Joe Z. Tsien

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Joe Z. Tsien is a neuroscientist who pioneered Cre/lox-neurogenetics in the mid-1990s,[1] a versatile toolbox for neuroscientists to study the complex relationships between genes, neural circuits, and behaviors.[2] He is also known as the creator of the smart mouse Doogie in the late 1990s while being a faculty member at Princeton University.[3][4] Recently, he developed the Theory of Connectivity in an effort to explain the origin of intelligence, or the basic design principle underlying brain computation and intelligence.[5][6] The theory states that brain computation is organized by a power-of-two-based permutation logic in constructing cell assemblies - the basic building blocks of neural circuits.[7] The theory has received initial validation from experiments. The discovery of this basic computational logic of the brain can have important implications for the development of artificial general intelligence.


Tsien earned his A.B. in Biology/Physiology from East China Normal University in Shanghai (1984) and his Ph.D. in Molecular Biology from the University of Minnesota in 1990. He completed two postdoctoral fellowships with two Nobel laureates, Dr. Eric Kandel at Columbia University and Dr. Susumu Tonegawa at MIT.[citation needed]


In 1997, he became a faculty member in the Department of Molecular Biology at Princeton University. He is currently a Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology, professor of Neurology and co-director of the Brain and Behavior Discovery Institute in the Medical College of Georgia at Augusta University in Augusta, Georgia, United States. Tsien leads a team of neuroscientists, computer scientists and mathematicians, working on the BRAIN DECODING project initiated in 2007 by Georgia Research Alliance.[8]


Tsien pioneered Cre-loxP-mediated brain subregion- and cell type-specific genetic techniques in 1996,[2] enabling researchers to manipulate or introduce any gene in a specific brain region or a given type of neuron.[1] This transformative technique has led to NIH Blueprint for Neuroscience Research in launching several Cre-driver Mouse Resource projects. Over the past 20 years, Cre-lox recombination-mediated neurogenetics has emerged as one of the most powerful and versatile technology platforms for cell-specific gene knockouts, transgenic overexpression, neural circuit tracing, Brainbow, optogenetics, CLARITY, voltage imaging and chemical genetics.[1][9][10]

Tsien is also widely known as the creator of the smart mouse Doogie.[11] While as a faculty at Princeton University, Tsien has speculated that one of the NMDA receptor's subunit may hold the key for superior learning and memory at young ages. Accordingly, his laboratory genetically engineered a transgenic mouse in which they over-expressed the NR2B subunit of the NMDA receptor in the mouse cortex and hippocampus. In 1999, his team reported that the transgenic mouse, nicknamed Doogie, indeed showed to have enhanced synaptic plasticity and enhanced learning and retention as well as greater flexibility in learning new patterns.[3] The discovery of the NR2B as a key genetic factor for memory enhancement prompted other researchers to discover over two dozen other genes for memory enhancement, many of which regulate the NR2B pathway.[12] One of the NR2B-based memory-enhancement strategies, via dietary supplements of a brain-penetrating magnesium ion, magnesium L-threonate, is currently undergoing clinical trials for memory improvement.[13][14]

Tsien has also made several other major discoveries, including the unified cell-assembly mechanism for explaining how episodic memory and semantic memory are generated in the memory circuits.[15][16][17] His laboratory also discovered the nest cells in the mouse brain, revealing how animals recognize the abstract concept of nest or home.[18][19]

Tsien is also the first to show that defective Alzheimer's genes (e.g. presenilin-1) impaired adult neurogenesis in the dentate gyrus of the hippocampus,[20] revealing the role of adult neurogenesis in memory clearance.[21][22]

In addition, Tsien has developed a method capable of selectively erasing a memory of choice, such as a particular fear memory, in the mouse brain.[23][24]

Tsien also demonstrated that the NMDA receptor in the dopamine circuit plays a crucial role in the formation of habit.[25][26][27]

Tsien is currently leading a team of neuroscientists, computer scientists and mathematicians, who are working on the Brain Decoding Project,[28] a large-scale brain activity mapping effort, which he and his colleagues have initiated since 2007 with the support from the Georgia Research Alliance (GRA).[29]

In 2015, Tsien developed the Theory of Connectivity to explain the design principle upon which evolution and development may construct the brain to be capable of generating intelligence.[5][6] This theory has made six predictions which have received supportive evidence by a recent set of experiments on both the mouse brain and hamster brain.[7] At its core, the Theory of Connectivity predicts that the cell assemblies in the brain are not random, rather they should conform to the power-of-two-based equation, N = 2i - 1, to form the pre-configured building block termed as the functional connectivity motif (FCM). Instead of using a single neuron as the computational unit in some extremely simple brains, the theory denotes that in most brains, a group of neurons exhibiting similar tuning properties, termed as a neural clique, should serve as the basic computing processing unit (CPU). Defined by the power-of-two-based equation, N = 2i - 1, each FCM consists of principal-projection neuron cliques (N), ranging from those specific cliques receiving specific information inputs (i) to those general and sub-general cliques receiving various combinatorial convergent inputs. As the evolutionarily conserved logic, its validation requires experimental demonstrations of the following three major properties: 1) Anatomical prevalence - FCMs are prevalent across neural circuits, regardless of gross anatomical shapes; 2) Species conservancy - FCMs are conserved across different animal species; and 3) Cognitive universality - FCMs serve as a universal computational logic at the cell-assembly level for processing a variety of cognitive experiences and flexible behaviors. More importantly, this Theory of Connectivity further predicts that the specific-to-general combinatorial connectivity pattern within FCMs should be pre-configured by evolution, and emerge innately from development as the brain's computational primitives. This proposed design principle can also explain the general purpose and computational algorithm of the neocortex. This proposed design principle of intelligence can be examined via various experiments and also be modeled by neuromorphic engineers and computer scientists. However, Dr. Joe Tsien cautions that artificial general intelligence based on the brain's principles can come with great benefits and, potentially, even greater risks.[30]


Tsien has received awards for his research contributions, including:

  • 2012 Distinguished Scientist Award from the International Behavioral and Neural Genetics Society
  • Keck Distinguished Young Scholar Award
  • Burroughs Wellcome Young Investigator Award
  • Scientific Achievement Award from the Association of Chinese Americans
  • Beckman Young Investigator Award

Popular science[edit]

Tsien has contributed articles to Scientific American in the areas of neuroscience of memory enhancement and memory decoding.[4][31] He has written chapters on learning and memory for several popular textbooks.


According to the Song dynasty book, Tongzhi, the Qian surname (Tsien) descends from one of the legendary Five Emperors (Zhuanxu, mythological emperor of ancient China, Shang dynasty, Chinese: 商朝). Emperor Zhuanxu (Chinese: trad. 顓頊, simp. 颛顼, pinyin Zhuānxū), also known as Gaoyang (t 高陽, s 高阳, p Gāoyáng) who was the grandson of the first Chinese Emperor known as Yellow Emperor, ruled the Yellow River valley, the origin of China, in the second millennium BC from 2514 BC – 2436 BC (Early Bronze Age). During the Five Dynasties and Ten Kingdoms period (907-960), King Qian Liu and his descendants ruled the independent kingdom of Wuyue in south-eastern China. Joe Tsien was born in 1962 in Wuxi and is the 42nd generation of Qian Liu descendants.


  1. ^ a b c Tsien et al. (1996). "Subregion- and cell type-restricted gene knockout in mouse brain". Cell. 87: 1317–26. doi:10.1016/S0092-8674(00)81826-7. PMID 8980237.CS1 maint: Uses authors parameter (link)
  2. ^ a b Tsien JZ. (2016). Cre-lox neurogenetics: 20 years of versatile applications in brain research and counting...Front. Genet. | doi: 10.3389/fgene.2016.00019.
  3. ^ a b Tang, YP; Shimizu, E; Dube, GR; Rampon, C; Kerchner, GA; Zhuo, M; Liu, G; Tsien, JZ (Sep 1999). "Genetic enhancement of learning and memory in mice". Nature. 401 (6748): 63–9. doi:10.1038/43432. PMID 10485705.
  4. ^ a b Tsien, Building a Brainer Mouse. Scientific American, April, p62-68, 2000.
  5. ^ a b Tsien, JZ (2016). "Principles of Intelligence: On Evolutionary Logic of the Brains". Front. Syst. Neurosci. 9. doi:10.3389/fnsys.2015.00186.
  6. ^ a b Tsien, JZ (Nov 2015). "A Postulate on the Brain's Basic Wiring Logic". Trends Neurosci. 38 (11): 669–71. doi:10.1016/j.tins.2015.09.002.
  7. ^ a b Xie et al. "Brain Computation Is Organized via Power-of-Two-Based Permutation Logic". Frontiers in Systems Neuroscience. 10. doi:10.3389/fnsys.2016.00095.CS1 maint: Uses authors parameter (link)
  8. ^ "Meaning of the mind (Georgia Research Alliance)".
  9. ^ Taniguchi, H; He, M; Wu, P; Kim, S; Paik, R; Sugino, K; Kvitsiani, D; Fu, Y; Lu, J; Lin, Y; Miyoshi, G; Shima, Y; Fishell, G; Nelson, SB; Huang, ZJ (September 22, 2011). "A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex". Neuron. 71 (6): 995–1013. doi:10.1016/j.neuron.2011.07.026. PMC 3779648. PMID 21943598.
  10. ^ Cre lines characterized by the JAX Cre Resource (
  11. ^ Wade, Nicholas (1999-09-07). "SCIENTIST AT WORK: Joe Z. Tsien; Of Smart Mice and an Even Smarter Man". The New York Times. ISSN 0362-4331.
  12. ^ Lehrer, Jonah (2009-10-14). "Neuroscience: Small, furry … and smart". Nature News. 461 (7266): 862–864. doi:10.1038/461862a.
  13. ^ Cyranoski, David. "Testing magnesium's brain-boosting effects". Nature. doi:10.1038/nature.2012.11665.
  14. ^ Liu, G; Weinger, JG; Lu, ZL; Xue, F; Sadeghpour, S. (2015). "Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Elderly: A Randomized, Double-Blind, Placebo-Controlled Trial". J Alzheimers Dis (2015 Oct 27).
  15. ^ Lin, L; Osan, R; Shoham, S; Jin, W; Zuo, W; Tsien, JZ (Apr 2005). "Identification of network-level coding units for real-time representation of episodic experiences in the hippocampus". Proc Natl Acad Sci U S A. 102 (17): 6125–30. doi:10.1073/pnas.0408233102. PMC 1087910. PMID 15833817.
  16. ^ Lin, L; Osan, R; Tsien, JZ (Jan 2006). "Organizing principles of real-time memory encoding: neural clique assemblies and universal neural codes". Trends Neurosci. 29 (1): 48–57. doi:10.1016/j.tins.2005.11.004. PMID 16325278.
  17. ^ The Boston Globe: The mouse that remembered Terror of Disney ride sparks brain insight.
  18. ^ Lin, L; Chen, G; Kuang, H; Wang, D; Tsien, JZ (Apr 2007). "Neural encoding of the concept of nest in the mouse brain". Proc Natl Acad Sci U S A. 104 (14): 6066–71. doi:10.1073/pnas.0701106104. PMC 1851617. PMID 17389405.
  19. ^
  20. ^ Feng; et al. (2001). "Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces". Neuron. 32 (5): 911–26. doi:10.1016/s0896-6273(01)00523-2. PMID 11738035.
  21. ^ News by Nature magazine.
  22. ^
  23. ^ Cao; et al. (Oct 2008). "Inducible and selective erasure of memories in the mouse brain via chemical-genetic manipulation". Neuron. 60 (2): 353–66. doi:10.1016/j.neuron.2008.08.027. PMC 2955977. PMID 18957226.
  24. ^ ‘Eternal Sunshine’ drug selectively erases memories by New Scientist.
  25. ^ Wang; et al. "NMDA Receptors in Dopaminergic Neurons Are Crucial for Habit Learning". Neuron. 72 (6): 1055–1066. doi:10.1016/j.neuron.2011.10.019. PMC 3246213. PMID 22196339.
  26. ^ Wall Street Journal: How Habits Hold Us.
  27. ^ Video Abstract from NEURON magazine.
  28. ^
  29. ^ "On initial Brain Activity Mapping of episodic and semantic memory code in the hippocampus". Neurobiology of Learning and Memory. 105: 200–210. doi:10.1016/j.nlm.2013.06.019.
  30. ^ Tsien, Joe Z. (2016). "Principles of Intelligence: On Evolutionary Logic of the Brain". Frontiers in Systems Neuroscience. 9. doi:10.3389/fnsys.2015.00186. ISSN 1662-5137.
  31. ^ Tsien, The memory code, Scientific American, July, 2007;

External links[edit]