About

Susumu Tonegawa is the Picower Professor of Biology and Neuroscience at MIT and serves as the Director of the RIKEN-MIT Laboratory for Neural Circuit Genetics. His research investigates the biological underpinnings of learning and memory in rodents. His laboratory generates genetically engineered mice and analyzes them through multiple methods, including molecular and cellular biology, electrophysiology, microscopic imaging, optogenetic engineering, and behavioral studies. The ultimate goal of his work is to detect the effects of manipulations at multiple levels in the brain, thereby deducing which behaviors or cognitions are causally linked to specific processes and events taking place at the molecular, cellular, and neuronal circuit levels.

Research topics

• Biology
• Neuroscience
• Molecular biology
• Cell biology
• Psychology

Selected publications

• Dopamine induces fear extinction by activating the reward-responding amygdala neurons

  Proceedings of the National Academy of Sciences · 2025-04-28 · 18 citations

  articleOpen accessSenior authorCorresponding

  The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder. Fear extinction takes place when animals form a new memory that suppresses the original fear memory. In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by Ppp1r1b + neurons. These memory engram cells suppress the activity of the original fear-responding Rspo2 + engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the Ppp1r1b + neurons is unknown. Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations. We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors. Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons. Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning. Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively. Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.

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• POTENTIAL DIAGNOSTIC BIOMARKERS FOR HUMAN MESENCHYMAL TUMORS, ESPECIALLY LMP2/Β1I AND CYCLIN E1/MIB1 DIFFERENTIAL EXPRESSION: PRUM-IBIO STUDY.

  PubMed · 2024-05-01

  article

  Most mesenchymal tumors found in the uterine corpus are benign tumors; however, uterine leiomyosarcoma is a malignant tumor with unknown risk factors that repeatedly recurs and metastasizes. In some cases, the histopathologic findings of uterine leiomyoma and uterine leiomyosarcoma are similar and surgical pathological diagnosis using excised tissue samples is difficult. It is necessary to analyze the risk factors for human uterine leiomyosarcoma and establish diagnostic biomarkers and treatments. Female mice deficient in the proteasome subunit low molecular mass peptide 2 (LMP2)/β1i develop uterine leiomyosarcoma spontaneously. MATERIAL AND METHODS: Out of 334 patients with suspected uterine mesenchymal tumors, patients diagnosed with smooth muscle tumors of the uterus were selected from the pathological file. To investigate the expression status of biomarker candidate factors, immunohistochemical staining was performed with antibodies of biomarker candidate factors on thin-cut slides of human uterine leiomyosarcoma, uterine leiomyoma, and other uterine mesenchymal tumors. RESULTS AND DISCUSSION: In human uterine leiomyosarcoma, there was a loss of LMP2/β1i expression and enhanced cyclin E1 and Ki-67/MIB1 expression. In human uterine leiomyomas and normal uterine smooth muscle layers, enhanced LMP2/β1i expression and the disappearance of the expression of E1 and Ki-67/MIB1 were noted. The pattern of expression of each factor in other uterine mesenchymal tumors was different from that of uterine leiomyosarcoma. CONCLUSIONS: LMP2/β1i, cyclin E1, and Ki-67/MIB1 may be candidate factors for biomarkers of human uterine leiomyosarcoma. Further large-cohort clinical trials should be conducted to establish treatments and diagnostics for uterine mesenchymal tumors.

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• Importance of diagnostic methods for round ligament leiomyomas in clinical practice

  Quantitative Imaging in Medicine and Surgery · 2023-02-23 · 3 citations

  editorialOpen access

  The incidence of large round ligament leiomyoma is rare.Wei et al. reported a rare case of mesenchymal primary leiomyoma in the round ligament of a 45-year-old woman (1).In routine outpatient visits, magnetic resonance imaging (MRI) is performed for diagnostic purposes before surgical treatment, and round ligament leiomyoma is usually diagnosed based on the evaluation of the MRI reports.Patients have a favorable prognosis if the tumor can be completely resected.Wei et al. noted that in clinical practice, round ligament leiomyomas may be difficult to diagnose, and laparoscopic imaging is the best procedure for the management of symptomatic leiomyomas (1). Classification of uterine smooth muscle tumorsUterine smooth muscle tumors, which are the most common uterine tumors, are mesenchymal tumors that differentiate into smooth muscle cells.They are broadly classified into three types depending on their malignancy: leiomyoma (benign uterine mesenchymal tumors), leiomyosarcoma (malignant uterine mesenchymal tumors), and smooth muscle tumor of uncertain malignant potential (STUMP) (2).The malignancy of uterine mesenchymal tumors is detected via histopathological examination and is based on indicators such as nuclear atypia, mitotic number, and coagulative necrosis.Uterine smooth muscle cells are morphologically characterized by mutually orthogonal fascicles of spindle-shaped cells with obtuse elongated nuclei and eosinophilic cytoplasm at both ends (2).Both leiomyomas and leiomyosarcomas exhibit the same morphological characteristics as those of uterine smooth muscle cells.Therefore, these features are considered indicative of smooth muscle tumors during oncological diagnosis.Among leiomyomas, in addition to typical smooth muscle tumors (usual type), those with distinctive characteristics (a special type) occur (2).These variants include mitotically active leiomyoma (a variant with increased mitotic

  PublisherDOI

• Tribute to Professor Takashi Yura

  Cell Stress and Chaperones · 2023-06-21

  editorialOpen access1st authorCorresponding
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• Cingulate-motor circuits update rule representations for sequential choice decisions

  Nature Communications · 2022-08-04 · 12 citations

  articleOpen accessSenior author

  Anterior cingulate cortex mediates the flexible updating of an animal's choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the terminal projections of cingulate cortical neurons in secondary motor cortex in the rat disrupts choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreases rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that is temporally targeted to error trials immediately after rule switches exacerbates errors in the following trials. These results suggest that cingulate cortex monitors behavioral errors and updates rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.

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• Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions

  Nature Communications · 2022-04-04 · 217 citations

  articleOpen accessSenior authorCorresponding

  Abstract Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos + brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.

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• Importance of diagnostic methods for round ligament leiomyomas in clinical practice

  2022-11-21

  preprintOpen access

  Benign uterine leiomyoma (U.LMA) and malignant uterine leiomyosarcoma (U.LMS), which are both uterine mesenchymal tumors, are distinguished by the number of cells with mitotic activity. However, uterine mesenchymal tumors contain tumor cells with various cell morphologies; therefore, making a diagnosis, including differentiation between benign tumors and malignant tumors, is difficult. For example, round ligament leiomyomas are uterine leiomyomas with a very rare placental lobed tissue morphology that can be misdiagnosed as a malignant uterine leiomyosarcoma because of its rarity and characteristic appearance on gross examination. Similar to the detection of a suspicious malignant mass during magnetic resonance imaging (MRI) examination by medical staff, healthcare professionals must understand the characteristic appearance of round ligament leiomyomas. Clinicians and pathologists must understand the oncologic features of round ligament leiomyomas to prevent misdiagnosis of malignancy and consequent overtreatment.

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• Crucial role for CA2 inputs in the sequential organization of CA1 time cells supporting memory

  Proceedings of the National Academy of Sciences · 2021-01-11 · 52 citations

  articleOpen accessSenior author

  There is considerable evidence for hippocampal time cells that briefly activate in succession to represent the temporal structure of memories. Previous studies have shown that time cells can be disrupted while leaving place cells intact, indicating that spatial and temporal information can be coded in parallel. However, the circuits in which spatial and temporal information are coded have not been clearly identified. Here we investigated temporal and spatial coding by dorsal hippocampal CA1 (dCA1) neurons in mice trained on a classic spatial working-memory task. On each trial, the mice approached the same choice point on a maze but were trained to alternate between traversing one of two distinct spatial routes (spatial coding phase). In between trials, there was a 10-s mnemonic delay during which the mouse continuously ran in a fixed location (temporal coding phase). Using cell-type-specific optogenetic methods, we found that inhibiting dorsal CA2 (dCA2) inputs into dCA1 degraded time cell coding during the mnemonic delay and impaired the mouse's subsequent memory-guided choice. Conversely, inhibiting dCA2 inputs during the spatial coding phase had a negligible effect on place cell activity in dCA1 and no effect on behavior. Collectively, our work demonstrates that spatial and temporal coding in dCA1 is largely segregated with respect to the dCA2-dCA1 circuit and suggests that CA2 plays a critical role in representing the flow of time in memory within the hippocampal network.

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• Reply to Lehr and Stöber: What’s in a name? On the distinction between temporal coding and internally driven activity

  Proceedings of the National Academy of Sciences · 2021-09-13 · 2 citations

  letterOpen accessSenior authorCorresponding

  Emotions coordinate our behavior and physiological states during survival-salient events and pleasurable interactions. Even though we are often consciously aware of our current emotional state, such as anger or happiness, the mechanisms giving ...Emotions are often felt in the body, and somatosensory feedback has been proposed to trigger conscious emotional experiences. Here we reveal maps of bodily sensations associated with different emotions using a unique topographical self-report method. In ...

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• Author Correction: Hippocampal neurons represent events as transferable units of experience

  Nature Neuroscience · 2021-01-05

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

Recent grants

• NIH Grant R37AI017879

  NIH · $2.7M · 1996

• NIH Grant R01AI017879

  NIH · $277k · 1986

• NIH Grant R01MH078821

  NIH · $2.6M · 2011

• NIH Grant R01NS032925

  NIH · $6.0M · 2006

• NIH Grant P50MH058880

  NIH · $27.0M · 2011

Frequent coauthors

• Shigeyoshi Itohara

  RIKEN Center for Brain Science

  332 shared

• Peter Mombaerts

  Max Planck Research Unit for Neurogenetics

  323 shared

• Marc Bonneville

  Institut Mérieux (France)

  317 shared

• Juan J. Lafaille

  New York University

  283 shared

• Luc Van Kaer

  275 shared

• I. Ishida

  271 shared

• Yohtaroh Takagaki

  University of Washington

  261 shared

• Osami Kanagawa

  École Normale Supérieure de Lyon

  238 shared

Labs

• MIT Department of Biology - Susumu Tonegawa LabPI

Awards & honors

• Nobel Prize in Physiology or Medicine (1987)
• Albert and Mary Lasker Award in Basic Research (1987)
• Member of the National Academy of Sciences (1986)