Miao, X., Li, Y., & Tritsch, N. X.# (2023). Intrinsic dopamine and acetylcholine dynamics in the striatum of mice. Nature, https://doi.org/10.1038/s41586-023-05995-9.
  4. Yu, X., Zhao, G., Wang, D., ...Li, Y., Dong, H.#, Franks, N.# & William, W. # (2022). A specific circuit in the midbrain detects stress and induces restorative sleep. Science, 377, 63-72.
  5. Provencher, V. #, Drummond, G., Feng, J., Li, Y. & Sur, M. # (2022). Spatiotemporal dynamics of noradrenaline during learned behavior. Nature, 606, 732-738.
  6. Liu, C. #, Cai, X., Ritzau-Jost, A., Kramer, P.F., Li, Y., Khaliq, Z.M., Hallermann, S. & Kaeser P.S. # (2022). An action potential initiation mechanism in distal axons for the control of dopamine release. Science, 375, 1378-1385.
  7. Hasegawa, E., Miyasaka, A., Sakurai, K., Cherasse, Y., Li, Y., & Sakurai, T. # (2022). Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice. Science, 375(6584), pp.994-1000.
  8. Deng, H., Xiao, X., Yang, T., …, Li, Y., Huang, J. & Li, B. #. (2021) A genetically defined insula-brainstem circuit selectively controls motivational vigor. Cell, 184, 6344-6360.
  9. Wang, J.#, Li, J.#, Yang, Q.#, Xie, Y.-K., Wen, Y.-L., Xu, Z.-Z., Li, Y., Xu, T., Wu, Z.-Y., Duan, S., & Xu, H.* (2021). Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons. Proceedings of the National Academy of Sciences，118(7), e2019295118. https://doi.org/10.1073/pnas.2019295118.
  10. Kim, H. R.*, Malik, A. N., Mikhael, J. G., Bech, P., Tsutsui-Kimura, I., Sun, F., Zhang, Y., Li, Y., Watabe-Uchida, M., Gershman, S. J., & Uchida, N.* (2020). A Unified Framework for Dopamine Signals across Timescales. Cell, https://doi.org/https://doi.org/10.1016/j.cell.2020.11.013.
  11. Peng, W.#, Wu, Z.#, Kun, S.#, Zhang, S., Li, Y. & Min, X.* (2020). Regulation of sleep homeostasis mediator adenosine by basal forebrain glutamatergic neurons. Science, 369, 1208.
  12. Mazzone, C.M., Liang-Guallpa, J.,Li, C., Wolcott, N. S., Boone, M. H., Southern, M., Kobzar, N. P., Salgado, I. A., Reddy, D. M., Sun, F., Zhang, Y., Li, Y., Cui, G. * & Krashes, M. J.* (2020). High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nature Neuroscience, https://doi.org/10.1038/s41593-020-0684-9.
  13. Lin, R., Liang, J., Wang, R., Yan, T., Zhou, Y., Liu, Y., Feng, Q., Sun, F.,, Li, Y., Li, A., Gong, H., & Luo, M.* (2020). The Raphe Dopamine System Controls the Expression of Incentive Memory. Neuron, 1420-19.
  14. Handler, A., Graham, T. G. M., Cohn, R., Morantte, I., Siliciano, A. F., Zeng J., Li, Y. & Ruta, V.* (2019). Distinct dopamine receptor pathways underlie the temporal sensitivity of associative learning. Cell, 178(1), 60-75.
  15. Li, B.#, Wong, C.#, Gao, S. M., Zhang, R., Sun, R., Li, Y., & *Song, Y. (2018). The retromer complex safeguards against neural progenitor-derived tumorigenesis by regulating Notch receptor trafficking. eLife, 7, e38181.
  16. Tanaka, M., Sun, F., Li, Y., & Mooney, R.* (2018). A mesocortical dopamine circuit enables the cultural transmission of vocal behaviour. Nature, 563(7729), 117-120.
  17. Shen, Y., Ge, W. P., Li, Y., Hirano, A., Lee, H. Y., Rohlmann, A., Missler, M., Tsien, R. W., Jan, L. Y., Fu, Y. H.* & Ptacek, L. J.* (2015). Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis. Proceedings of the National Academy of Sciences, 112(10), 2935-2941.
  18. Liang, L., Li, Y., Potter, C. J., Yizhar, O., Deisseroth, K., Tsien, R. W., & Luo, L.* (2013). GABAergic Projection Neurons Route Selective Olfactory Inputs to Specific Higher-Order Neurons. Neuron, 79(5), 917-931.
  19. Park, H., Li, Y., & Tsien, R. W.* (2012). Influence of synaptic vesicle position on release probability and exocytotic fusion mode. Science, 335(6074), 1362-1366.
  20. Yoo, A. S.*, Sun, A. X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R. E., Tsien R. W. & Crabtree, G. R.* (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature, 476(7359), 228-231.
  21. Zhang, Q., Li, Y., & Tsien, R. W.* (2009). The dynamic control of kiss-and-run and vesicular reuse probed with single nanoparticles. Science, 323(5920), 1448-1453.
  22. Kuner, T.*, Li, Y., Gee, K. R., Bonewald, L. F., & Augustine, G. J. (2008). Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release. Proceedings of the National Academy of Sciences, 105(1), 347-352.

综述 & 书评

  1. Qian, T., Wang, H., Xia, X., & Li, Y.# (2023) Current and emerging methods for probing neuropeptide transmission. Current Opinion in Neurobiology, 81, 102751.
  2. Dong, C.*, Zheng, Y.*, Long-Iyer, K., Wright, E. C., Li, Y. #, & Tian, L. # (2022). Fluorescence imaging of neural activity, neurochemical dynamics, and drug-specific receptor conformation with genetically encoded sensors. Annual Review of Neuroscience, 44:1.
  3. Wu, Z., Lin, D. & Li, Y. # (2022). Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators. Nature Reviews Neuroscience, 23, 257-274.
  4. Zhuo, Y. & Li, Y. # (2022). New imaging methods for monitoring dopaminergic neurotransmission. Sci China Life Sci, 65(4): 838-841.
  5. Q&A: Yulong Li. (2021). Neuron, 109(21), 3346-3348.
  6. Wu, Z. #, & Li, Y. # (2020). New frontiers in probing the dynamics of purinergic transmitters in vivo. Neuroscience research, 152, 35-43.
  7. Wan, J. & Li, Y.* (2020). Recent Advances in Detection Methods for Neurotransmitters. Chinese Journal of Analytical Chemistry, 48(3), 307-315. (In Chinese)
  8. Wu, Z.* & Li, Y.* (2020). New frontiers in probing the dynamics of purinergic transmitters in vivo. Neuroscience Research, https://doi.org/10.1016/j.neures.2020.01.008.
  9. Zeng, J., Sun, F., Wan, J., Feng, J. & Li, Y.* (2019). New optical methods for detecting monoamine neuromodulators. Current Opinion in Biomedical Engineering, https://doi.org/10.1016/j.cobme.2019.09.010.
  10. Jing, M., Zhang, Y., Wang, H. & Li, Y.* (2019). GPCR‐based sensors for imaging neurochemicals with high sensitivity and specificity. Journal of Neurochemistry, https://doi.org/10.1111/jnc.14855.
  11. Dong, A.*, Liu, S., & Li, Y.* (2018). Gap Junctions in the Nervous System: Probing Functional Connections Using New Imaging Approaches. Frontiers in Cellular Neuroscience, 12, 320.
  12. Wang, H., Jing, M., & Li, Y.* (2018). Lighting up the brain: genetically encoded fluorescent sensors for imaging neurotransmitters and neuromodulators. Current Opinion in Neurobiology, 50, 171-178.
  13. Wang, A.#, Feng, J.#, Li, Y.*, & Zou, P.* (2018). Beyond Fluorescent Proteins: Hybrid and Bioluminescent Indicators for Imaging Neural Activities. ACS chemical neuroscience, 9(4), 639-650.
  14. Qian, C., & Li, Y.* (2015). Spine maturation and pruning during development: Cadherin/Catenin complexes come to help. Science China. Life sciences,58(9), 929.
  15. Li, Y.*, & Rao, Y.* (2015). Pied Piper of Neuroscience. Cell, 163(2), 267-268.

实验室网站：

http://www.yulonglilab.org/