Kaoru InokuchiNaoki MatsuoTatsuhiro HisatsuneYoshihiro YoshiharaMinoru Saitoe

Azusa KamikouchiTetsuya TabataTakeshi IshiharaYuichi Iino

Research projects

Memory dynamics based on the reconsolidation process in rodents

Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
Kaoru Inokuchi

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Memories change its quality even after consolidated in the brain through dynamic processes including destabilization, reconsolidation, association, and transfer. Many memories become labile state upon retrieval, and then consolidated again via reconsolidation process. Memory reconsolidation is assumed to be a key process through which new information, if related to the existing ones, would be integrated into the old memories. In this project, we plan to investigate (1) mechanisms underlying synaptic level reconsolidation in the hippocampal LTP in vivo, and (2) mechanisms underlying memory reconsolidation, specifically focusing on the involvement of autophagy.

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Dynamism of Neuronal Ensembles Encoding a Memory

Graduate School of Medicine, Osaka University
Naoki Matsuo

Memory system in animals' brain involves far more dynamic processes than previously acknowledged. This dynamism makes animals possible to survive in the ever-changing environment, and might produce human creativity. However, the mechanism how memories change after the initial acquisition remains largely elusive.

Our aim is to capture the dynamic changes in neuronal ensembles encoding a memory associated with memory modification processes, and to understand the neural basis. To this aim, we will take advantage of a combinational approach including behavioral analysis, manipulation of a neuronal activity, imaging, and in vivo multiunit recording. We will also make effort to develop genetically engineered mice to push on our projects.

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Understanding of Memory Dynamism through a Study of Functional Brain Aging

Dept. Integrated Biosciences, GSFS, The University of Tokyo
Tatsuhiro Hisatsune

Memory function gradually decreases as age progresses. The reason for age-dependent cognitive decline has not been fully clarified yet. Recent studies have well shown that the degree of hippocampal neurogenesis decreases as age progresses and adult-born hippocampal neurons contribute to memory, therefore, the decrease in hippocampal neurogenesis can be a reason for age-dependent cognitive decline. In this study, we utilized a number of rodent model for functional brain aging including Alzheimer’s Disease transgenic mice, radiation-induced cognitive dysfunction (RICD) mice, New neuron-specific functional ablation mice (New neuron TeTX) mice, etc. To visualize the hippocampal circuit responsible for this cognitive decline, we have developed fMRI-based bioimaging methods, opto-fMRI, rs-fMRI, and memory fMRI.

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Molecular, cellular, and neural circuit mechanisms underlying olfactory memory dynamism in zebrafish

RIKEN Brain Science Institute
Yoshihiro Yoshihara

The olfactory system is highly elaborated to receive and discriminate odorants and pheromones, to transmit their signals to the brain, and to evoke fundamental behaviors important for survival of individuals and preservation of species, including food finding, predator avoidance, social communication, mate choice, and spawning migration. Fish can detect a huge variety of odorants that are dissolved in the water, such as amino acids, nucleotides, bile acids, amines, steroids, and prostaglandins. However, it remains largely unknown what neural elements and circuits are involved in olfactory memory in zebrafish. In this research group, we aim to elucidate molecular, cellular, and neural circuit mechanisms of olfactory memory in zebrafish, focusing on two types of behaviors: olfactory imprinting and olfactory conditioning. We will analyze these behaviors with a combination of genetic, optical imaging, electrophysiological, and neuroanatomical methods for elucidation of neural circuit mechanisms underlying olfactory memory and behavioral plasticity.

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Identification of networks and mechanisms generating memory dynamism in Drosophila.

Principal investigator
Tokyo Metropolitan Institute of Medical Science
Minoru Saitoe

Collaborators
Tokyo Metropolitan University
Takaomi Sakai
Nagoya City University
Kazuhiko Kume
University of Tokyo
Moritoshi Sato

In Drosophila, various genes, brain regions, and cellular populations involved in learning and memory have been identified. Despite this, the mechanisms underlying learning and memory are still not clear. For example, although important brain regions are identified, the precise neural networks that encode learning and memory within these regions are unknown. Also, it is still unclear how memory-associated genes regulate functions of neural networks during memory acquisition, consolidation and retrieval. To address these issues, it is necessary to identify memory-encoding neural networks by measuring neuronal activity during learning and recall in brains of individual organisms.

In our research, we employ both in vivo and in vitro brain imaging to identify networks, and elucidate their operating principles. While in vivo imaging allows monitoring of neural activity in brain regions during learning, storage and memory recall, accessible brain regions and pharmacological treatments are limited, and brain movement during performance hinders precise analyses at the synaptic level. In vitro imaging overcomes these limitations, and a combination of these two approaches is promising.

During olfactory aversive conditioning, flies are exposed simultaneously to an odor (the conditioned stimulus or CS) and aversive electric shocks (the unconditioned stimulus or US). Pairing the two stimuli causes flies to associate the odor with shocks, such that flies subsequently avoid the odor. In the brain, both CS and US information are conveyed to the mushroom bodies (MBs), where olfactory associations are formed, and an increase in CS induced Ca2+ influx into the MBs can be observed after aversive conditioning using in vivo imaging techniques. A similar phenomenon can also be observed in in vitro cultured brains. In this case, simultaneous electrical stimulation of the antennal lobes (ALs), which convey odor information to the MBs, and the ascending fibers of the ventral nerve chord (AFV), which conveys shock information, causes a subsequent long-term enhancement (LTE) of AL-induced Ca2+ responses in the MBs.

By measuring enhancement of neuronal activity in vivo and in vitro, we are identifying neural networks involved in formation of olfactory associations, and investigating what neurotransmitter receptors and signal transduction mechanisms they employ. In addition, we are identifying networks involved in the consolidation of labile short-term memories (STM) into stable long-term memories (LTM) and characterizing how these networks regulate transformation. We also study in how memory formation and stability is affected by various internal and external conditions. For example, although aversive LTM is usually formed after multiple trainings with rest intervals between each training session (spaced training), hungry flies are able to form aversive LTM after only a single training. We are currently characterizing mechanisms through which conditions such as hunger and sleep state, courtship and aging affect activity of neural networks to modulate acquisition, retention and recall of memory.

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Neural mechanisms of plasticity in the auditory behavior of fruit flies

Graduate School of Science, Nagoya University
Azusa Kamikouchi

Acoustic signals are widespread media to communicate with each other, from insects and fish to birds and humans. The song is an extreme example where continuous exposure of sound gradually modifies the recipients’ physiological and psychological conditions. Indeed, continuous exposure of specific type of sound dramatically changes the behavioral output of the recipient in a species-specific manner. However, the spatiotemporal dynamics how such continuous acoustic stimuli are temporally stored in the brain of a recipient and finally affect its physiological condition remain to be elucidated.

In this research project, we tackle this question by focusing on the auditory behavior of fruit flies. The mating behaviors of male and female flies are modified upon continuous exposure to their courtship song. The fruit fly would thus serve an excellent model to explore the neural mechanism how accumulation of acoustic information modifies the animal’s behavioral output. The purpose of this project is to (1) identify the neural substrates for a temporal storage of acoustic information that modify their mating behavior, (2) elucidate neuromolecular mechanism to control spatiotemporal dynamism of information storage, and (3) unravel the basic principle how acoustic information is temporally stored in the brain to modify the behavioral output of animals.

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Drosophila olfactory coding and memory

Principal investigator
IMCB, The University of Tokyo
Tetsuya Tabata

Collaborator

Graduate School of Agricultural and Life Sciences, The University of Tokyo
Aki Ejima

Olfactory information in Drosophila is mediated by projection neurons, which transmit signals from olfactory sensory neurons to Kenyon cells (KCs) in the mushroom body. Subsets of KCs respond to a given odor molecule, and the combination of these KCs represents the olfactory code. KCs are also thought to function as coincidence detectors for memory formation, associating odor information with a coincident punishment or reward stimulus.

The research in my laboratory includes the following:

  1. Imaging analysis of the neuronal activity of KCs and their downstream output neurons. Using the calcium indicator GCaMP and 2-photon microscopy, we aim to identify memory traces to elucidate the mechanisms underlying olfactory coding and memory formation.
  2. Functional analysis of CRE-responsive cells to study their roles in memory formation.
  3. Functional analysis of genes that are required for memory formation.
  4. Understanding the structure-function relationship and developmental mechanisms underlying the mushroom body.

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The regulatory mechanisms of memory forgetting in C. elegans

Kyushu University, Faculty of Sciences
Takeshi Ishihara

Animals acquire various kinds of memories from their environments. These memories lead to behavioral plasticity, in which experiences induce changes of behavioral responses to environmental stimuli. Most memories are retained for a few hours and are considered as a short term memories, if they are not consolidated to long term memories. Forgetting is important to regulate the retention time of memories to prevent excess memory capacity and the interference between memories. We plan to elucidate the molecular and neuronal mechanisms of forgetting by using C. elegans as a model organism.

C. elegans showed the olfactory adaptation to various odorants, which is sustained for a few hours. The molecular genetic analyses of mutants showing the prolonged retention of the olfactory adaptation revealed that the signals from a pair of sensory neurons, AWC, accelerate the forgetting in AWA neurons. In addition, the retention of the olfactory adaptation is regulated by the food conditions during forgetting. In this project, we plan to identify the molecular machinery and the neuronal circuits of the forgetting processes at the downstream of the forgetting signal. In addition, we are also interested in the regulation of the retention time via the forgetting process.

This study may lead to understand the regulatory mechanisms of the memory retention not only in C. elegans but also in higher organisms.

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Identification of novel molecules associated with learning and memory and elucidation of their roles in the nervous system.

Principal Investigator
Graduate School of Science, The University of Tokyo
Yuichi Iino

Collaborator
Graduate School of Medicine, The University of Tokyo
Atsu Aiba

In this research project, we plan to contribute to the understanding of the mechanisms of learning and memory by using the nematode C. elegans, which has only 302 neurons whose connectivity is fully known. Of various behaviors in this animal, chemotaxis, in which the animals approach (or avoid) salts and odorants, is an excellent experimental system that allows us to study every layer of information processing from sensory input to behavioral output, at the levels of molecules, cells and circuits.

We have so far looked for molecules that are necessary for chemotaxis and its plasticity, and found that insulin/PI 3-kinase pathway, Gq/PLC/DAG pathway, calsyntenin, phosphoinositide transfer protein, Ras-MAPK pathway, NMDA glutamate receptor are involved in these processes. Based on these pieces of knowledge, we are building a model to explain that collectively explain the behavior and underlying neural circuit.

In this project, we will focus on the question of how information flow changes by learning. Through imaging of the activities of neurons and the dynamics of functional molecules in living C. elegans, we will try to understand the mechanism of learning and memory, putting particular emphasis on,
1) dynamics of molecules in and outside the neurons, 2) dynamics of neural circuit and 3) dynamics of behaviors.

We will also make use of the power of genetics in C. elegans and identify novel genes involved in various aspects of learning and memory, and examine how these molecules act to change the behavior. Furthermore, for the molecules whose roles have been revealed at the cellular level in C. elegans, we will generate gene-targeted mice and study their neural activities and behavior. Through these lines of research that will be nourished by interactions with other members of this innovative area, we will contribute to obtaining an overview of learning and memory.

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