Takayuki HosokawaMasanori SakaguchiYu HayashiJunichi NakaiAyako Tonoki

Masahiro YamaguchiHaruhiko BitoHideaki TakeuchiHiroshi NomuraMasahiko Hibi

Yoshio SakuraiYukinori HiranoDan Ohtan WangTakeshi YagiDai Mitsushima

Takuya TakahashiRie KimuraKoichi HommaAyako M. WatabeToshiaki Furuta

Atsushi KuharaYoko Yazaki-SugiyamaMasaaki OgawaKeizo TakaoMasaaki Sato

Shogo Endo

Research projects

Neuronal mechanisms of formation and elaboration of memory

Graduate School of Life Sciences, Tohoku University
Takayuki Hosokawa

Primates have the ability to predict what will happen in the future by learning the relationship between an event (cue signal) and the following outcome. This ability is important for their adaptation to the environment. Learning in the early stage is probably in the form of a paired association between an event and its outcome. Then, as the learning progresses, animals recognize the stimuli with features in common as a category group. During this process, it is likely that stimuli categorized into the same group would form a stimulus-stimulus association. Categorized knowledge is considered to be the basis of abstract thinking in primates.

Previous studies have suggested that association memory is formed and stored in the inferotemporal (IT) cortex (including perirhinal cortex). Although some studies indicate that the primate prefrontal cortex (PFC) is implicated in categorical judgment, little is known about how categorical memory is formed in the learning process. In this project we aim to elucidate how categorical memory is formed, used, and updated in the brain by recording neuronal activity in the PFC and IT cortex while monkeys perform the “group-reversal” task, in which they are required to form and use categories in order to quickly adapt to an abrupt change of the task rule.

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Unraveling the function of adult-born neurons that are reactivated during sleep in memory consolidation

IIIS, The University of Tsukuba
Masanori Sakaguchi

In contrast with the other brain regions where neurogenesis is terminated in the adult stage, the dentate gyrus of the hippocampus including humans continues to generate new born neurons for a life time period. Our group provided an evidence that those adult born neurons could store information which plays critical role in discriminating similar but different information (Carvalho and Sakaguchi et al., J. Neurosci., 2011). Recent studies suggested the correlation between the adult born neurons and sleep. For example, sleep deprivation results in a decrease of the number of adult born neurons (Mirescu et al.,PNAS,2006,v103p19170); sleep after foraging promote removal of adult born neurons in the olfactory bulbs (Yokoyama et al.,Neuron,2011,v71p883). These and other studies suggest the functional correlation between adult neurogenesis and sleep, however, it has not been clarified yet. This is mainly because the technical difficulties to manipulate the activity of adult born neurons during each sleep periods with spatial and temporal specificity and to reveal the phenotype of the function of the adult born neurons in behavior. We are currently exploring the function of the adult born neurons in sleep by combining several genetics tools (e.g., pNes-ERt2 mice/Optogenetics) to specifically target adult born neurons and behavioral tests (e.g., modified visual discrimination task) in which the adult born neurons reveal its function in a highly sensitive manner.

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Neural circuit dynamics during sleep

IIIS, University of Tsukuba
Yu Hayashi

Every night our physiologic state changes dramatically during sleep. Sleep has recently been shown to affect memory dynamics. While we are awake, recall of a certain memory causes the memory to enter a vulnerable state. On the other hand, memory reactivation during sleep conversely stabilizes the memory. Yet how memories are differentially processed in the brain during the two states remains unknown. Therefore, in this study, we aim to directly observe the neural circuit dynamics during post-learning sleep in mice.

In addition, mammalian sleep is composed of REM (rapid eye movement) sleep and non-REM sleep. REM sleep is the major source of dreams, whereas non-REM sleep is accompanied by a synchronous activity termed slow waves. Whereas non-REM sleep is known to contribute to memory consolidation, the involvement of REM sleep is unclear. Through manipulation of neurons regulating REM sleep, we aim to increase or inhibit REM sleep and examine the effect on memory and neural circuit plasticity. Through our studies, we will address fundamental questions such as “Why we sleep?” and “Why we dream?” from the perspective of memory dynamics.

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Neuronal mechanism of memory consolidation of motor learning

Graduate School of Science and Engineering, Saitama University
Junichi Nakai

Motor learning is one of the fundamental function of the brain. Cerebellar cortex and nuclei are reported to be involved in motor learning. In motor learning memory consolidation that is a process transforming information from short term memory to long term memory plays important roles. However, the molecular mechanism of the memory consolidation of motor learning is not well-understood.

In this study we are going to use zebrafish as a model animal. Because zebrafish has several advantages. (1) The cerebellum of zebrafish has structurally and functionally similar to that of mammals. (2) Its brain size is small. (3) It has transparent body at the larval stage. These features makes zebrafish an ideal model animal for studying motor leaning with modern imaging techniques and optogenetics.

We have been developing GFP based calcium probe G-CaMP for studying neuronal circuit functions. We expressed G-CaMP in the zebrafish brain and succeeded in imaging hundreds of neuron activities in vivo. Using this technique and optogenetics, we will approach to understand the mechanism of neural circuits in zebrafish that play important roles in the memory consolidation of motor learning.

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Mechanisms of age-dependent memory impairment and metabolic homeostasis

Graduate School of Pharmaceutical Sciences, Chiba University
Ayako Tonoki

Aging impairs the formation of memory and metabolic homeostasis. Numerous reports have shown that the mechanisms of memory formation and the regulation of metabolic homeostasis are evolutionarily well conserved. We aim to elucidate the mechanisms of age-dependent memory impairment with alteration in metabolic homeostasis, using Drosophila olfactory memory as a model system. For this purpose, we will combine various techniques including genetics, behavior analysis, calcium imaging, and transcriptome analysis. The research plan in this project is as below.

  1. Elucidate the effect of metabolic homeostasis on memory formation.
  2. Elucidate the effect of age-dependent impairment in metabolic homeostasis on memory formation.
  3. Identify neural circuits affected by age-dependent impairment in metabolic homeostasis.
  4. Identify molecular network affected by age-dependent impairment in metabolic homeostasis.

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Understanding the odor-mediated learning and memory formation and the plasticity of olfactory neuronal circuit along wake-sleep cycle

Graduate School of Medicine, The University of Tokyo 
Masahiro Yamaguchi

Olfactory system underlies fundamental animal behaviors including food search and intake and escape from predators. To behave properly in changing odorous circumstances, learning and memory of olfactory system is critically important. Recent studies are revealing that olfactory memory formation is accompanied by the plasticity in the neuronal circuit of the olfactory bub (OB), the first relay of odor information processing. However, the molecular and neuronal mechanisms of circuit plasticity in the OB are poorly understood.

Local interneurons in the OB play crucial role in the plasticity of OB neuronal circuits. Especially, plasticity in inhibitory synaptic inputs from granule cells (GCs), the major local inhibitory interneurons, to OB projection neurons is considered to be central to the circuit plasticity. Remarkably, GCs in the OB are continually generated throughout life of the animal, providing highly plastic potential to the OB neuronal circuits. We have revealed that selection of newly generated GCs between life and death is conducted in a sequence of olfactory experience during waking period and subsequent sleep period. We also noticed that top-down synaptic inputs from the olfactory cortex to the OB during sleep promote GC selection.

Given these findings, this project aims to understand the mechanisms of learning and memory formation of the olfactory system with respect to the plasticity in the OB neuronal circuits along wake-sleep cycle. We are planning to address the electrophysiological property of OB neuronal circuits in mice during the learning and memory formation to odor-mediated tasks, information transfer between the OB and the olfactory cortex along wake-sleep cycle, and contribution of newly generated GCs to these processes.

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Deciphering long-term plasticity mechanisms using dual FRET technologies

Graduate School of Medicine, The University of Tokyo
Haruhiko Bito

Synaptic transmission triggers generation of EPSP as well as chemical signaling such as increase in intracellular Ca2+ concentration. Ca2+ signals play critical roles both for induction of long-term synaptic plasticity and for the signaling from the synapses to the nucleus. However, technical limitations have so far hampered elucidation of how Ca2+ signals transfer to the nucleus when only a tiny part of a dendrite is stimulated. Furthermore, it is not clear how phosphorylation cascades are initially turned on outside or inside the nucleus. To re-examine these fundamental issues of synapse-to-nucleus signaling, we will develop a sensitive FRET indicator for CREB phosphorylation. Using dFOMA (dual FRET with Optical Manipulation) technologies that we recently developed, we will perform quantitative imaging of pCREB and CaMKK-CaMKIV cascades in living neurons. Results of these studies are expected to shed light on important mechanisms underlying cellular consolidation of long-term memory.

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Exploring the neural network underlying social decision making

Graduate School of Natural Science and Technology, Okayama University
Hideaki Takeuchi

Within group-living animals, individuals appropriately tailor their attitudes and responses to other group members according to the social context and external environment. The territory between sensory input and behavioral output, which comprises the integrative circuits underlying decision-making processes, however, is vast and mysterious. To address this issue, we have focused on medaka fish, a model animal used mainly in the field of molecular genetics. Recent studies in the filed of behavioral ecology demonstrated the ability to recognize conspecific individuals in some fish species such as guppies and cichlids. Previously we also reported that medaka females recognize familiar males following prior visual exposure, and social familiarity influences female mating receptivity. Medaka females exhibit a positive response (high receptivity) to familiar males, and a negative response (low receptivity) to unfamiliar males. In addition, we revealed the essential role of a subpopulation of gonadotropin-releasing hormone-producing neurons (GnRH3 neurons) in switching from low to high female receptivity. Our aim here is to describe the neural network of the integrative circuits associated with individual recognition and the regulation of female receptivity.

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Internal state of neural network associated with memory formation and retrieval

Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hiroshi Nomura

Neuronal activities persist without the external stimuli. Neuronal membrane potentials fluctuate spontaneously, resulting in generation of action potentials. The spontaneous activity is produced not in a random manner but in a well-ordered manner. The previous memory studies focused on the strength of external stimuli and timing, and tried to understand the firing pattern and synaptic inputs responsive to the external stimuli and their changes. Therefore, these studies considered spontaneous activity as a background noise. However, we think that spontaneous activity reflect the brain’s internal state and is involved in memory formation and retrieval. Our study focuses on the following two issues. (1) We will measure the spontaneous activity, neural activity responsive to the external stimuli and neural plasticity, and will examine their correlation and causality. (2) We will examine the role of spontaneous activity in behavior. We will inhibit spontaneous activities of specific neurons in temporal precision. We will employ behavioral analysis, optogenetics, electrophysiology and imaging. Overall, we focus on spontaneous activity and try to understand the mechanisms underlying learning and memory.

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Deciphering roles of the cerebellar neural circuitry in the formation and maintenance of the memory for fear conditioning

Bioscience and Biotechnology Center, Nagoya University
Masahiko Hibi

The cerebellum is important in motor learning. It is also implicated in higher cognitive and emotional functions. Although the information is stored in the cerebellar neural circuitry during the learning process of higher brain functions, it is not clear how the memory is stored and used to make outputs. In teleosts and mammals, the repeated paring of a conditioned stimulus (CS; light) and an unconditioned stimulus (US; electric shock) leads to bradycardia and escape behaviors in response to the conditioned response (classical fear conditioning). Cerebellum lesions or drug-mediated silencing of the cerebellum function results in impairments in the classical fear conditioning, indicating that the cerebellum is involved in this process.

In this research project, we use zebrafish as the model system. (1) We shall establish transgenic zebrafish lines that express a modified version of Gal4 in cerebellar neurons or the input neurons, and cross them with UAS reporter or effector lines to monitor or manipulate activities of these neurons. Using these zebrafish, (2) we plan to seek for neurons that are activated or repressed during the classical fear conditioning. (3) We try to activate or inhibit individual components of the circuits and examine their effects on the fear conditioning. Combining these data, we shall reveal roles of the cerebellar neural circuitry in the fear conditioning.

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Analysis of cell assembly activity realizing formation and reformation of various contents of memory

Graduate School of Brain Science, Doshisha University
Yoshio Sakurai

Cognitive psychology has suggested that memory items are remembered and consolidated as networks of information items. It has also indicated that changes and reconstruction of such information networks make it possible to remember almost unlimited amount of memory in spite of the limited amount of neuronal networks in the brain. However, it is still unknown what neuronal networks actually realize the dynamic changes of information networks and how they work in the brain. How are functional groups of neurons, i.e., cell assemblies, which code information items constructed during formation of memory? How do such constructed cell assemblies change when new memory is formed and/or old memory is erased or reformed? The present study aims to clarify the activities and changes of cell assemblies underlying dynamics of memory formation and reformation. We record spike activities from closely neighboring multiple neurons with special electrodes during all processes when the same rat is acquiring multiple memory tasks (conditioned discrimination tasks) (Figure 1). We then separate the recorded multi-neuronal activities to activities from individual neurons by our spike-sorting method using independent component analysis (ICA) (Figure 2). We will finally show changes of firing rates of individual neurons and firing synchrony in large and small groups of neurons during the processes of memory formation and reformation. To-be-answered questions are 1) How do cell assemblies change during formation of memory A → memory B → memory C → memory A? 2) How different are such changes of cell assemblies in prefrontal cortex, motor cortex, and hippocampus? 3) How do macro circuits across the prefrontal cortex, motor cortex and hippocampus change during the dynamic formation of different memory?

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Study of molecular mechanisms and neural bases required for labile state of long-term memory

MIC, Kyoto University
Yukinori Hirano

Long-term memory (LTM) is consolidated through de novo gene expression. The consolidated memory is utilized for animals’ survival, although the consolidated memory should be modified or extinguished depending on the changeable environment. The extinction of LTM can be observed in a specific time window, called labile state, however, the mechanism underlying the labile state of memory is poorly understood.
Using Drosophila, I found that a transcription factor plays important role creating labile state of LTM. In this study, I first will focus on its target genes for LTM extinction. Second, the neural circuit required for LTM extinction will be analyzed using genetic tools established in Drosophila, in which the activity of targeted neurons is suppressed or activated. This study will help understanding the mechanism of LTM extinction at the molecular level, and the neural circuit level.

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Cellular environment-dependent RNA methylation at synapse during learning and memory

WPI-iCeMS, Kyoto University
Dan Ohtan Wang

How do neurons store information from past events? Memory extensively interacts with various cellular and environmental signals, including energy and nutrient availability. When the cellular environment is favorable (a healthy state), a memory can be formed and reinforced. When the environment is less favorable (diseased states), a person’s ability of learning and memory can be compromised. From a molecular point of view, the integration of environmental cues and memory can occur through epigenetic processes during which gene expression is regulated through a wealth of DNA and histone modifications.

Recent evidence has suggested that RNA methylation may occur as another functional link between energy consumption, cellular environment and memory storage, possibly at single synapse level. N6-methyladenosine (m6A), a highly prevalent mRNA modification in the brain increases along aging and regulates expression level of many proteins important for neuronal signaling, including dopamine receptors. Variations in the m6A modification enzymes not only predispose to obesity in humans, but also link to aging-dependent reduced brain volume, loss of memory, and risk of alcohol dependence. We hypothesize that m6A modulates spatiotemporal regulation of neuronal gene expression at synapse, which in turn, regulate cellular response of neurons to learning-related stimuli to store information of past events. This cellular mechanism may play critically important roles in aging-, nutrition-, alcohol-dependent “memory dynamism”.

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Molecular mechanism of local circuit formation for generating memory

FBS, Osaka University
Takeshi Yagi

Memory is dynamically generated by neural activities of cell assembly in the brain. The cell assembly is thought to be based on structures of complex neural circuits. It has not yet revealed mechanisms for building the structures of complex neural networks for generating memory. We have identified diverse cell adhesion molecules, clustered protocadherins (cPcdh), from the mammalian brain. They display differential and combinatorial expression in each individual neurons, suggesting that they are possible to regulate complex neural circuits at individual cell level. So far we have revealed that the cPcdhs contribute to memory function and regulate axonal and/or dendrite pattern formation. In this project, we will analyze molecular mechanism of cPcdhs for generating memory. This approach will reveal molecular mechanisms to generate structures of complex neural networks and will realize how to generate memory by neural activity of cell assembly .

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Manipulation of memory formation

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Real-time change in spontaneous firing of hippocampal CA1 neurons before, during, and after the exposure to specific episode

Department of Systems Neuroscience,Yamaguchi University,Graduate School of Medicine
Dai Mitsushima

Collaborators
Department of Systems Neuroscience,Yamaguchi University,Graduate School of Medicine
Junko Ishikawa
Hiroyuki Kida
Yuya Sakimoto

The hippocampus plays a central role to form new episodic memory in various species including humans (Scoville and Milner, 1957). The hippocampal neurons seem to process variety of information, such as spatial location (Wills et al, Science 2010), temporal information (Mitsushima et al, J Neurosci 2009), and emotional state (Chen et al, PLoS ONE 2009) within specific episodes (Gelbard-Sagiv et al, Science 2008). However, the critical mechanism how to sustain a piece of specific memory or what associates the memory fragment each other is still largely unknown.

We previously revealed that learning-dependent synaptic delivery of AMPA receptors into the CA3-CA1 synapses is required for hippocampal contextual learning (Mitsushima et al, PNAS 2011). Moreover, we find that the contextual learning strengthens not only AMPA receptor-mediated excitatory synapses, but also GABAA receptor-mediated inhibitory synapses on hippocampal CA1 neurons, inducing electrophysiological diversity of excitatory and inhibitory synapses (Mitsushima et al, Nat Commun, 2013). Since loss of the diversity severely impaired the learning, we hypothesized that the synaptic diversity encodes information of learned episode (Figure).

In this project, we analyze real-time change in spontaneous firing of hippocampal CA1 neurons in freely moving rats before, during, and after the exposure to specific episode. By analyzing the episode-specific changes in spontaneous firing and the synaptic plasticity, we are going to extract a law of learning in the hippocampus.

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Schema of CA1 neurons in untrained and trained rats. Learning strengthens not only AMPA receptor-mediated excitatory synapses, but also GABAA receptor-mediated inhibitory synapses, inducing electrophysiological diversity of CA1 neurons. We hypothesized that the synaptic diversity depicts cell-specific outputs processing experienced episodes.

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The spatial and temporal dynamics of memory formation

Department of Physiology, Yokohama City University Graduate School of Medicine
Takuya Takahashi

Brain changes in response to external stimuli, called plasticity. Synapses convey information from a neuron to other neurons. When presynaptic neurons are activated, neurotransmitter is released from the presynaptic terminal, binds to postsynaptic receptors, and information is transmitted to postsynaptic neurons. Approximately 90% of excitatory synapses are glutamatergic synapses. A number of glutamate receptors have been identified. Among them, AMPA receptors play crucial roles in the nervous system. Tetanic synaptic stimulation leads to the sustained enhancement of synaptic responses. This phenomenon is called “Long Term Potentiation:LTP” and thought to be a cellular mechanism of neural plasticity. When the LTP is expressed, AMPA receptors are delivered to synapses and the number of synaptic AMPA receptors is increased.

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Functional roles of the variability of neuronal activities in motor learning

Division of Visual Information Processing, National Institute for Physiological Sciences
Rie Kimura

The issue of how activities of multiple neurons in neocortex change during motor learning remains to be clarified. Most previous studies have analyzed the firing of cortical cells, averaged for many trials. In this research project, we will focus on the trial-to-trial variability of neuronal activities. We will perform multi-channel recordings of neuronal activities in visual and motor cortex of rats performing motor tasks initiated by visual cues. We will correlate the alteration in neuronal activities and their variability with the improvement of visual-motor tasks. To clarify the causal relationship between the trial-to-trial variability of neuronal activities and the performance of the visual-motor tasks, we will examine the effect of an artificial reduction of the variability using optogenetics on task performance. Our aim is to determine the changes of neuronal network activities underlying motor leaning and reveal the physiological significance of the variability of neuronal activities in cortical information processing.

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“Memory priming” conferred by thyroid hormone to start the sensitive period of imprinting in birds.

Fac. Pharmaceutical Sci., Teikyo University
Koichi Homma

The timing and duration of the sensitive period for learning has been believed to be developmentally fixed and unable to be changed. However, there is now reason to believe that the sensitive period can be flexible in terms of the timing and duration. In fact, learning itself starts the sensitive period, and once what we term "memory priming (MP)" occurs, the sensitive period does not close but remains open. We will investigate the molecular mechanism of sensitive period of filial imprinting using chicks as a model to memorize their parents (Figure 1).

Filial imprinting in birds is the process of forming a social attachment during a sensitive or critical period, restricted to the first few days after hatching. Imprinting is considered to be part of early learning to aid the survival of juveniles by securing maternal care. We showed that the thyroid hormone determines the start of the sensitive period. Imprinting training in chicks (Gallus gallus domesticus) causes rapid inflow of thyroid hormone. The hormone thus initiates and extends the sensitive period to last more than 1 week via non-genomic mechanisms. It can also confer MP to prime subsequent learning. Once chicks have achieved MP, it is maintained for long periods (Figure 2). Even in non-imprinted chicks whose sensitive period has ended, exogenous thyroid hormone enables imprinting. It is possible that the sensitive period closes only if MP is not conferred at an appropriate time of development. Under natural conditions, chicks will learn spontaneously with the help of parents and siblings. In a sense, the closing of the sensitive period for learning may not exist under usual physiological conditions probably because the sensitive period does not close as long as MP is acquired. Our study elucidates the critical role of imprinting to subsequent learning as being governed by the acute action of thyroid hormone. There may exist determining factors among higher intelligent animals as well that can cause the opening of a sensitive period. The implications of this study reach beyond the sensitive period of imprinting and learning in chicks and deepen our understanding of the processes of learning.

Figure 1 Filial imprinting
Newly hatched chicks follow the first conspicuous moving object they see. This is the biological mother under normal conditions. However, under experimental conditions it can be, in theory, be any other object. The chicks learn the color and shape of the object and become attached to it.

Figure 2 The sensitive period and memory priming
The concentration of thyroid hormone in brains peaked around hatching, and further increase of thyroid hormone induced by imprinting is required for imprinting. The additional wave of thyroid hormone confers memory priming (MP) through rapid non-genomic action. Once chicks are primed and conferred MP, the sensitive period remains open for over 1 week, driving subsequent learning and enhancing memory.

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Neural mechanisms underlying emotional memory dynamism

Dept. Neuroscience, Jikei University School of Medicine
Ayako M. Watabe

Aversive memory to associate sensory information with aversive stimuli is critical for animal survival. Among such aversive stimuli, pain is one of the most powerful signals. Pain has emotional and sensory aspects, whereby noxious stimuli detected by nociceptors are integrated and associated with negative emotional factors. Pain and negative emotion thus can dynamically influence each other. In fact, epidemiological studies showed patients with anxiety disorders and depression have higher susceptibility to chronic pain. Furthermore, aversive learning triggers neural plasticity resulting in memory formation, which would consequently provides a trace of noxious experience, thereby allowing animals to more readily associate sensory signals with concurrent aversive signals. However, the neural mechanisms underlying such aversive memory dynamism are yet to be elucidated.

The central amygdala, which plays a key role in aversive learning by attaching emotional value to various sensory input, receives direct nociceptive signals from parabrachial nucleus (PB). Previously, we have reported synaptic potentiation of these synapses following establishment of chronic pain as well as acquisition of aversive memory. Also, we found that temporal inactivation of PB significantly impaired aversive learning. Therefore, the purpose of this project is to (1) elucidate the molecular mechanisms underlying the metaplasticity of CeA synapses. (2) examine the physiological role of CeA in aversive memory dynamism. (3) examine the neuronal mechanisms how aversive memory would regulate the perception of pain.

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Design and synthesis of new chemical tools to manipulate neuronal signaling pathways

Faculty of Science, Toho University
Toshiaki Furuta

Caged compounds are synthetic molecules whose biological activities are temporally masked by covalent attachment of an appropriately designed photo-removable protecting group. We have designed and synthesized caged compounds of biologically related molecules including neurotransmitters, second messengers, mRNAs and DNAs, which can be photo-chemically reactivated under one and two photon excitation conditions. The compounds have been used to control gene expression, signal transduction and neuronal signaling. Examples of application include local stimulation of an intracellular signaling pathway within subcellular spatial resolution.

In this project, we will develop new chemical tools designed to manipulate a neuronal circuit involved in memory and learning. (1) We have designed new caged second messengers which enable cell type specific photo-manipulation of an intracellular signaling pathway. (2) We have developed a facile and practical method for preparation of caged oligonucleotides and applied the method to photo-mediated gene expression in cultured mammalian cells. We will elucidate whether the newly developed caged oligonucleotides can manipulate photo-chemically local protein synthesis within dendrites.

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Molecular physiology of the memory for temperature habituation

Faculty of Science and Engineering & Institute for Integrative Neurobiology, Konan University
Atsushi Kuhara

Temperature is essential information for survival and proliferation of animal. We are using cold habituation as a model for studying temperature sensation and memory. 15℃-cultivated animals can survive at 2℃, however, 20℃- or 25℃-cultivated animals can not survive after cold shock. We unexpectedly found that cold tolerance is established only two to three hours after the cultivation temperature was changed from 25 to 15°C, and that cold tolerance is diminished 2–3 hours after the cultivation temperature was changed from 15 to 25°C. These suggest that temperature memory for the formation of cold tolerance can be replaced within 2 to 3 hours. We are utilizing this memory aspect of cold habituation to find novel insight into fundamental mechanisms underlying memory formation. In this project, we are planning to isolate the genes and tissue network underlying cold habituation memory, by the combination analysis of molecular genetics, optogenetics, and DNA microarray analysis. Our study will be exhibited a systematic regulation for controlling temperature memory.

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Behavioral state control of auditory memory formation in zebra finch song learning

Okinawa Institute of Science and Technology (OIST) Graduate University, Neuronal Mechanim of Critical Period Unit
Yoko Yazaki-Sugiyama

How do we discriminate between a directed human voices within betweenanda massive pervasive background auditory information, when we are and learning to speak by mimickingmimicking those voices it in during the juvenile periodearly childhood ?

Like humans learning to speak, zebra finches learn to sing by mimicking adult songs during a discrete developmental time window. Interestingly, although birds do not learn by passively listening to a pre-recorded song, they can learn from a recording, once it is played as a reward. Moreover, normally birds preferentially learn songs of their fathers, with which they have a closer social relationship compared to unrelated birds, suggesting that a young bird’s internal state controls which song to learn.

Here we try to understand the neuronal basis of attention level control of auditory memory formation in zebra finch song learning. We also focus on modulation of this process by norepinephrine, which plays a central role in controlling attention and alertness. The following two lines of experiments are being employed:

  1. Investigating neuronal activity in the zebra finch auditory cortex and its plasticity in relations to auditory experiences, using electrophysiological techniques combined with pharmacological and pharmacogenetics techniques.
  2. Investigating noradrenergic modulation of the activity of zebra finch auditory cortex neurons, as well as learning behavior.

The zebra finch serves as the premier model of learning behavior because of its anatomically well identified brain circuits. By employing this model we will contribute to understanding discrete neuronal circuits subserving memory formation in learning behavior.

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Figure:Plastic changes in auditory responses t the song playback in cortical neurons

Auditory responses to each song played back before and after hearing a live tutor singing. Responses to only the tutor song increased upon hearing a real tutor singing, suggesting that neuronal modulation results from auditory experience with heightened attention.

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Neural mechanisms of reward-related memory dynamism

Department of Developmental Physiology, National Institute for Physiological Sciences
Masaaki Ogawa

In order to live better, animals, including human, must make a search for important reward-related information to be learned, and subsequently use that information to control one’s behavior, while maintaining motivation. The orbitofrontal cortex (OFC), a prefrontal cortex region, could be a higher control center for this kind of reward-related “memory dynamism”, but the precise role of the OFC in such “memory dynamism” is not clear. Rodents and primates’ orbitofrontal cortex are similar in terms of the pattern of connectivity with other brain regions such as amygdala and striatum. Recent evidence has suggested that fundamental functions of OFC to regulate reward-related behavior could be common between the species. As such, OFC in rodents is a good model system to address a fundamental neural mechanism of reward-related “memory dynamism”.

To address a fundamental role of neural circuits involving OFC as a higher control center for reward-related “memory dynamism”, we will manipulate activity of rodents’ OFC and its neural circuits in a timing- and context-specific manner in stimulus-outcome associative learning. We will use cutting-edge optogenetics combined with in vivo electrophysiology and immunohistochemistry. Further, we will develop genetically engineered animals that enable manipulation and observation of specific neural activity, to be used in new behavioral paradigms.

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The functional role of dentate gyrus maturity in infant amnesia

Life Science Research Center, University of Toyama
Keizo Takao

Processing and fixation of memory are essential for the formation of long-term memory, which is one of the most important functions of the brain that allows humans to socialize. Human infants can remember their experiences over short-term, however, by the time they become adults, they often loose their memory for events that occurred before they were approximately three years old. This phenomenon is called infant amnesia and is observed in a wide variety of species, including humans and rodents. We screened more than 160 mutant mouse strains using a large-scale comprehensive behavioral test battery and identified several strains with behavioral traits related to psychiatric disorders. The molecular and electrophysiological features of dentate gyrus (DG) neurons in the adult hippocampus of these mouse strains were similar to those of immature DG neurons in normal mice, a phenomenon termed the immature DG (iDG).

Mice possessing the iDG phenotype commonly display impairments in remote memory. Therefore, iDG might play an important role in remote memory impairment. Homeostatic synaptic plasticity is considered to be a mechanism by which neurons maintain function in the face of perturbations. The DG might become immature through homeostatic synaptic plasticity mechanisms induced by the application of electroconvulsive shock. Our study is based on the hypothesis that immaturity of DG causes infant amnesia. We will manipulate the maturity of the DG bidirectionally by changing activity of DG neurons in mice using optogenetics and other techniques, and will elucidate the functional role of maturity of the DG in infant amnesia.

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Imaging dynamic memory representation and its underlying mechanisms in the hippocampus

RIKEN Brain Science Institute
Masaaki Sato

While hippocampal function has been studied extensively in relation to spatial navigation in rodents for decades, it has been also proposed that the neural computation for position and distance in the physical world has much commonalities with the navigation in mental space required for episodic memory and planning. Because the output from hippocampal CA3 area and the input from entorhinal cortex layer 3 converge in hippocampal CA1 area, the CA1 circuit has been thought to operate as a “comparator” of information processed within the hippocampal circuitry and that from the external world.

In this project, we investigate the dynamic nature of memory representation and its underlying mechanisms in hippocampal CA1 area using two-photon calcium imaging in awake behaving mice. We particularly focus on experience-dependent changes of place cell maps induced by training in virtual memory tasks and the roles of signaling pathways activated by different neurotransmitters and neuromodulators. We also establish imaging of activity of inhibitory interneurons and study their roles in memory information processing.

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Study on the spacing effect of motor memory mediated by reactive oxygen species.

Tokyo Metropolitan Institute of Gerontology
Shogo Endo

One of the fundamental but attractive questions in the field of neuroscience is to understand the mechanisms underlying memory. Spacing effects is a mechanism important for acquisition of information and is observed commonly in a variety of species. The significance of the spacing effect suggests the importance of the inter-trial intervals (ITI) in addition to the mechanisms induced during the trials. However, the mechanisms for the ITI are largely unknown. Recently, it is reported that the ROS (reactive oxygen species) is generated during ITI and that the production of 8-nitro-cGMP, a long-lasting cGMP derivative, was mediated by the interaction of ROS and NO (nitric oxide). Based on these studies, we will test the following hypothesis; “The long-lasting signal produced from NO and ROS during intertribal interval contributes to the spacing effect of memory” using the cerebellum-dependent motor memory (optokinetic response adaptation, OKR adaptation) as a model of memory.

The study on, the spacing effect will create the potential new research field including Redox Neuroscience and ITI Neuroscience. Furthermore, the study may provide the optimum ITI and the molecular target for the efficient physical therapy and rehabilitation. The results derived from the study will benefit the quality of life in our aging society.

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A, traditional cGMP pathway and 8-nitro-cGMP pathway. NO and ROS yield RNS (Reactive Nitrogen Species). RNS acts on GTP to generate 8-nitro-GTP. Then, 8-nitro-GTP is converted into 8-nitro-cGMP by sGC(soluble guanylate cyclase).
B, the measurement of adaptation of OKR, a cerebellum-dependent motor memory. The mouse is seeing the scree shutting right-left. The eye movement induced by the screen movement is observed through CCD camera and analyzed.

 

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