Min Zhuo (born 1964) is a pain neuroscientist at the University of Toronto in Canada. He is 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. Zhou was hosted in 2017-2018 as a guest professor at the pharmacology institute at Heidelberg University, Heidelberg.
Education
At the age of 16, Zhuo was admitted to the University of Science and Technology of China in Hefei — graduating in 1985. He obtained his PhD at the University of Iowa 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.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 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,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. GluN2B and AC1 are novel therapeutic targets for treating chronic painWei 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.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. In 2003, he moved to the University of Toronto, and identified NB001 as a selective inhibitor for AC1.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). He co-established two online journals, Molecular Pain and Molecular Brain. In 2009, he was elected to Fellow of the 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 1988-1992 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.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.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.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.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.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, 2928-2941Zhuo 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. 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 relieve chronic pain.Gebhart GF (2004) Descending modulation of pain. Neuroscience & Biobehavioral Reviews 27:729-737
LTP and memory: Columbia & Stanford 1992-1995 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.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, 1946-1950.3. 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. 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.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. Recent genetic studies confirm the importance of PKGs in central plasticity.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):e1001283Eguchi 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):517-29Saywell 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 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).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.
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 provided key synaptic mechanisms for possible recruitment of such silent nociceptive pathways in chronic pain conditions.Li, P., and Zhuo, M. (1998). Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393, 695-698.Zhuo M (2000). Silent glutamatergic synapses and long-term facilitation in spinal dorsal horn neurons. Prog Brain Res 129, 101-113 (review). It also provided 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 animal model of chronic pain.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. 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 University, where they discovered 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.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 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.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 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).[See "Going North"] In Toronto, Zhuo decided to focus on synaptic plasticity in the anterior cingulate cortex, a key cortical region for pain, and has mapped the signalling pathways for LTP and LTD in the ACC.Zhuo, M. (2008) Cortical plasticity and chronic pain. Trends in Neurosciences, 31:199-207. (Review) 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