Min Zhuo

Min Zhuo (born 1964) is a pain neuroscientist at the University of Toronto in Canada. He is also the Michael Smith Chair in Neuroscience and Mental Health as well as the Canada Research Chair in Pain and Cognition and a Fellow of the Royal Society of Canada. Supported by the Heidelberg Pain Consortium, Zhou was hosted in 2017-2018 as a Guest Professor at the Pharmacology Institute at Heidelberg University, Heidelberg.

In this Chinese name, the family name is Zhuo.
Min Zhuo

Education

Zhuo was born in 1964 in Xiapu. At the age of 16, he was admitted to the University of Science and Technology of China in Hefei — graduating in 1985. At the University of Iowa, he completed his PhD in Professor Jerry Gebhart's laboratory. In 1992, Zhuo joined Eric Kandel's laboratory at Columbia University where he showed CO-cGMP as key messengers for presynaptic LTP.[1] In 1995, Zhuo spent one year in Richard Tsien's laboratory at Stanford University. In 1996, Zhuo moved to Washington University in St. Louis and focused on pain plasticity in the spinal cord and cortex. He showed that 'smart' mice suffered more pain,[2] GluN2B and AC1 are novel therapeutic targets for treating chronic pain[3][4] In 2003, he moved to the University of Toronto, and identified NB001 as a selective inhibitor for AC1.[5] He co-established two online journals, Molecular Pain and Molecular Brain. In 2009, he was elected to Fellow of Royal Society of Canada.

Research

Early interests in pain and acupuncture: Shanghai

Born in 1964 in Xiapu, a seaside town in Fujian, China, Zhuo grew up inspired by the mountain villages and scenery. He started painting with the help of his mother and planned to pursue a career in art — perhaps as a teacher. It was not until later in life that he became interested in pursuing a career in science. In 1980, he was accepted into the University of Science and Technology of China in Hefei, from which he graduated in 1985. From there he went on to the Chinese Academy of Sciences, Shanghai Branch where his work focused mainly on the basic mechanism of acupuncture and pain.

Descending modulation of pain: Iowa

In 1988, Zhuo joined Jerry Gebhart's laboratory at the University of Iowa as a visiting student. He then joined the graduate program as a PhD student. Using integrative pharmacological, electrophysiological and behavioral methods, he discovered a novel descending facilitatory modulation of spinal nociceptive transmission from the RVM.[6][7][8][9][10][11] Descending facilitation has a general impact on spinal sensory transmission, inducing sensory inputs from cutaneous and visceral organs. Recent studies found that descending facilitation is likely activated or to be up-regulated in chronic pain conditions, providing basic evidence for inhibiting descending facilitation to help to relief chronic pain.[12]

LTP and memory: Columbia & Stanford

In 1992, Zhuo graduated from University of Iowa with PhD degree in Pharmacology. The same year, he joined Eric Kandel's laboratory at Columbia University. During this time, Zhuo worked on hippocampal plasticity and showed that carbon monoxide (CO), together with nitric oxide (NO), may serves as retrograde messengers in hippocampal LTP.[13][14] Together with Dr. Yinhe Hu, he further discovered that soluble guanylyl clcyaes (sGC) and cGMP-dependent protein kinase (PKG) act downstream from these diffusible messengers.[15] Recent genetic studies confirm the importance of PKGs in central plasticity.[16][17][18] In 1995, after being offered an independent faculty job at Washington University in St Louis, Zhuo joined Richard Tsien’s laboratory in Stanford for one year. While at Stanford Zhuo mastered whole-cell patch-clamp techniques and was the first one to show that direct patching of dendrites in isolated hippocampal neuronal preparations. Together with Ege Kavalali and Haruhiko Bito, they published together a key study on voltage-gated calcium channels in neuronal dendrites (or called dendrosomes).[19]

Silent synapses in the cord: St Louis

After finishing his postdoctoral training, Zhuo started his own laboratory, in 1996, at Washington University in St Louis. He decided to combine his knowledge of pain and synaptic plasticity of hippocampal memory, and explored possible changes in spinal cord dorsal horn. With the research assistance of Ms Ping Li, he identified silent synapses in spinal cord dorsal horn, and provides key synaptic mechanisms for possible recruitment of such silent nociceptive pathways in chronic pain conditions.[20][21] It also provides synaptic mechanism for G protein coupled pathways in the facilitatory modulation of spinal sensory transmission. He further demonstrated that the interaction between AMPA receptor and PDZ proteins is critical, and inhibiting such interaction provide analgesic effects in animals model of chronic pain.[22] He is the founding member of Washington University Pain center, and acted as chief for basic research until he left for Toronto in 2003.

From 'smart mice' to chronic pain

While working in St Louis Zhuo collaborated on a project with Professor Guosong Liu of MIT and Joe Tsien of Princeton Universitywhere they made the discovery that enhancing NMDA NR2B receptors in the forebrain neurons enhanced LTP in the hippocampus. More importantly, such enhancement is selective, since LTD is not affected in the same mice. This work provides direct evidence that enhancing LTP can increase learning capacity.[23] Because NMDA NR2B (GluN2B) is developmentally regulated, Zhuo decided to explore whether or not there is any evolutionary disadvantage to being 'smart'. Zhuo found that NR2B expression lead to the enhancement of chronic pain.[24] These genetic and behavioral studies provide the first direct evidence that forebrain NMDA receptors play important roles in persistent pain.

Cortical plasticity as a key mechanism for chronic pain

In 2003, Zhuo moved to University of Toronto in Canada as EJLB-Michael Smith Chair in Neuroscience and mental health and Canada Research Chair (CRC).[25] In Toronto, Zhuo decided to focus on synaptic plasticity in the anterior cingulate cortex, a key cortical region for pain, and has mapped the signaling pathways for LTP and LTD in the ACC.[26] The discovery of LTP in pain-related cortex provides direct evidence for pathological mechanism of chronic pain as well as pain-related emotional disorders. Before these discoveries, most of academic and pharmaceutical investigators mainly focused on DRG and spinal cord when searching for new treatments for chronic pain.

Upregulation of cortical AMPAR and NMDA NR2B receptor after nerve injury

Upregulation of AMPARs and/or the increase of presynaptic release are known to contribute to synaptic potentiation and behavioral learning, while postsynaptic NMDA receptors are not significantly affected. Unlike in learning and memory, Zhuo found that cortical synapses and circuits are undergoing dramatic changes after peripheral never injury. In addition to postsynaptic AMPARs, Min found that NMDA receptors are significantly increased in the ACC as well as insular cortex. Inhibiting NMDA NR2B receptors in these brain areas produced significant analgesic effects in animal models of neuropathic pain.[27][28][29] Positive feedback mechanisms at synaptic and circuit levels are proposed to explain why chronic pain is long-lasting and difficult to treat.[30]

AC1 as a key target for pain plasticity and chronic pain

Between the time in St Louis and Toronto, Zhuo identified calcium stimulated adenylyl cyclase subtype 1 as being a key enzyme for triggering injury-related LTP in the ACC.[31][32] Using gene knockout mice lacking AC1, he discovered that AC1 is critical for ACC LTP (including early- and late-phase LTP). While acute pain responses are normal in AC1 knockout mice, behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant as well as nerve injury were reduced or abolished. Considering AC1 is highly expressed in neurons including the ACC, Zhuo proposed that AC1 acts as a key drug target for inhibiting chronic pain related plasticity in the brains.[33] Unlike other targets, learning-related hippocampal LTP and behavioral learning and memory are not affected by AC1 gene deletion.

Gain in translation: NB001 as a novel drug for treating chronic pain in future

To search selective inhibitors for AC1, Zhuo has carried out rational drug design and chemical screening, and has a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, NB001, when administered intraperitoneally or orally, was found to have an analgesic effect in animal models of neuropathic pain, without any apparent side effects. The study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.[34]

Honors and awards
  • 2005: The EJLB-CIHR Michael Smith Chair in Neuroscience and Mental Health
  • 2005: Canada Research Chair in Pain and Cognition, Tier I
  • 2005: Chang Jiang Visiting Scholar in Neurobiology
  • 2008: World-Class University Scholar, Seoul National University
  • 2009: Elected to Royal Society of Canada
  • 2012: AND investigator award

References
  1. Zhuo M, Small SA, Kandel ER, Hawkins RD (1993). Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 260, 1946-1950
  2. Wei F, Wang GD, Kerchner GA, Kim SJ, Xu HM, Chen ZF, Zhuo M (2001). Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci 4, 164-169.
  3. Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, Zhuo M (2002). Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.
  4. Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, Zhuo M (2002). Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713-726.
  5. Wang H, Xu H, Wu LJ, Kim SS, Chen T, Koga K, Descalzi G, Gong B, Vadakkan KI, Zhang X, Kaang BK, Zhuo M. (2011) Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Science Translational Medicine, ;3(65):65ra3 (Comment in: Nat Rev Drug Discov. 2011 Mar;10(3):176).
  6. Zhuo M and Gebhart GF (1990). Characterization of descending inhibition and facilitation from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. Pain 42, 337-350.
  7. Zhuo M and Gebhart GF (1992). Characterization of descending facilitation and inhibition of spinal nociceptive transmission from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. J Neurophysiol 67, 1599-1614.
  8. Zhuo M and Gebhart GF (1997). Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. J Neurophysiol 78, 746-758.
  9. Zhuo M and Gebhart GF (2002). Facilitation and attenuation of a visceral nociceptive reflex from the rostroventral medulla in the rat. Gastroenterology 122, 1007-1019.
  10. Zhuo M and Gebhart GF (2002). Modulation of noxious and non-noxious spinal mechanical transmission from the rostral medial medulla in the rat. J Neurophysiol 88, 2928-2941
  11. Zhuo M, Sengupta JN, Gebhart GF (2002). Biphasic modulation of spinal visceral nociceptive transmission from the rostroventral medial medulla in the rat. J Neurophysiol 87, 2225-2236.
  12. Gebhart GF (2004) Descending modulation of pain. Neuroscience & Biobehavioral Reviews 27:729-737
  13. Zhuo, M., Small, S. A., Kandel, E. R., and Hawkins, R. D. (1993). Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 260, 1946-1950.
  14. 3. Zhuo, M., Hu, Y., Schultz, C., Kandel, E. R., and Hawkins, R. D. (1994). Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature 368, 635-639.
  15. Zhuo, M., Hu, Y., Schultz, C., Kandel, E. R., and Hawkins, R. D. (1994). Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation. Nature 368, 635-639.
  16. Luo C, Gangadharan V, Bali KK, Xie RG, Agarwal N, Kurejova M, Tappe-Teodor A, Tegeder I, Feil S, Lewin G, Polgar E, Todd AJ, Schlossmann J, Hofmann F, Liu DL, Hu SJ, Kuner T, Kuner R (2012) Presynaptically localized cyclic GMP-dependent protein kinase 1 is a key determinant of spinal potentiation and pain hypersensitivity. PLoS Biol. 10(3):e1001283
  17. Eguchi K, Nakanishi S, Takagi H, Taoufiq Z, Takahashi T. (2012) Maturation of a PKG-dependent retrograde mechanism for exoendocytic coupling of synaptic vesicles. Neuron. 10;74(3):517-29
  18. Saywell SA, Babiec WE, Neverova NV, Feldman JL (2010) Protein kinase G-dependent mechanisms modulate hypoglossal motoneuronal excitability and long-term facilitation. J Physiol 588(22):4431-9
  19. Kavalali, E. T., Zhuo, M., Bito, H., and Tsien, R. W. (1997). Dendritic Ca2+ channels characterized by recordings from isolated hippocampal dendritic segments. Neuron 18, 651-663.
  20. Li, P., and Zhuo, M. (1998). Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393, 695-698.
  21. Zhuo M (2000). Silent glutamatergic synapses and long-term facilitation in spinal dorsal horn neurons. Prog Brain Res 129, 101-113 (review).
  22. Li, P., Kerchner, G. A., Sala, C., Wei, F., Huettner, J. E., Sheng, M., and Zhuo, M. (1999). AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 2, 972-977.
  23. Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., and Tsien, J. Z. (1999). Genetic enhancement of learning and memory in mice. Nature 401, 63-69
  24. Wei, F., Wang, G. D., Kerchner, G. A., Kim, S. J., Xu, H. M., Chen, Z. F., and Zhuo, M. (2001). Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci 4, 164-169
  25. [See "Going North"]
  26. Zhuo, M. (2008) Cortical plasticity and chronic pain. Trends in Neurosciences, 31:199-207. (Review)
  27. Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, Wei F, Xu TL, Muglia LJ, Chen ZF, Auberson YP, Kaang BK, Zhuo M. (2005). Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci 25, 11107-11116.
  28. Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M. (2010) Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 330:1400-1404.
  29. Qiu S, Chen T, Koga K, Guo YY, Xu H, Song Q, Wang JJ, Descalzi G, Kaang BK, Luo JH, Zhuo M, Zhao MG. (2013) An Increase in Synaptic NMDA Receptors in the Insular Cortex Contributes to Neuropathic Pain. Sci Signal 6:ra34
  30. Zhuo, M (2008) Cortical plasticity and chronic pain. Trends in Neurosci, 31:199-207.
  31. Wei, F., Qiu, C. S., Kim, S. J., Muglia, L., Maas, J. W., Pineda, V. V., Xu, H. M., Chen, Z. F., Storm, D. R., Muglia, L. J., and Zhuo, M. (2002). Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713-726.
  32. Liauw J, Wu LJ, Zhuo M (2005). Calcium-stimulated adenylyl cyclases required for long-term potentiation in the anterior cingulate cortex. J Neurophysiol 94, 878-882.
  33. Zhuo, M (2012) AC1 as a target for treating chronic pain. Drug Discovery Today, 17:573-582.
  34. Wang H, Xu H, Wu LJ, Kim SS, Chen T, Koga K, Descalzi G, Gong B, Vadakkan KI, Zhang X, Kaang BK, Zhuo M. (2011) Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Science Translational Medicine, ;3(65):65ra3 (Comment in: Nat Rev Drug Discov. 2011 Mar;10(3):176).
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