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  3. Susumu Tonegawa
Tonegawa, S 150623 color resized.jpg
Tonegawa
Susumu
Ph.D.
Picower Professor
Biology; Brain & Cognitive Sciences
Principal Investigator
RIKEN-MIT Center for Neural Circuit Genetics
Investigator
Picower Institute for Learning and Memory
Investigator
Howard Hughes Medical Institute
Faculty Appointment
Joint
Building
46
Email
tonegawa@mit.edu
Phone
9999999999
Lab website
    About

    Susumu Tonegawa received his Ph.D. from UCSD. He then undertook postdoctoral work at the Salk Institute in San Diego, before working at the Basel Institute for Immunology in Basel, Switzerland, where he performed his landmark immunology experiments. Tonegawa won the Nobel Prize for Physiology or Medicine in 1987 for “his discovery of the genetic principle for generation of antibody diversity.” He has since continued to make important contributions but in an entirely different field: neuroscience.

    Using advanced techniques of gene manipulation, Tonegawa is now unraveling the molecular, cellular and neural circuit mechanisms that underlie learning and memory. His studies have broad implications for psychiatric and neurologic diseases. Tonegawa is currently the Picower Professor of Biology and Neuroscience at MIT and an investigator at the Howard Hughes Medical Institute.

    Research

    Learning and memory are vital for day-to-day living—from finding our way home to playing tennis to giving a cohesive speech. Some of us have personally witnessed the devastating consequences of memory disorders, whether it’s the severe inability to form new memories, as seen in Alzheimer’s patients, or difficulty in suppressing a recall of a memory of a highly unpleasant experience, as seen in PTSD patients.

    The main research interest in my laboratory is to decipher brain mechanisms subserving learning and memory. We seek to understand what happens in the brain when a memory is formed, when a fragile short-term memory is consolidated to a solid long-term memory, and when a memory formed previously is recalled on subsequent occasions. We also seek to understand the role of memory in decision-making, and how various external or internal factors, such as reward, punishment, attention and the subject’s emotional state, affect learning and memory. In summary, we study how the central nervous system in the brain enables our mind, with a focus on learning and memory.

    Because much of the fundamental processes of and neuronal mechanisms for memory are expected to be shared among mammals, and a vastly greater variety of experimental procedures is available for rodents than humans, we use laboratory mice as the primary model for memory research. With mice or other animals, memory can be monitored only through the behaviors. Thus, it is inevitable that we use a whole, live animal. At the same time, researchers must identify the crucial events and processes that are ongoing inside the brain, permitting the specific and diverse aspects of learning and memory. This latter task is the challenge for memory researchers and neuroscientists in general because the brains of higher organisms are incredibly complex—organized in a multilayer of complexity, from tens of thousands of molecules, to thousands of different types of cells, to hundreds of functionally and structurally distinct cellular assemblies, and extensive yet specific networkings of these assemblies.

    In order to meet this challenge, we employ highly specific genetic manipulation techniques, creating mutant mouse strains in which a specific gene, and hence its gene product, such as neurotransmitter receptors and enzymes, is deleted or inactivated only in a specific type of cell (spatial restriction) and/or a specific period of a behaviorally defined learning or memory process (temporal restriction). Alternatively, the gene encoding the tetnus toxin can be introduced to a specific type of cell and activated in a temporally controllable manner to block a neural signal transmission. This technique, generally called the conditional transgenic method, can be accomplished by micro-manipulating mouse eggs or embryos using the site specific recombination system, Cre-loxP, and the tetracycline-controlled transcriptional system, tTA-Otet. Virus vector (AAV, Lenti, HSV, etc.)-mediated genetic manipulation can be combined with these conditional transgenic methods. Further, the recently invented optogenetic methods—including those based on the channel rhodopsin and halorhodopsin, which activate and inactivate neurons, respectively, at a millisecond timescale—can be combined with the Cre-loxP system to rapidly manipulate neural transmission in a specific cellular circuit.

    We then subject these genetically engineered mouse strains along with the standard strain (called control mice) to a variety of analytical methods in order to detect the effect of the genetic manipulation (called phenotype detection). These methods include behavioral tasks (for example, maze and conditioning), recordings of cellular activities via single and multiple electrodes (in vivo electrophysiology with tetrodes and EEG) surgically implanted into a specific area of the brain, recordings of transmission at specific synapses of brain slices or cultured neurons (in vitro electrophysiology by field and patch clamp recordings), in vivo and in vitro optical imaging (with confocal and two-photon microscopy), and molecular and cellular biology. The abnormality one may observe in the genetically altered mouse strains in comparison with the control mice could be a deficiency or augmentation of a particular activity (phenotype). The phenotype observed at various levels of organizational complexities and associated specifically with the known genetic manipulation of the mutant will be very informative in our understanding the brain mechanisms subserving its behavior and cognition

    Publications

    Takeuchi, D., Roy, D.S., Muralidhar, S., Kawai, T., Lovett, C., Sullivan, H.A., Wickersham, I.R., Tonegawa, S. Cingulate-motor circuits update rule representations for sequential choice decisions. Nat Commun (2022).

    Roy, D.S., Park, YG., Kim, M.E., Zhang, Y., Ogawa, S.K., DiNapoli, N., Gu, X., Cho, J.H., Choi, H., Kamentsky, L., Martin, J., Mosto, O., Aida, T., Chung, K., Tonegawa, S. Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions. Nat Commun 13, 1799 (2022). https://doi.org/10.1038/s41467-022-29384-4

    Christopher J. MacDonald, Susumu Tonegawa. Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory. Proceedings of the National Academy of Sciences Jan 2021, 118 (3) e2020698118; DOI: 10.1073/pnas.2020698118
     
    Bari, A., Xu, S., Pignatelli, M., Takeuchi, D., Feng, J., Li, Y., Tonegawa, S. Differential attentional control mechanisms by two distinct noradrenergic coeruleo-frontal cortical pathways. Proceedings of the National Academy of Sciences Nov 2020, 202015635; DOI: 10.1073/pnas.2015635117
     
    Lak, A., Hueske, E., Hirokawa, J., Masset, P., Ott, T., Urai, A.E., Donner, T.H., Carandini, M., Tonegawa, S., Uchida, N., Kepecs, A. Reinforcement biases subsequent perceptual decisions when confidence is low, a widespread behavioral phenomenon. eLife (2020);9:e49834. DOI:10.7554/eLife.49834

    Awards + Honors

    2018 Member, National Academy of Sciences of the United States (converted from Foreign Associate) 
    2010 David M. Bonner Lifetime Achievement Award, UCSD
    2008 University College London (UCL) Prize Lecturer in Clinical Science
    2007 Gold Medal, Spanish National Research Council, Cajal Institute (CSIC), Madrid
    2007 RIKEN Fellow, Saitama, Japan
    2002 Presidential Lecturer, Society for Neuroscience Annual Meeting
    2002 Professorship, Picower Foundation
    1999 Professorship, Whitehead Family Funds 1
    1999 Mike Hogg Award, the University of Texas M.D. Anderson Cancer Center
    1994 Honorary member of the Polish Academy of Medicine and awarded the Golden Medal Medicus Magnus
    1994 Professorship, Amgen, Inc. 1991 Order of the Southern Cross, presented by Fernando Collor de Melo, President of Brazil, Sao Paolo, Brazil
    1989 Rabbi Shai Shacknai Memorial Prize in Immunology and Cancer Research, Jerusalem, Israel 1989 Distinguished Investigator Award of American College of Rheumatology, Atlanta, U.S.A.
    1988 Kihara Prize of Japanese Society for Genetics, Kyoto, Japan
    1987 Nobel Prize for Physiology or Medicine, Stockholm, Sweden
    1987 Albert and Mary Lasker Award (Basic Research), New York City
    1986 Foreign Associate, National Academy of Sciences of the United States
    1986 Robert Koch Prize of the Robert Koch Foundation, Bonn, West Germany
    1986 Bristol-Myers Award for Distinguished Achievement in Cancer Research, New York, U.S.A.
    1984 Fellow, American Academy of Arts and Sciences
    1984 Order of Culture “Bunkakunsho” from the Emperor of Japan
    1983 Person of Cultural Merit “Bunkakorosha” of the Japanese Government
    1983 Gairdner Foundation International Awards of the Gairdner Foundation, Toronto, Canada
    1983 The V.D. Mattia Award of the Roche Institute of Molecular Biology, Nutley, U.S.A.
    1982 Louisa Gross Horwitz Prize of Columbia University, New York, U.S.A.
    1982 Asahi Prize of Asahi – Shimbun (Asahi Press), Tokyo, Japan
    1981 Avery Landsteiner Prize of the Gesselshat fur Immunologie, West Germany
    1981 Genetics Grand Prize of Genetics Promotion Foundation, Japan
    1980 Warren Triennial Prize of the Massachusetts General Hospital, U.S.A.
    1978 The Cloetta Prize of Foundation Professor Dr. Max Cloetta, Switzerland

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