Showing papers by "Susumu Tonegawa published in 2017"

Engrams and circuits crucial for systems consolidation of a memory.

Abstract: Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.

Engrams and circuits crucial for systems consolidation of a memory

Abstract: The representation of contextual fear memories evolves over time in the hippocampus, amygdala, and prefrontal cortex. The network of memory consolidation Memories are thought to be formed in the hippocampus and later moved to the neocortex for long-term storage. However, little is known about the mechanisms that underlie the formation and maturation of neocortical memories and their interaction with the hippocampal network. Kitamura et al. discovered that at the onset of learning, neurons for contextual fear memory are quickly produced in the prefrontal cortex. This process depends on the activity of afferents from both the hippocampus and the amygdala. Over time, the prefrontal neurons consolidate their role in memory expression. In contrast, the hippocampal neurons slowly lose this function. Science, this issue p. 73 Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.

Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories

Abstract: The formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum. Here, we show that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. Our data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses.

Silent memory engrams as the basis for retrograde amnesia.

Abstract: Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.

Dorsal Raphe Serotonergic Neurons Control Intertemporal Choice under Trade-off

Abstract: Appropriate choice about delayed reward is fundamental to the survival of animals. Although animals tend to prefer immediate reward, delaying gratification is often advantageous. The dorsal raphe (DR) serotonergic neurons have long been implicated in the processing of delayed reward, but it has been unclear whether or when their activity causally directs choice. Here, we transiently augmented or reduced the activity of DR serotonergic neurons, while mice decided between differently delayed rewards as they performed a novel odor-guided intertemporal choice task. We found that these manipulations, precisely targeted at the decision point, were sufficient to bidirectionally influence impulsive choice. The manipulation specifically affected choices with more difficult trade-off. Similar effects were observed when we manipulated the serotonergic projections to the nucleus accumbens (NAc). We propose that DR serotonergic neurons preempt reward delays at the decision point and play a critical role in suppressing impulsive choice by regulating decision trade-off.

In Search of Engram Cells

Abstract: One of the most fascinating aspects of an animal's brain is its ability to acquire new information from experience and retain this information over time as memory. The search for physical correlates of memory, the memory engram, has been a long-standing question in modern neurobiology. Recent advances in transgenics and optogenetic tools have enabled the identification, visualization, and manipulation of natural, sensory-evoked, engram ensembles unique to individual brain regions, and specific learning events. We suggest that these recent studies are paving the way not only to understand memory mechanisms in unprecedented detail but also to engineer the memory-mediated state of mind and behaviors.

A novel diagnostic biomarker for human uterine leiomyosarcoma: PSMB9/β1i.

Abstract: Takuma Hayashi (Shinshu University School of Medicine) discussed a novel biomarker for detecting human uterine leiomyosarcoma (LMS).

Tagging activated neurons with light.

Abstract: Two new protein tools translate neuronal activity into gene expression during a light-defined time window.

Manipulating memory in space and time

Abstract: One of the most fascinating aspects of an animal’s brain is its ability to acquire new information from experience and retain this information over time as memory. The search for physical correlates of memory, the memory engram, has been a longstanding endeavor in modern neurobiology. Recent advances in transgenic and optogenetic tools have enabled the identification, visualization, and manipulations of natural, sensory-evoked, engram cells for a specific memory residing in specific brain regions. These studies are paving the way not only to understand memory mechanisms in unprecedented detail, but also to repair the abnormal state of mind associated with memory by engineering.

Manipulating memory in space and time

Abstract: One of the most fascinating aspects of an animal’s brain is its ability to acquire new information from experience and retain this information over time as memory. The search for physical correlates of memory, the memory engram, has been a longstanding endeavor in modern neurobiology. Recent advances in transgenic and optogenetic tools have enabled the identification, visualization, and manipulations of natural, sensory-evoked, engram cells for a specific memory residing in specific brain regions. These studies are paving the way not only to understand memory mechanisms in unprecedented detail, but also to repair the abnormal state of mind associated with memory by engineering.

Pathobiology of Human Uterine Leiomyosarcoma for Development of Novel Diagnosis and Clinical Therapy

Abstract: Uterine sarcomas comprise a group of rare tumours with differing tumour pathobiology, natural history and response to clinical treatment. Diagnosis is often made following surgical treatment for presumed malignant mesenchymal tumours and benign tumours. Currently pre-operative diagnosis does not reliably distinguish between malignant mesenchymal tumours, Uterine Leiomyosarcoma (U-LMS) and benign tumours including Leiomyomas (LMA). U-LMS is the most common sarcoma but other subtypes include endometrial stromal sarcoma (low grade and high grade), undifferentiated uterine sarcoma and adeno sarcoma. Clinical trials have shown no definite survival benefit for adjuvant radiotherapy or chemotherapy, and have been hampered by the rarity and heterogeneity of these tumour types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at U-LMS reference centres. In patients with metastatic LMS then systemic chemotherapy can be considered. Accordingly, it is necessary to analyse risk factors associated with human U-LMS, in order to establish a treatment method. Proteasome β-subunit 9 (PSMB9)/β1i-deficient mice spontaneously develop U-LMS, with a disease prevalence of ~37% by 12 months of age. We found PSMB9/β1i expression to be absent in human U-LMS, but present in human LMA. Therefore, defective PSMB9/β1i expression may be one of the risk factors for human U-LMS. PSMB9/β1i is a potential diagnostic-biomarker for human U-LMS, and may be targeted-molecule for a new therapeutic approach.

The somatic mutations in Interferon-γ signal molecules in human uterine leiomyosarcoma

Abstract: Human uterine leiomyosarcoma (Ut-LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human UtLMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome subunit beta type (PSMB) 9, an interferon (IFN)-g inducible factor, spontaneously develop Ut-LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-g signaling pathway is important for control of tumor growth and invasion and has been implicated in several malignant tumors. In this study, experiments with human tissues revealed a defective expression of PSMB9 in human Ut-LMS that was traced to the IFN-g signal cascade and the significant effect of somatic mutations of Janus kinase (JAK) 1 molecule or PSMB9 gene promoter region on the PSMB9 gene transcriptional activation. Understanding the molecular mechanisms of human Ut-LMS may lead to identification of new diagnostic candidates or therapeutic targets in human Ut-LMS.

Biological Analyses for Characterization of the Uterine Sarcoma Using Mouse Model

Abstract: Uterine sarcomas are neoplastic malignancies that typically arise in tissues of a mesenchymal origin in uterine body. The identifi cation of novel molecular mechanisms leading to sarcoma formation, and the establishment of new therapies and biomarkers has been hampered by several critical factors.