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Takuya Sasaki

Section

Graduate School of Pharmaceutical Sciences

Job title

Professor

Degree

博士（薬学）（東京大学）
修士（薬学）（東京大学）

researchmap

https://researchmap.jp/TS580224

J-GLOBAL ID

201101030005166538

Research History 11

2022/04 - Present

東北大学大学院医学系研究科　神経薬学分野　教授（兼任）
2021/07 - Present

Graduate School of Pharmaceutical Sciences　Department of Pharmacology　Professor
2020/07 - 2021/06

東京大学大学院薬学系研究科特任准教授
2017/10 - 2021/03

Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency
2014/10 - 2020/06

Graduate School of Pharmaceutical Sciences, The University of Tokyo
2013/02 - 2014/09

University of California, San Diego
2011/04 - 2013/03

National Institute for Physiological Sciences
2010/04 - 2011/03

埼玉大学・脳科学融合研究センター　学振特別研究員(PD)
2007/04 - 2010/03

The University of Tokyo　Graduate School of Pharmaceutical Sciences
2005/04 - 2007/03

The University of Tokyo　Graduate School of Pharmaceutical Sciences
2001/04 - 2005/03

Tohoku University　Faculty of Pharmaceutical Sciences

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Professional Memberships 5

Society for Neuroscience
日本生理学会
日本神経科学学会
日本薬理学会
日本薬学会

Research Interests 16

トランスクリプトーム解析
孤束核
島皮質
内受容感覚
神経薬理学
迷走神経
ストレス応答
前頭前皮質
中枢末梢連関
マルチユニット記録
optogenetics
イメージング
パッチクランプ
海馬
包括脳ネットワーク
神経生理学

Research Areas 3

Life sciences / Clinical pharmacy /
Life sciences / Physiology /
Life sciences / Neuroscience - general /

Awards 17

文部科学大臣表彰若手科学者賞

2020/04
日本薬学会奨励賞

2019/03
日本薬理学会学術奨励賞

2017/03
井上リサーチアォード

2016/02
コニカミノルタ画像科学奨励賞

2016/02
井上研究奨励賞

2013/02
日本神経科学学会奨励賞

2012/08
SfN special travel award

2011/11
包括脳ネットワーク夏のワークショップ優秀発表賞

2011/08
光科学技術研究振興財団研究表彰

2011/03
グリアクラブ賞

2011/02
日本薬理学会年会優秀発表賞

2010/03
生理学若手研究者フォーラム若手研究者奨励賞

2009/07
先端技術大賞フジテレビジョン賞

2007/07
東京大学総長賞

2007/03
東京大学発明コンテスト優秀賞

2007/01
ファーマバイオフォーラム最優秀賞

2006/12

Show all ︎Show 5

Papers 115

Heart rate changes related to risky selections and outcomes in rat gambling tasks. International-journal

Fumiya Fukushima, Atsushi Tamura, Nahoko Kuga, Takuya Sasaki

The journal of physiological sciences : JPS　75　(2)　100022-100022　2025/04/10

DOI： 10.1016/j.jphyss.2025.100022 　

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Risk-taking behavior is crucial to increase potential outcomes and alter arousal states in the brain and body represented by heart rates. In this study, we monitored changes in heart rate as rats performed a 50:50 gambling task in which they selected either a certain outcome with 100 % probability (sure option) or a double outcome with 50 % probability (risky option). When rats selected risky options, they exhibited significantly greater decreases in their heart rates before selection than when they selected certain options. In addition, we observed significantly larger increases in heart rates when the rats recognized larger outcomes after selecting the risky options than the sure options. Similar dynamic changes in heart rates were observed in a 25:75 gambling condition with different reward magnitudes and probabilities. These results demonstrate that animals can dynamically alter their heart rates in response to risky selection and outcomes.
Effects of nanocurcumin supplementation on metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials. International-journal

Gofarana Wilar, Cecep Suhandi, Kohji Fukunaga, Masanori Shigeno, Ichiro Kawahata, Rizky Abdulah, Takuya Sasaki

Pharmacological research　213　107641-107641　2025/03

DOI： 10.1016/j.phrs.2025.107641 　

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BACKGROUND: Metabolic syndrome (MetS) encompasses metabolic risk factors like elevated blood glucose, abnormal lipid levels, and hypertension. Nanocurcumin, a nanoscale formulation of curcumin, may offer therapeutic benefits for MetS management. This systematic review and meta-analysis evaluates the impact of nanocurcumin supplementation on key MetS parameters. METHODS: A systematic literature search identified 20 randomized controlled trials (RCTs) with 1394 participants. Data were pooled using a random-effects model, and standardized mean differences (SMDs) were calculated for key outcomes. RESULTS: Nanocurcumin supplementation significantly improved waist circumference (WC) (standardized mean difference (SMD): -0.30 cm), fasting blood sugar (FBS) (SMD: -0.34 mg/dL), HbA1c (SMD: -0.33 %), and quantitative insulin sensitivity check index (QUICKI) score (SMD: 0.73). Lipid profile parameters, including total cholesterol (SMD: -0.18 mg/dL), LDL-C (SMD: -0.16 mg/dL), and HDL-C (SMD: 0.32 mg/dL), also reduced significantly. Improvement in diastolic blood pressure (DBP) (SMD: -0.32 mmHg), total antioxidant capacity (TAC) (SMD: 0.44 mmol/L), malondialdehyde (MDA) (SMD: -0.37 mmol/L), tumor necrosis factor-α (TNF-α) (SMD: -2.30 ng/L), interleukin-6 (IL-6) (SMD: -1.07 ng/L), and high-sensitivity C-reactive protein (hs-CRP) (SMD: -0.34 mg/L) were observed. CONCLUSION: Nanocurcumin supplementation significantly improves multiple MetS-related parameters, including anthropometric measures, glycemic control, lipid profile, blood pressure, oxidative stress markers, and inflammatory biomarkers. These findings highlight nanocurcumin's potential as an effective adjunctive therapy for managing MetS. However, the variability in study participant ages, treatment durations, and sample sizes suggests the need for further well-designed RCTs to establish optimal usage guidelines.
Hybrid probe combining MicroLED and neural electrode for precise neural modulation and multi-site recording

Gota Shinohara, Tasuku Kayama, Ayumu Okui, Wataru Oda, Atsushi Nishikawa, Alexander Loesing, Nahoko Kuga, Takuya Sasaki, Hiroto Sekiguchi

Applied Physics Express　18　(2)　026501-026501　2025/02/01
Publisher: IOP Publishing
DOI： 10.35848/1882-0786/adaf0a 　

ISSN： 1882-0778

eISSN： 1882-0786

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Abstract Optogenetics enables precise neural control but is limited by conventional optical fibers in complex networks. We present a hybrid device integrating multi-point micro-light-emitting diodes (MicroLEDs) with neural electrodes for localized light stimulation and simultaneous neural recording. Fabricated via direct bonding, it ensures optimal alignment for high spatial-temporal resolution. The thin MicroLED probes minimize invasiveness while maintaining optical performance. Validated in mouse brain models, the system achieves selective neural activation and recording with minimal thermal effects. This scalable, flexible tool overcomes integration challenges, advancing optogenetic research and opening avenues for exploring neural dynamics and targeted neurological therapies.
Distinct roles of dentate gyrus and medial entorhinal cortex inputs for phase precession and temporal correlations in the hippocampal CA3 area. International-journal

Siavash Ahmadi, Takuya Sasaki, Marta Sabariego, Christian Leibold, Stefan Leutgeb, Jill K Leutgeb

Nature communications　16　(1)　13-13　2025/01/02

DOI： 10.1038/s41467-024-54943-2 　

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The hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta-modulated external excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs sharpen the temporal precision throughout the theta cycle. A computational model that accounts for empirical findings suggests that the unique contribution of DG inputs to theta-related spike timing is supported by targeting precisely timed inhibitory oscillations. Our results thus identify a novel and unique functional role of the DG for sequence coding in the CA3 circuit.
Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation. International-journal

Peng-Xiang Min, Li-Li Feng, Yi-Xuan Zhang, Chen-Chen Jiang, Hong-Zhen Zhang, Yan Chen, Kohji Fukunaga, Fang Liu, Yu-Jie Zhang, Takuya Sasaki, Xu Qian, Katsuhisa Horimoto, Jian-Dong Jiang, Ying-Mei Lu, Feng Han

Cell death and differentiation　2025

DOI： 10.1038/s41418-025-01534-3 　

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The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.
How the brain senses the body

Takuya Sasaki

Nature　2024/11
Transformer-based classification of visceral pain-related local field potential patterns in the brain. International-journal

Tasuku Kayama, Atsushi Tamura, Tuo Xiaoying, Ken-Ichiro Tsutsui, Keiichi Kitajo, Takuya Sasaki

Scientific reports　14　(1)　24372-24372　2024/10/17

DOI： 10.1038/s41598-024-75616-6 　

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Neuronal ensemble activity entrained by local field potential (LFP) patterns underlies a variety of brain functions, including emotion, cognition, and pain perception. Recent advances in machine learning approaches may enable more effective methods for analyzing LFP patterns across multiple brain areas than conventional time-frequency analysis. In this study, we tested the performance of two machine learning algorithms, AlexNet and the Transformer models, to classify LFP patterns in eight pain-related brain regions before and during acetic acid-induced visceral pain behaviors. Over short time windows lasting several seconds, applying AlexNet to LFP power datasets, but not to raw time-series LFP traces from multiple brain areas, successfully achieved superior classification performance compared with simple LFP power analysis. Furthermore, applying the Transformer directly to the raw LFP traces achieved significantly superior classification performance than AlexNet when using LFP power datasets. These results demonstrate the utility of the Transformer in the analysis of neurophysiological signals, and pave the way for its future applications in the decoding of more complex neuronal activity patterns.
Optogenetic estimation of synaptic connections in brain slices. International-journal

Tetsuhiko Kashima, Takuya Sasaki, Yuji Ikegaya

Journal of neuroscience methods　412　110298-110298　2024/10/01

DOI： 10.1016/j.jneumeth.2024.110298 　

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BACKGROUND: Detection of synaptic connections is essential for understanding neural circuits. By using optogenetics, current injection, and glutamate uncaging to activate presynaptic cells and simultaneously recording the subsequent response of postsynaptic cells, the presence of synaptic connections can be confirmed. However, these methods present throughput challenges, such as the need for simultaneous multicellular patch-clamp recording and two-photon microscopy. These challenges lead to a trade-off between sacrificing resolution and experimental throughput. NEW METHOD: We adopted the laser, typically used for local field ablation, and combined this with post hoc analysis. We successfully approximated the synaptic connection probabilities using only an epi-fluorescence microscope and single-cell recordings. RESULTS: We sequentially stimulated the channelrhodopsin 2-expressing cells surrounding the recorded cell and approximated the synaptic connection probabilities. This probability value was comparable to that obtained from simultaneous multi-cell patch-clamp recordings, which included more than 600 pairs. COMPARISON WITH EXISTING METHODS: Our setup allows us to estimate connection probabilities within 100s, outperforming existing methods. We successfully estimated synaptic connection probabilities using only the optical path typically used by an epi-fluorescence microscope and single-cell recordings. It may also be suitable for dendritic ablation experiments. CONCLUSIONS: The proposed method simplifies the estimation of connection probabilities, which is expected to advance the study of neural circuits in conditions such as autism and schizophrenia where connection probabilities vary. Furthermore, this approach is applicable not only to local circuits but also to long-range connections, thus increasing experimental throughput.
The Posterior Insular Cortex is Necessary for Feeding-Induced Jejunal Myoelectrical Activity in Male Rats. International-journal

Reina Shiratori, Taiki Yokoi, Kosuke Kinoshita, Wenfeng Xue, Takuya Sasaki, Nahoko Kuga

Neuroscience　553　40-47　2024/08/16

DOI： 10.1016/j.neuroscience.2024.06.025 　

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The gastrointestinal tract exhibits coordinated muscle motility in response to food digestion, which is regulated by the central nervous system through autonomic control. The insular cortex is one of the brain regions that may regulate the muscle motility. In this study, we examined whether, and how, the insular cortex, especially the posterior part, regulates gastrointestinal motility by recording jejunal myoelectrical signals in response to feeding in freely moving male rats. Feeding was found to induce increases in jejunal myoelectrical signal amplitudes. This increase in the jejunal myoelectrical signals was abolished by vagotomy and pharmacological inhibition of the posterior insular cortex. Additionally, feeding induced a decrease and increase in sympathetic and parasympathetic nervous activities, respectively, both of which were eliminated by posterior insular cortical inhibition. These results suggest that the posterior insular cortex regulates jejunal motility in response to feeding by modulating autonomic tone.
Integrating physiological and transcriptomic analyses at the single-neuron level. International-journal

Haruya Yagishita, Takuya Sasaki

Neuroscience research　2024/05/29

DOI： 10.1016/j.neures.2024.05.003 　

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Neurons generate various spike patterns to execute different functions. Understanding how these physiological neuronal spike patterns are related to their molecular characteristics is a long-standing issue in neuroscience. Herein, we review the results of recent studies that have addressed this issue by integrating physiological and transcriptomic techniques. A sequence of experiments, including in vivo recording and/or labeling, brain tissue slicing, cell collection, and transcriptomic analysis, have identified the gene expression profiles of brain neurons at the single-cell level, with activity patterns recorded in living animals. Although these techniques are still in the early stages, this methodological idea is principally applicable to various brain regions and neuronal activity patterns. Accumulating evidence will contribute to a deeper understanding of neuronal characteristics by integrating insights from molecules to cells, circuits, and behaviors.
Trial Analysis of Brain Activity Information for the Presymptomatic Disease Detection of Rheumatoid Arthritis. International-journal

Keisuke Maeda, Takahiro Ogawa, Tasuku Kayama, Takuya Sasaki, Kazuki Tainaka, Masaaki Murakami, Miki Haseyama

Bioengineering (Basel, Switzerland)　11　(6)　2024/05/21

DOI： 10.3390/bioengineering11060523 　

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This study presents a trial analysis that uses brain activity information obtained from mice to detect rheumatoid arthritis (RA) in its presymptomatic stages. Specifically, we confirmed that F759 mice, serving as a mouse model of RA that is dependent on the inflammatory cytokine IL-6, and healthy wild-type mice can be classified on the basis of brain activity information. We clarified which brain regions are useful for the presymptomatic detection of RA. We introduced a matrix completion-based approach to handle missing brain activity information to perform the aforementioned analysis. In addition, we implemented a canonical correlation-based method capable of analyzing the relationship between various types of brain activity information. This method allowed us to accurately classify F759 and wild-type mice, thereby identifying essential features, including crucial brain regions, for the presymptomatic detection of RA. Our experiment obtained brain activity information from 15 F759 and 10 wild-type mice and analyzed the acquired data. By employing four types of classifiers, our experimental results show that the thalamus and periaqueductal gray are effective for the classification task. Furthermore, we confirmed that classification performance was maximized when seven brain regions were used, excluding the electromyogram and nucleus accumbens.
A method to analyze gene expression profiles from hippocampal neurons electrophysiologically recorded in vivo

Haruya Yagishita, Yasuhiro Go, Kazuki Okamoto, Nariko Arimura, Yuji Ikegaya, Takuya Sasaki

Frontiers in Neuroscience　18　2024/04/17
Publisher: Frontiers Media SA
DOI： 10.3389/fnins.2024.1360432 　

eISSN： 1662-453X

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Hippocampal pyramidal neurons exhibit diverse spike patterns and gene expression profiles. However, their relationships with single neurons are not fully understood. In this study, we designed an electrophysiology-based experimental procedure to identify gene expression profiles using RNA sequencing of single hippocampal pyramidal neurons whose spike patterns were recorded in living mice. This technique involves a sequence of experiments consisting of in vivo juxtacellular recording and labeling, brain slicing, cell collection, and transcriptome analysis. We demonstrated that the expression levels of a subset of genes in individual hippocampal pyramidal neurons were significantly correlated with their spike burstiness, submillisecond-level spike rise times or spike rates, directly measured by in vivo electrophysiological recordings. Because this methodological approach can be applied across a wide range of brain regions, it is expected to contribute to studies on various neuronal heterogeneities to understand how physiological spike patterns are associated with gene expression profiles.
A Comparative Overview of DSCAM and its Multifunctional Roles in Drosophila and Vertebrates International-journal

Kento Hizawa, Takuya Sasaki, Nariko Arimura

Neuroscience Research　202　1-7　2024/02
Publisher: Elsevier BV
DOI： 10.1016/j.neures.2023.12.005 　

ISSN： 0168-0102

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DSCAM (Down syndrome cell adhesion molecule) is a unique neuronal adhesion protein with extensively documented multifaceted functionalities. DSCAM also has interesting properties in vertebrates and invertebrates, respectively. In Drosophila species, particularly, Dscam exhibits remarkable genetic diversity, with tens of thousands of splicing isoforms that modulate the specificity of neuronal wiring. Interestingly, this splice variant diversity of Dscam is absent in vertebrates. DSCAM plays a pivotal role in mitigating excessive adhesion between identical cell types, thereby maintaining the structural and functional coherence of neural networks. DSCAM contributes to the oversight of selective intercellular interactions such as synaptogenesis; however, the precise regulatory mechanisms underlying the promotion and inhibition of cell adhesion involved remain unclear. In this review, we aim to delineate the distinct molecules that interact with DSCAM and their specific roles within the biological landscapes of Drosophila and vertebrates. By integrating these comparative insights, we aim to elucidate the multifunctional nature of DSCAM, particularly its capacity to facilitate or deter intercellular adhesion.
Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation. International-journal Peer-reviewed

Ken-Ichi Dewa, Nariko Arimura, Wataru Kakegawa, Masayuki Itoh, Toma Adachi, Satoshi Miyashita, Yukiko U Inoue, Kento Hizawa, Kei Hori, Natsumi Honjoya, Haruya Yagishita, Shinichiro Taya, Taisuke Miyazaki, Chika Usui, Shoji Tatsumoto, Akiko Tsuzuki, Hirotomo Uetake, Kazuhisa Sakai, Kazuhiro Yamakawa, Takuya Sasaki, Jun Nagai, Yoshiya Kawaguchi, Masaki Sone, Takayoshi Inoue, Yasuhiro Go, Noritaka Ichinohe, Kozo Kaibuchi, Masahiko Watanabe, Schuichi Koizumi, Michisuke Yuzaki, Mikio Hoshino

Nature communications　15　(1)　458-458　2024/02/01

DOI： 10.1038/s41467-023-44579-z 　

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In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.
Stress-induced vagal activity influences anxiety-relevant prefrontal and amygdala neuronal oscillations in male mice. International-journal

Toya Okonogi, Nahoko Kuga, Musashi Yamakawa, Tasuku Kayama, Yuji Ikegaya, Takuya Sasaki

Nature communications　15　(1)　183-183　2024/01/09

DOI： 10.1038/s41467-023-44205-y 　

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The vagus nerve crucially affects emotions and psychiatric disorders. However, the detailed neurophysiological dynamics of the vagus nerve in response to emotions and its associated pathological changes remain unclear. In this study, we demonstrated that the spike rates of the cervical vagus nerve change depending on anxiety behavior in an elevated plus maze test, and these changes were eradicated in stress-susceptible male mice. Furthermore, instantaneous spike rates of the vagus nerve were negatively and positively correlated with the power of 2-4 Hz and 20-30 Hz oscillations, respectively, in the prefrontal cortex and amygdala. The oscillations also underwent dynamic changes depending on the behavioral state in the elevated plus maze, and these changes were no longer observed in stress-susceptible and vagotomized mice. Chronic vagus nerve stimulation restored behavior-relevant neuronal oscillations with the recovery of altered behavioral states in stress-susceptible mice. These results suggested that physiological vagal-brain communication underlies anxiety and mood disorders.
Non-canonical interplay between glutamatergic NMDA and dopamine receptors shapes synaptogenesis. International-journal

Nathan Bénac, G Ezequiel Saraceno, Corey Butler, Nahoko Kuga, Yuya Nishimura, Taiki Yokoi, Ping Su, Takuya Sasaki, Mar Petit-Pedrol, Rémi Galland, Vincent Studer, Fang Liu, Yuji Ikegaya, Jean-Baptiste Sibarita, Laurent Groc

Nature communications　15　(1)　27-27　2024/01/02

DOI： 10.1038/s41467-023-44301-z 　

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Direct interactions between receptors at the neuronal surface have long been proposed to tune signaling cascades and neuronal communication in health and disease. Yet, the lack of direct investigation methods to measure, in live neurons, the interaction between different membrane receptors at the single molecule level has raised unanswered questions on the biophysical properties and biological roles of such receptor interactome. Using a multidimensional spectral single molecule-localization microscopy (MS-SMLM) approach, we monitored the interaction between two membrane receptors, i.e. glutamatergic NMDA (NMDAR) and G protein-coupled dopamine D1 (D1R) receptors. The transient interaction was randomly observed along the dendritic tree of hippocampal neurons. It was higher early in development, promoting the formation of NMDAR-D1R complexes in an mGluR5- and CK1-dependent manner, favoring NMDAR clusters and synaptogenesis in a dopamine receptor signaling-independent manner. Preventing the interaction in the neonate, and not adult, brain alters in vivo spontaneous neuronal network activity pattern in male mice. Thus, a weak and transient interaction between NMDAR and D1R plays a structural and functional role in the developing brain.
Development of an in vitro compound screening system that replicate the in vivo spine phenotype of idiopathic ASD model mice. International-journal

Kazuma Maeda, Miki Tanimura, Yusaku Masago, Tsukasa Horiyama, Hiroshi Takemoto, Takuya Sasaki, Ryuta Koyama, Yuji Ikegaya, Koichi Ogawa

Frontiers in pharmacology　15　1455812-1455812　2024

DOI： 10.3389/fphar.2024.1455812 　

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Autism Spectrum Disorder (ASD) is a developmental condition characterized by core symptoms including social difficulties, repetitive behaviors, and sensory abnormalities. Aberrant morphology of dendritic spines within the cortex has been documented in genetic disorders associated with ASD and ASD-like traits. We hypothesized that compounds that ameliorate abnormalities in spine dynamics might have the potential to ameliorate core symptoms of ASD. Because the morphology of the spine is influenced by signal inputs from other neurons and various molecular interactions, conventional single-molecule targeted drug discovery methods may not suffice in identifying compounds capable of ameliorating spine morphology abnormalities. In this study, we focused on spine phenotypes in the cortex using BTBR T + Itpr3 tf /J (BTBR) mice, which have been used as a model for idiopathic ASD in various studies. We established an in vitro compound screening system using primary cultured neurons from BTBR mice to faithfully represent the spine phenotype. The compound library mainly comprised substances with known target molecules and established safety profiles, including those approved or validated through human safety studies. Following screening of this specialized library containing 181 compounds, we identified 15 confirmed hit compounds. The molecular targets of these hit compounds were largely focused on the 5-hydroxytryptamine receptor (5-HTR). Furthermore, both 5-HT1AR agonist and 5-HT3R antagonist were common functional profiles in hit compounds. Vortioxetine, possessing dual attributes as a 5-HT1AR agonist and 5-HT3R antagonist, was administered to BTBR mice once daily for a period of 7 days. This intervention not only ameliorated their spine phenotype but also alleviated their social behavior abnormality. These results of vortioxetine supports the usefulness of a spine phenotype-based assay system as a potent drug discovery platform targeting ASD core symptoms.
Distinct Olfactory Bulb-Cortex Neural Circuits Coordinate Cognitive Function in Parkinson's Disease. International-journal

Shuai-Shuai Wang, Xing-Feng Mao, Zhi-Shen Cai, Wen Lin, Xiu-Xiu Liu, Bei Luo, Xiang Chen, Yue Yue, Heng-Yu Fan, Takuya Sasaki, Kohji Fukunaga, Wen-Bin Zhang, Ying-Mei Lu, Feng Han

Research (Washington, D.C.)　7　0484-0484　2024

DOI： 10.34133/research.0484 　

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Cognitive dysfunction stands as a prevalent and consequential non-motor manifestation in Parkinson's disease (PD). Although dysfunction of the olfactory system has been recognized as an important predictor of cognitive decline, the exact mechanism by which aberrant olfactory circuits contribute to cognitive dysfunction in PD is unclear. Here, we provide the first evidence for abnormal functional connectivity across olfactory bulb (OB) and piriform cortex (PC) or entorhinal cortex (EC) by clinical fMRI, and dysfunction of neural coherence in the olfactory system in PD mice. Moreover, we discovered that 2 subpopulations of mitral/tufted (M/T) cells in OB projecting to anterior PC (aPC) and EC precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies in mice. In addition, the transcriptomic profiling analysis and functional genetic regulation analysis further revealed that biorientation defective 1 (Bod1) may play a pivotal role in encoding OBM/T-mediated cognitive function. We also verified that a new deep brain stimulation protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice. Together, aberrant coherent activity in the olfactory system can serve as a biomarker for assessing cognitive function and provide a candidate therapeutic target for the treatment of PD.
Microglia induce auditory dysfunction after status epilepticus in mice. International-journal

Tasuku Araki, Toshimitsu Hiragi, Nahoko Kuga, Cong Luo, Megumi Andoh, Kohtaroh Sugao, Hidetaka Nagata, Takuya Sasaki, Yuji Ikegaya, Ryuta Koyama

Glia　2023/09/25

DOI： 10.1002/glia.24472 　

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Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus. We further demonstrated that microglia reduced inhibitory synapses on MGB relay neurons over an 8-week period after status epilepticus, resulting in auditory pathway hyperactivity. In addition, we found that local removal of microglia from the MGB attenuated the increase in c-Fos+ relay neurons and improved auditory discrimination. These findings reveal that thalamic microglia are involved in auditory dysfunction in epilepsy.
Awake hippocampal synchronous events are incorporated into offline neuronal reactivation. International-journal

Saichiro Yagi, Hideyoshi Igata, Yuji Ikegaya, Takuya Sasaki

Cell reports　42　(8)　112871-112871　2023/08/29

DOI： 10.1016/j.celrep.2023.112871 　

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Learning novel experiences reorganizes hippocampal neuronal circuits, represented as coordinated reactivation patterns in post-experience offline states for memory consolidation. This study examines how awake synchronous events during a novel run are related to post-run reactivation patterns. The disruption of awake sharp-wave ripples inhibited experience-induced increases in the contributions of neurons to post-experience synchronous events. Hippocampal place cells that participate more in awake synchronous events are more strongly reactivated during post-experience synchronous events. Awake synchronous neuronal patterns, in cooperation with place-selective firing patterns, determine cell ensembles that undergo pronounced increases and decreases in their correlated spikes. Taken together, awake synchronous events are fundamental for identifying hippocampal neuronal ensembles to be incorporated into synchronous reactivation during subsequent offline states, thereby facilitating memory consolidation.
Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model. International-journal

An Cheng, Wenbin Jia, David I Finkelstein, Nadia Stefanova, Haoyang Wang, Takuya Sasaki, Ichiro Kawahata, Kohji Fukunaga

Acta pharmacologica Sinica　2023/08/21

DOI： 10.1038/s41401-023-01138-y 　

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Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (αSyn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced αSyn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated αSyn-associated pathological processes in PLP-hαSyn transgenic mice (PLP-αSyn mice), a wildly used MSA mouse model with overexpressing αSyn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-αSyn mice were orally administered MF6 (0.1, 1 mg ·kg-1 ·d-1) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced αSyn aggregation levels in both cerebellum and basal ganglia of PLP-αSyn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and αSyn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced αSyn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting αSyn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.
Effects of theta phase precessing optogenetic intervention on hippocampal neuronal reactivation and spatial maps

Yuki Aoki, Taiki Yokoi, Shota Morikawa, Nahoko Kuga, Yuji Ikegaya, Takuya Sasaki

iScience　107233-107233　2023/06
Publisher: Elsevier BV
DOI： 10.1016/j.isci.2023.107233 　

ISSN： 2589-0042
Selective serotonin reuptake inhibitors suppress sharp wave ripples in the ventral hippocampus.

Hiromi Shiozaki, Nahoko Kuga, Tasuku Kayama, Yuji Ikegaya, Takuya Sasaki

Journal of pharmacological sciences　152　(2)　136-143　2023/06

DOI： 10.1016/j.jphs.2023.04.003 　

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Biased memory processing contributes to the development and exacerbation of depression, and thus could represent a potential therapeutic target for stress-induced mental disorders. Synchronized spikes in hippocampal neurons, corresponding to sharp wave ripples (SWRs), may play a crucial role in memory reactivation. In this study, we showed that the frequency of SWRs increased in the ventral hippocampus, but not in the dorsal hippocampus, after stress exposure. Administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine inhibited the generation of ventral hippocampal SWRs and reduced locomotor activity and local field potential power in the gamma bands. These results suggest that the antidepressant effects of SSRIs may be mediated by the suppression of ventral hippocampal SWRs.
Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation. International-journal

An Cheng, Ichiro Kawahata, Yifei Wang, Wenbin Jia, Wang Haoyang, Tomoki Sekimori, Yi Chen, Hiroyoshi Suzuki, Atsushi Takeda, Nadia Stefanova, David I Finkelstein, Wenbo Ma, Min Chen, Takuya Sasaki, Kohji Fukunaga

Brain : a journal of neurology　146　(8)　3172-3180　2023/04/21

DOI： 10.1093/brain/awad137 　

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Multiple system atrophy (MSA) is a neurodegenerative disease characterised by the accumulation of misfolded α-synuclein (αSyn) and myelin disruption. However, the mechanism underlying αSyn accumulation in MSA brains remains unclear. Here, we aimed to identify epsin-2 as a potential regulator of αSyn propagation in MSA brains. In the MSA mouse model, PLP-hαSyn mice, and FABP7/αSyn hetero-aggregate-injected mice, we initially discovered that fatty acid-binding protein 7 (FABP7) is related to MSA development and forms hetero-aggregates with αSyn, which exhibit stronger toxicity than αSyn aggregates. Moreover, the injected FABP7/αSyn hetero-aggregates in mice selectively accumulated only in oligodendrocytes and Purkinje neurons, causing cerebellar dysfunction. Furthermore, bioinformatic analyses of whole blood from MSA patients and FABP7 knock-down mice revealed that epsin-2, a protein expressed in both oligodendrocytes and Purkinje cells, could potentially regulate FABP7/αSyn hetero-aggregate propagation via clathrin-dependent endocytosis. Lastly, AAV5-dependent epsin-2 knock-down mice exhibited decreased levels of αSyn aggregate accumulation in Purkinje neurons and oligodendrocytes, as well as improved myelin levels and Purkinje neuron function in the cerebellum and motor performance. These findings suggest that epsin-2 plays a significant role in αSyn accumulation in MSA, and we propose epsin-2 as a novel therapeutic target for MSA.
Hippocampal sharp wave ripples underlie stress susceptibility in male mice

Nahoko Kuga, Ryota Nakayama, Shota Morikawa, Haruya Yagishita, Daichi Konno, Hiromi Shiozaki, Natsumi Honjoya, Yuji Ikegaya, Takuya Sasaki

Nature Communications　14　(1)　2023/04/20
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41467-023-37736-x 　

eISSN： 2041-1723

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Abstract The ventral hippocampus (vHC) is a core brain region for emotional memory. Here, we examined how the vHC regulates stress susceptibility from the level of gene expression to neuronal population dynamics in male mice. Transcriptome analysis of samples from stress-naïve mice revealed that intrinsic calbindin (Calb1) expression in the vHC is associated with susceptibility to social defeat stress. Mice with Calb1 gene knockdown in the vHC exhibited increased stress resilience and failed to show the increase in the poststress ventral hippocampal sharp wave ripple (SWR) rate. Poststress vHC SWRs triggered synchronous reactivation of stress memory-encoding neuronal ensembles and facilitated information transfer to the amygdala. Suppression of poststress vHC SWRs by real-time feedback stimulation or walking prevented social behavior deficits. Taken together, our results demonstrate that internal reactivation of memories of negative stressful episodes supported by ventral hippocampal SWRs serves as a crucial neurophysiological substrate for determining stress susceptibility.
Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor International-journal Peer-reviewed

Wenbin Jia, Ichiro Kawahata, An Cheng, Takuya Sasaki, Toshikuni Sasaoka, Kohji Fukunaga

International Journal of Molecular Sciences　24　(7)　2023/04

DOI： 10.3390/ijms24076644 　

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We previously demonstrated that fatty acid-binding protein 3 null (FABP3-/-) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system.
An open-source application to identify the three-dimensional locations of electrodes implanted into the rat brain from computed tomography images. International-journal

Mikuru Kudara, Nobuyoshi Matsumoto, Nahoko Kuga, Kotaro Yamashiro, Airi Yoshimoto, Yuji Ikegaya, Takuya Sasaki

Neuroscience research　193　20-27　2023/03/30

DOI： 10.1016/j.neures.2023.03.003 　

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Electrophysiological recordings using metal electrodes implanted into the brains have been widely utilized to evaluate neuronal circuit dynamics related to behavior and external stimuli. The most common method for identifying implanted electrode tracks in the brain tissue has been histological examination following postmortem slicing and staining of the brain tissue, which consumes time and resources and occasionally fails to identify the tracks because the brain preparations have been damaged during processing. Recent studies have proposed the use of a promising alternative method, consisting of computed tomography (CT) scanning that can directly reconstruct the three-dimensional arrangements of electrodes in the brains of living animals. In this study, we developed an open-source Python-based application that estimates the location of an implanted electrode from CT image sequences in a rat. After the user manually sets reference coordinates and an area from a sequence of CT images, this application automatically overlays an estimated location of an electrode tip on a histological template image; the estimates are highly accurate, with less than 135 µm of error, irrespective of the depth of the brain region. The estimation of an electrode location can be completed within a few minutes. Our simple and user-friendly application extends beyond currently available CT-based electrode localization methods and opens up the possibility of applying this technique to various electrophysiological recording paradigms.
Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice Peer-reviewed

Haoyang Wang, Kohji Fukunaga, An Cheng, Yifei Wang, Nariko Arimura, Hiroshi Yoshino, Takuya Sasaki, Ichiro Kawahata

Journal of Pharmacological Sciences　152　(1)　30-38　2023/03

DOI： 10.1016/j.jphs.2023.02.008 　

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Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy.
Feasibility and considerations of epsin2 as a candidate target for multiple system atrophy treatment. International-journal

An Cheng, Bo Cai, Kohji Fukunaga, Takuya Sasaki, Aparna Lakkaraju

Expert opinion on therapeutic targets　27　(11)　1031-1034　2023

DOI： 10.1080/14728222.2023.2277227 　
Endothelial TFEB signaling-mediated autophagic disturbance initiates microglial activation and cognitive dysfunction. International-journal

Yaping Lu, Xiang Chen, Xiuxiu Liu, Yi Shi, Zhaocong Wei, Lili Feng, Quan Jiang, Weifeng Ye, Takuya Sasaki, Kohji Fukunaga, Yong Ji, Feng Han, Ying-Mei Lu

Autophagy　1-18　2023/01/01

DOI： 10.1080/15548627.2022.2162244 　

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Cognitive impairment caused by systemic chemotherapy is a critical question that perplexes the effective implementation of clinical treatment, but related molecular events are poorly understood. Herein, we show that bortezomib exposure leads to microglia activation and cognitive impairment, this occurs along with decreased nuclear translocation of TFEB (transcription factor EB), which is linked to macroautophagy/autophagy disorder, STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL23A (interleukin 23 subunit alpha) expression. Pharmacological enhancement of TFEB nuclear translocation by digoxin restores lysosomal function and reduces STAT3-dependent endothelial IL23A secretion. As a consequence, we found that brain endothelial-specific ablation of Il23a ameliorated both microglia activation and cognitive dysfunction. Thus, the endothelial TFEB-STAT3-IL23A axis in the brain represents a critical cellular event for initiating bortezomib-mediated aberrant microglial activation and synapse engulfment. Our results suggest the reversal of TFEB nuclear translocation may provide a novel therapeutic approach to prevent symptoms of cognitive dysfunction during clinical use of bortezomib.Abbreviations: AAV: adeno-associated virus; BBB: blood-brain barrier; BTZ: bortezomib; DG: digoxin; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; HBMECs: human brain microvascular endothelial cells; HP: hippocampus; IL23A: interleukin 23 subunit alpha; MBVECs: mouse brain vascular endothelial cells; mPFC: medial prefrontal cortex; NORT: novel object recognition test; OLT: object location test; PLX5622: 6-fluoro-N-([5-fluoro-2-methoxypyridin-3-yl]methyl)-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3- yl)methyl; PPP3/calcineurin: protein phosphatase 3; SBEs: STAT3 binding elements; shRNA: small hairpin RNA; SLC17A7/VGLUT1: solute carrier family 17 member 7; SLC32A1/VGAT: solute carrier family 32 member 1; STAT3: signal transducer and activator of transcription 3, TFEB: transcription factor EB; Ub: ubiquitin.
Decreased synapse-associated proteins are associated with the onset of epileptic memory impairment in endothelial CDK5-deficient mice. International-journal

Zheng-Mao Li, Xiu-Xiu Liu, Chen Li, Zhao-Cong Wei, Yi Shi, Heng-Yi Song, Xiang Chen, Yu Zhang, Jia-Wei Li, Rui-Fang Zhu, Ben-Hui Hu, Wei-Feng Ye, Da Huo, Guo-Jun Jiang, Takuya Sasaki, Li Zhang, Feng Han, Ying-Mei Lu

MedComm　3　(3)　e128　2022/09

DOI： 10.1002/mco2.128 　

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Accumulating evidence indicates that epilepsy has a higher risk of inducing memory impairment and dementia. However, the underlying onset mechanism remains unclear. Here, we found that mice with spontaneous epilepsy induced by endothelial CDK5 deficiency exhibited hippocampal-dependent memory impairment at 6 months of age, but not at 2 months of age. Moreover, the persistent epileptic seizures induce aberrant changes in phosphorylation of CaMKII protein in the hippocampus of spontaneous epileptic mice. Using genome-wide RNA sequencing and intergenic interaction analysis of STRING, we found that in addition to epilepsy-related genes, there are changes in synaptic organization pathway node genes, such as Bdnf and Grin1. The synapse-related proteins by Western blot analysis, such as NMDA receptors (NR1 and NR2B), PSD95, and the phosphorylation of synapsin1, are progressively decreased during epileptic seizures in Cdh5-CreERT2;CDK5f/f mice. Notably, we found that valproate (VPA) and phenytoin (PHT) augment mRNA expression and protein levels of synapse-related genes and ameliorate memory impairment in Cdh5-CreERT2;CDK5f/f mice. Our study elucidates a potential mechanism of memory deficits in epilepsy, and pharmacological reversal of synaptic pathology targeting might provide a new therapeutic intervention for epileptic memory deficits.
Humanized substitutions of Vmat1 in mice alter amygdala-dependent behaviors associated with the evolution of anxiety. International-journal

Daiki X Sato, Yukiko U Inoue, Nahoko Kuga, Satoko Hattori, Kensaku Nomoto, Yuki Morimoto, Giovanni Sala, Hideo Hagihara, Takefumi Kikusui, Takuya Sasaki, Yuji Ikegaya, Tsuyoshi Miyakawa, Takayoshi Inoue, Masakado Kawata

iScience　25　(8)　104800-104800　2022/08/19

DOI： 10.1016/j.isci.2022.104800 　

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The human vesicular monoamine transporter 1 (VMAT1) harbors unique substitutions (Asn136Thr/Ile) that affect monoamine uptake into synaptic vesicles. These substitutions are absent in all known mammals, suggesting their contributions to distinct aspects of human behavior modulated by monoaminergic transmissions, such as emotion and cognition. To directly test the impact of these human-specific mutations, we introduced the humanized residues into mouse Vmat1 via CRISPR/Cas9-mediated genome editing and examined changes at the behavioral, neurophysiological, and molecular levels. Behavioral tests revealed reduced anxiety-related traits of Vmat1 Ile mice, consistent with human studies, and electrophysiological recordings showed altered oscillatory activity in the amygdala under anxiogenic conditions. Transcriptome analyses further identified changes in gene expressions in the amygdala involved in neurodevelopment and emotional regulation, which may corroborate the observed phenotypes. This knock-in mouse model hence provides compelling evidence that the mutations affecting monoaminergic signaling and amygdala circuits have contributed to the evolution of human socio-emotional behaviors.
Memory-related neurophysiological mechanisms in the hippocampus underlying stress susceptibility. International-journal

Nahoko Kuga, Takuya Sasaki

Neuroscience research　2022/08/02

DOI： 10.1016/j.neures.2022.07.010 　

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Stress-induced psychiatric symptoms, such as increased anxiety, decreased sociality, and depression, differ considerably across individuals. The cognitive model of depression proposes that biased negative memory is a crucial determinant in the development of mental stress-induced disorders. Accumulating evidence from both clinical and animal studies has demonstrated that such biased memory processing could be triggered by the hippocampus, a region well known to be involved in declarative memories. This review mainly describes how memory-related neurophysiological mechanisms in the hippocampus and their interactions with other related brain regions are involved in the regulation of stress susceptibility and discusses potential interventions to prevent and treat stress-related psychiatric symptoms. Further neurophysiological insights based on memory mechanisms are expected to devise personalized prevention and therapy to confer stress resilience.
BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination. International-journal

Xiu-Xiu Liu, Xing-Hui Chen, Zhi-Wei Zheng, Qin Jiang, Chen Li, Lin Yang, Xiang Chen, Xing-Feng Mao, Hao-Yang Yuan, Li-Li Feng, Quan Jiang, Wei-Xing Shi, Takuya Sasaki, Kohji Fukunaga, Zhong Chen, Feng Han, Ying-Mei Lu

Signal transduction and targeted therapy　7　(1)　170-170　2022/06/01

DOI： 10.1038/s41392-022-00989-x 　

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Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα+ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobePCs → FNCaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
Prefrontal-amygdalar oscillations related to social behavior in mice. International-journal

Nahoko Kuga, Reimi Abe, Kotomi Takano, Yuji Ikegaya, Takuya Sasaki

eLife　11　2022/05/17

DOI： 10.7554/eLife.78428 　

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The medial prefrontal cortex and amygdala are involved in the regulation of social behavior and associated with psychiatric diseases but their detailed neurophysiological mechanisms at a network level remain unclear. We recorded local field potentials (LFPs) from the dorsal medial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) while male mice engaged on social behavior. We found that in wild-type mice, both the dmPFC and BLA increased 4-7 Hz oscillation power and decreased 30-60 Hz power when they needed to attend to another target mouse. In mouse models with reduced social interactions, dmPFC 4-7 Hz power further increased especially when they exhibited social avoidance behavior. In contrast, dmPFC and BLA decreased 4-7 Hz power when wild-type mice socially approached a target mouse. Frequency-specific optogenetic manipulations replicating social approach-related LFP patterns restored social interaction behavior in socially deficient mice. These results demonstrate a neurophysiological substrate of the prefrontal cortex and amygdala related to social behavior and provide a unified pathophysiological understanding of neuronal population dynamics underlying social behavioral deficits.
Weak representation of awake/sleep states by local field potentials in aged mice

Daichi Konno, Yuji Ikegaya, Takuya Sasaki

Scientific Reports　12　(1)　2022/05/11
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41598-022-11888-0 　

eISSN： 2045-2322

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Abstract Senescence affects various aspects of sleep, and it remains unclear how sleep-related neuronal network activity is altered by senescence. Here, we recorded local field potential signals from multiple brain regions covering the forebrain in young (10-week-old) and aged (2-year-old) mice. Interregional LFP correlations across these brain regions could not detect pronounced differences between awake and sleep states in both young and aged mice. Multivariate analyses with machine learning algorithms with uniform manifold approximation and projection and robust continuous clustering demonstrated that LFP correlational patterns at multiple frequency bands, ranging from delta to high gamma bands, in aged mice less represented awake/sleep states than those in young mice. By housing aged mice in an enriched environment, the LFP patterns were changed to more precisely represent awake/sleep states. Our results demonstrate senescence-induced changes in neuronal activity at the network level and provide insight into the prevention of pathological symptoms associated with sleep disturbance in senescence.
Nociceptor-derived Reg3γ prevents endotoxic death by targeting kynurenine pathway in microglia

Erika Sugisawa, Takeshi Kondo, Yutaro Kumagai, Hiroki Kato, Yasunori Takayama, Kayako Isohashi, Eku Shimosegawa, Naoki Takemura, Yoshinori Hayashi, Takuya Sasaki, Mikaël M. Martino, Makoto Tominaga, Kenta Maruyama

Cell Reports　38　(10)　110462-110462　2022/03
Publisher: Elsevier BV
DOI： 10.1016/j.celrep.2022.110462 　

ISSN： 2211-1247
Phasic firing of dopaminergic neurons in the ventral tegmental area triggers peripheral immune responses

Tasuku Kayama, Yuji Ikegaya, Takuya Sasaki

Scientific Reports　12　(1)　2022/01/27
Publisher: Springer Science and Business Media LLC
DOI： 10.1038/s41598-022-05306-8 　

eISSN： 2045-2322

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Abstract Dopaminergic neurons in the ventral tegmental area (VTA) play a crucial role in the processing of reward-related information. Recent studies with pharmacological manipulations of VTA neuronal activity demonstrated a VTA-induced immunoenhancement in peripheral organs. Here, to examine the detailed physiological dynamics, we took an optogenetic approach in which VTA dopaminergic neurons were selectively activated with millisecond precision. Optogenetic phasic, rather than tonic, stimulation of VTA dopaminergic neurons increased serum cytokine levels, such as IL-2, IL-4 and TNF-α. These results provide direct evidence to link dopaminergic neuronal phasic firing to peripheral immunity. Next, we tested whether cytokine induction in male mice was boosted by female encounters, a natural condition that induces increased active VTA neurons and gamma power. Female encounters increased serum IL-2 levels, which were abolished by pharmacological inhibition of VTA neuronal activity. Taken together, our results highlight the importance of the brain reward system in the treatment and management of immune-related disorders.
Concurrent recordings of hippocampal neuronal spikes and prefrontal synaptic inputs from an awake rat. International-journal

Yuya Nishimura, Yuji Ikegaya, Takuya Sasaki

STAR protocols　2　(2)　100572-100572　2021/06/18

DOI： 10.1016/j.xpro.2021.100572 　

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A major challenge in neuroscience is linking synapses to cognition and behavior. Here, we developed an experimental technique to concurrently conduct a whole-cell recording of a prefrontal neuron and a multiunit recording of hippocampal neurons from an awake rat. This protocol includes surgical steps to establish a cranial window and 3D printer-based devices to hold the rat. The data sets allow us to directly compare how subthreshold synaptic transmission is associated with suprathreshold spike patterns of neuronal ensembles. For complete details on the use and execution of this protocol, please refer to Nishimura et al. (2021).
Hippocampal beta oscillations predict mouse object-location associative memory performance

Satoshi Iwasaki, Takuya Sasaki, Yuji Ikegaya

Hippocampus　31　(5)　503-511　2021/05/01
Publisher: John Wiley and Sons Inc
DOI： 10.1002/hipo.23311 　

ISSN： 1098-1063 1050-9631
Prioritized experience replays on a hippocampal predictive map for learning

Hideyoshi Igata, Yuji Ikegaya, Takuya Sasaki

Proceedings of the National Academy of Sciences　118　(1)　e2011266118-e2011266118　2021/01/05
Publisher: Proceedings of the National Academy of Sciences
DOI： 10.1073/pnas.2011266118 　

ISSN： 0027-8424

eISSN： 1091-6490

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Hippocampal cells are central to spatial and predictive representations, and experience replays by place cells are crucial for learning and memory. Nonetheless, how hippocampal replay patterns dynamically change during the learning process remains to be elucidated. Here, we designed a spatial task in which rats learned a new behavioral trajectory for reward. We found that as rats updated their behavioral strategies for a novel salient location, hippocampal cell ensembles increased theta-sequences and sharp wave ripple-associated synchronous spikes that preferentially replayed salient locations and reward-related contexts in reverse order. The directionality and contents of the replays progressively varied with learning, including an optimized path that had never been exploited by the animals, suggesting prioritized replays of significant experiences on a predictive map. Online feedback blockade of sharp wave ripples during a learning process inhibited stabilizing optimized behavior. These results implicate learning-associated experience replays that act to learn and reinforce specific behavioral strategies.
Prefrontal synaptic activation during hippocampal memory reactivation

Yuya Nishimura, Yuji Ikegaya, Takuya Sasaki

Cell Reports　2021
Minute-encoding neurons in hippocampal-striatal circuits Peer-reviewed

Yu Shikano, Yuji Ikegaya, Takuya Sasaki

Current Biology　in press　2021/01
Optogenetic Manipulation of the Vagus Nerve. International-journal

Toya Okonogi, Takuya Sasaki

Advances in experimental medicine and biology　1293　459-470　2021

DOI： 10.1007/978-981-15-8763-4_30 　

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The vagus nerve plays a pivotal role in communication between the brain and peripheral organs involved in the sensory detection and the autonomic control of visceral activity. While the lack of appropriate experimental techniques to manipulate the physiological activity of the vagus nerve has been a long-standing problem, recent advancements in optogenetic tools, including viral vectors and photostimulation devices, during the late 2010s have begun to overcome this technical hurdle. Furthermore, identifying promoters for expressing transgenes in a cell-type-specific subpopulation of vagal neurons enables the selective photoactivation of afferent/efferent vagal neurons and specific visceral organ-innervating vagal neurons. In this chapter, we describe recent optogenetic approaches to study vagus nerve physiology and describe how these approaches have provided novel findings on the roles of vagus nerve signals in the cardiac, respiratory, and gastrointestinal systems. Compared with studies of the central nervous system, there are still few insights into vagus nerve physiology. Further studies with optogenetic tools will be useful for understanding the fundamental characteristics of vagus nerve signals transferred throughout the body.
Urethane anesthesia suppresses hippocampal subthreshold activity and neuronal synchronization. International-journal

Haruya Yagishita, Yuya Nishimura, Asako Noguchi, Yu Shikano, Yuji Ikegaya, Takuya Sasaki

Brain research　1749　147137-147137　2020/12/15

DOI： 10.1016/j.brainres.2020.147137 　

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Urethane, an anesthetic utilized for animal experiments, induces neocortical slow oscillations in which a large number of neurons emit rhythmic synchronized activity. However, it remains unclear how urethane affects neuronal activity in the hippocampus. In this study, we obtained in vivo patch-clamp recordings from dorsal hippocampal CA1 neurons in mice and found a reduction in the fluctuation of subthreshold membrane potentials during urethane anesthesia, implying reduced synaptic activity in the hippocampus. We then performed spike unit recordings from dorsal hippocampal CA1 neuronal ensembles in rats and found prominent reductions in the spike rates of the majority of hippocampal units, especially spatially selective units, during urethane anesthesia, whereas a subset of nonspatial units exhibited increased spike rates. The overall reductions in neuronal spike rates induced by urethane led to prominent decreases in spike synchronization across neuronal units. Consistently, the magnitude of hippocampal sharp wave ripples was also reduced by urethane. The suppression of hippocampal neuronal synchronization by urethane may lead to the disruption of offline memory reactivation mechanisms.
Dual real-time in vivo monitoring system of the brain-gut axis. International-journal Peer-reviewed

Yuya Nishimura, Yota Fukuda, Toya Okonogi, Soichiro Yoshikawa, Hajime Karasuyama, Naomi Osakabe, Yuji Ikegaya, Takuya Sasaki, Takahiro Adachi

Biochemical and biophysical research communications　524　(2)　340-345　2020/04/02

DOI： 10.1016/j.bbrc.2020.01.090 　

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The brain-gut axis which is an interaction between recognition and emotion and the gut sensory system for food and microbiota is important for health. However, there is no real-time monitoring system of the brain and the gut simultaneously so far. We attempted to establish a dual real-time monitoring system for the brain-gut axis by a combination of intravital Ca2+ imaging of the gut and electroencephalogram. Using a conditional Yellow Cameleon 3.60 expression mouse line, we performed intravital imaging of the gut, electrophysiological recordings of the vagus nerve, and electroencephalogram recordings of the various cortical regions simultaneously upon capsaicin stimuli as a positive control. Upon capsaicin administration into the small intestinal lumen, a simultaneous response of Ca2+ signal in the enteric nervous system and cortical local field potentials (LFPs) was successfully observed. Both of them responded immediately upon capsaicin stimuli. Capsaicin triggered a significant increase in the frequency of vagus nerve spikes and a significant decrease in the slow-wave power of cortical LFPs. Furthermore, capsaicin induced delayed and sustained Ca2+ signal in intestinal epithelial cells and then suppressed intestinal motility. The dual real-time monitoring system of the brain and the gut enables to dissect the interaction between the brain and the gut over time with precision.
Acute Effects of Ethanol on Hippocampal Spatial Representation and Offline Reactivation. International-journal

Kosaku Miyake, Saichiro Yagi, Yuki Aoki, Yu Shikano, Yuji Ikegaya, Takuya Sasaki

Frontiers in cellular neuroscience　14　571175-571175　2020

DOI： 10.3389/fncel.2020.571175 　

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Acute alcohol exposure impairs hippocampus-dependent spatial memory. However, there is little evidence for the effects of ethanol on the spike patterns of hippocampal cell populations. Here, we examined how the spatial firing patterns of place cells, neurons that encode specific locations, were altered in rats that were intraperitoneally injected with 1.5 g/kg ethanol. Ethanol administration partly reduced or abolished place-selective spiking of a subset of place cells during running periods in a spatial task, whereas a subset of place fields newly emerged, suggesting a partial reorganization of hippocampal spatial maps by ethanol. On the other hand, ethanol administration did not significantly alter the frequency of hippocampal sharp-wave ripple (SWRs) and synchronous spike patterns during resting periods, suggesting that offline memory consolidation and retrieval mechanisms underpinned by hippocampal neuronal synchronization are not strongly affected by ethanol. These results indicate that acute ethanol intake mainly affects the encoding of external information but has little impact on internal memory processing.
Sniffing behaviour-related changes in cardiac and cortical activity in rats. International-journal

Nahoko Kuga, Ryota Nakayama, Yu Shikano, Yuya Nishimura, Toya Okonogi, Yuji Ikegaya, Takuya Sasaki

The Journal of physiology　597　(21)　5295-5306　2019/11

DOI： 10.1113/JP278500 　

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KEY POINTS: High-frequency (HF) sniffing represents active odour sampling and an increase in the animal's motivation. We examined how HF sniffing affects the physiological activity of the brain-body system. During HF sniffing, heart rates and the ratio of theta to delta critical local field potential power were comparable to those observed during motion periods. Vagus nerve spike rates did not vary depending on HF sniffing. Our results suggest that physiological factors in the central nervous system and the periphery are not simply determined by locomotion but are crucially associated with HF sniffing. ABSTRACT: Sniffing is a fundamental behaviour for odour sampling, and high-frequency (HF) sniffing, generally at a sniff frequency of more than 6 Hz, is considered to represent an animal's increased motivation to explore external environments. Here, we examined how HF sniffing is associated with changes in physiological signals from the central and peripheral organs in rats. During HF sniffing while the rats were stationary, heart rates, the magnitude of dorsal neck muscle contraction, and the ratio of theta to delta local field potential power in the motor cortex were comparable to those observed during motion periods and were significantly higher than those observed during resting respiration periods. No pronounced changes in vagus nerve spike rates were detected in relation to HF sniffing. These results demonstrate that central and peripheral physiological factors are crucially associated with the emergence of HF sniffing, especially during quiescent periods. Behavioural data might be improved to more accurately evaluate an animal's internal psychological state if they are combined with a sniffing pattern as a physiological marker.
Cortical-wide functional correlations are associated with stress-induced cardiac dysfunctions in individual rats. International-journal

Ryota Nakayama, Yuji Ikegaya, Takuya Sasaki

Scientific reports　9　(1)　10581-10581　2019/07/22

DOI： 10.1038/s41598-019-47171-y 　

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Mental stress-induced biological responses considerably differ across animals, which may be explained by intrinsic brain activity patterns. To address this hypothesis, we recorded local field potential signals from six cortical areas, electrocardiograms, and electromyograms from freely moving rats. Based on their stress-induced changes in cardiac signals, individual defeated rats were classified into stress susceptible and resilient groups. Rats with lower correlations in theta power across wide ranges of cortical regions before the stress challenge had higher probability to be stress-susceptible rats as defined based on the irregularity of heartbeat signals. A combination of principal component analysis and the support vector machine algorithm revealed that functional connections across cortical regions could be predictive factors accounting for individual differences in future stress susceptibility. These results suggest that individual differences in cortical activity may be a mechanism that causes abnormal activity of peripheral organs in response to mental stress episodes. This evidence will advance the understanding of the neurophysiological correlates of mind-body associations during mental stress exposure.
Social defeat stress causes selective attenuation of neuronal activity in the ventromedial prefrontal cortex. International-journal

Reimi Abe, Sakura Okada, Ryota Nakayama, Yuji Ikegaya, Takuya Sasaki

Scientific reports　9　(1)　9447-9447　2019/07/01

DOI： 10.1038/s41598-019-45833-5 　

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The ventromedial prefrontal cortex (vmPFC) plays key roles in higher cognitive abilities, including mental representations and the regulation of emotion. Previous studies have reported that vmPFC activity is altered in depressed human patients, highlighting this subregion as a major site of dysfunction in neuropsychiatric diseases. To examine how neuronal activity at spike levels in the vmPFC is altered by social defeat stress, we performed electrophysiological multiunit recordings along the dorsoventral axis of the mPFC of freely moving mice. Chronic social defeat stress-susceptible mice showing an impairment in social interaction exhibited significant reductions in the overall spike frequencies of neurons in the vmPFC, but not in the dorsal mPFC. Analysis of local field potentials revealed that the vmPFC generated spatially constrained 20-40 Hz events lasting hundreds of milliseconds, with an average event frequency of 0.05 Hz; during these events, a subset of neurons were transiently inhibited. The frequency of 20-40 Hz events in the vmPFC was reduced in defeated stress-susceptible animals, and this decrease was reversed by systemic ketamine administration. The novel neurophysiological correlates of stress-induced changes in the vmPFC advance the understanding of the neural basis of stress-induced dysregulation of social behavior.
Vagus nerve spiking activity associated with locomotion and cortical arousal states in a freely moving rat. International-journal Peer-reviewed

Yu Shikano, Yuya Nishimura, Toya Okonogi, Yuji Ikegaya, Takuya Sasaki

The European journal of neuroscience　49　(10)　1298-1312　2019/05

DOI： 10.1111/ejn.14275 　

ISSN： 0953-816X

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The vagus nerve serves as a central pathway for communication between the central and peripheral organs. Despite traditional knowledge of vagus nerve functions, detailed neurophysiological dynamics of the vagus nerve in naïve behavior remain to be understood. In this study, we developed a new method to record spiking patterns from the cervical vagus nerve while simultaneously monitoring central and peripheral organ bioelectrical signals in a freely moving rat. When the rats transiently elevated locomotor activity, the frequency of vagus nerve spikes was correspondingly increased, and this activity was retained for several seconds after the increase in running speed terminated. Spike patterns of the vagus nerve were not robustly associated with which arms the animals entered on an elevated plus maze. During sniffing behavior, vagus nerve spikes were nearly absent. During stopping, the vagus nerve spike patterns differed considerably depending on external contexts and peripheral activity states associated with cortical arousal levels. Stimulation of the vagus nerve altered rat's running speed and cortical arousal states depending on running speed at the instant of stimulation. These observations are a new step for uncovering the physiological dynamics of the vagus nerve modulating the visceral organs such as cardiovascular, respiratory, and gastrointestinal systems.
Synchronous spike patterns in differently mixed cultures of human iPSC-derived glutamatergic and GABAergic neurons. Peer-reviewed

Sasaki T, Suzuki I, Yokoi R, Sato K, Ikegaya Y

Biochemical and biophysical research communications　513　(2)　300-305　2019/05

DOI： 10.1016/j.bbrc.2019.03.161 　

ISSN： 0006-291X
Non-structured spike sequences of hippocampal neuronal ensembles in awake animals. International-journal Peer-reviewed

Takuya Sasaki

Neuroscience research　142　1-6　2019/05
Publisher: Elsevier Ireland Ltd
DOI： 10.1016/j.neures.2018.05.005 　

ISSN： 1872-8111 0168-0102
Collection of biochemical samples with brain-wide electrophysiological recordings from a freely moving rodent Peer-reviewed

Daichi Konno, Ryota Nakayama, Makoto Tsunoda, Takashi Funatsu, Yuji Ikegaya, Takuya Sasaki

JOURNAL OF PHARMACOLOGICAL SCIENCES　139　(4)　346-351　2019/04

DOI： 10.1016/j.jphs.2019.02.006 　

ISSN： 1347-8613

eISSN： 1347-8648
The Integration of Goal-Directed Signals onto Spatial Maps of Hippocampal Place Cells. Peer-reviewed

Aoki Y, Igata H, Ikegaya Y, Sasaki T

Cell reports　27　(5)　1516-1527.e5　2019/04

DOI： 10.1016/j.celrep.2019.04.002 　
Immature electrophysiological properties of human-induced pluripotent stem cell-derived neurons transplanted into the mouse cortex for 7 weeks. Peer-reviewed

Kayama T, Okamoto K, Gao M, Ikegaya Y, Sasaki T

Neuroreport　30　(3)　169-173　2019/02

DOI： 10.1097/WNR.0000000000001178 　

ISSN： 0959-4965
Analysis of mental states based on peripheral organ activity

Ryota Nakayama, Yuji Ikegaya, Takuya Sasaki

Folia Pharmacologica Japonica　153　(4)　161-166　2019
Publisher: Japanese Pharmacological Society
DOI： 10.1254/fpj.153.161 　

ISSN： 1347-8397 0015-5691
A Physiolomics Approach to Reveal Systemic Organ Dynamics in a Rodent.

Takuya Sasaki

Biological & pharmaceutical bulletin　42　(7)　1059-1063　2019

DOI： 10.1248/bpb.b19-00182 　

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The central nervous system controls the activity states of the peripheral organs in response to various environmental changes. However, the physiological interactions across multiple organs remain largely unknown. Recently, we have developed an electrophysiological recording system that simultaneously captures neuronal population activity patterns in the brain, heartbeat signals, muscle contraction signals, respiratory signals, and vagus nerve action potentials in freely moving rodents. This paper summarizes several recent insights obtained from this recording system, including the observations that some but not all brain activity patterns are associated with peripheral organ activity in a behavioral test, and that functions across cortical networks can predict stress-induced changes in cardiac function in rats. The evidence suggests that adding information on peripheral physiological signals to behavioral data assists in a more accurate estimation of animals' mental states. The concept of such a research approach opens a new field of large-scale analysis of systemic physiological signals, termed "physiolomics," which is expected to unveil further physiological issues involving mind-body associations in health and disease.
The Pharmacological Assessment of GABA_A Receptor Activation in Experimental Febrile Seizures in Mice. Peer-reviewed

Kasahara Y, Igata H, Sasaki T, Ikegaya Y, Koyama R

eNeuro　6　(1)　2019/01

DOI： 10.1523/ENEURO.0429-18.2019 　
Sharp wave-associated activity patterns of cortical neurons in the mouse piriform cortex. International-journal Peer-reviewed

Kazuki Katori, Hiroyuki Manabe, Ai Nakashima, Eer Dunfu, Takuya Sasaki, Yuji Ikegaya, Haruki Takeuchi

The European journal of neuroscience　48　(10)　3246-3254　2018/11

DOI： 10.1111/ejn.14099 　

ISSN： 0953-816X

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The olfactory piriform cortex (PC) is thought to participate in olfactory associative memory. Like the hippocampus, which is essential for episodic memory, it belongs to an evolutionally conserved paleocortex and comprises a three-layered cortical structure. During slow-wave sleep, the olfactory PC becomes less responsive to external odor stimuli and instead displays sharp wave (SPW) activity similar to that observed in the hippocampus. Neural activity patterns during hippocampal SPW have been intensively studied in terms of memory consolidation; however, little is known about the activity patterns of olfactory cortical neurons during olfactory cortex sharp waves (OC-SPWs). In this study, we recorded multi-unit neural activities in the anterior PC in urethane-anesthetized mice. We found that the activity patterns of olfactory cortical neurons during OC-SPWs were non-randomly organized. Individual olfactory cortical neurons varied in the timings of their peak firing rates during OC-SPW events. Moreover, specific pairs of olfactory cortical neurons were more frequently activated together than expected by chance. On the basis of these observations, we speculate that coordinated activation of specific subsets of olfactory cortical neurons repeats during OC-SPWs, thereby facilitating synaptic plasticity underlying the consolidation of olfactory associative memories.
Temporal coding and rate remapping: Representation of non-spatial information in the hippocampus. Peer-reviewed

Sanders H, Ji D, Sasaki T, Leutgeb JK, Wilson MA, Lisman JE

Hippocampus　29　(2)　111-127　2018/08

DOI： 10.1002/hipo.23020 　

ISSN： 1050-9631
Time-varying synchronous cell ensembles during consummatory periods correlate with variable numbers of place cell spikes Peer-reviewed

Saichiro Yagi, Hideyoshi Igata, Yu Shikano, Yuki Aoki, Takuya Sasaki, Yuji Ikegaya

Hippocampus　28　(7)　471-483　2018/07/01
Publisher: John Wiley and Sons Inc.
DOI： 10.1002/hipo.22846 　

ISSN： 1098-1063 1050-9631
Simultaneous monitoring of mouse respiratory and cardiac rates through a single precordial electrode. Peer-reviewed

Sato M, Matsumoto N, Noguchi A, Okonogi T, Sasaki T, Ikegaya Y

Journal of pharmacological sciences　137　(2)　177-186　2018/06

DOI： 10.1016/j.jphs.2018.06.009 　

ISSN： 1347-8613
Simultaneous Recordings of Cortical Local Field Potentials, Electrocardiogram, Electromyogram, and Breathing Rhythm from a Freely Moving Rat. International-journal Peer-reviewed

Yu Shikano, Takuya Sasaki, Yuji Ikegaya

Journal of visualized experiments : JoVE　2018　(134)　2018/04/02
Publisher: Journal of Visualized Experiments
DOI： 10.3791/56980 　

ISSN： 1940-087X
Hippocampal ripples down-regulate synapses. International-journal Peer-reviewed

Hiroaki Norimoto, Kenichi Makino, Mengxuan Gao, Yu Shikano, Kazuki Okamoto, Tomoe Ishikawa, Takuya Sasaki, Hiroyuki Hioki, Shigeyoshi Fujisawa, Yuji Ikegaya

Science (New York, N.Y.)　359　(6383)　1524-1527　2018/03/30

DOI： 10.1126/science.aao0702 　

ISSN： 0036-8075

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The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the N-methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples.
Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons Peer-reviewed

Takuya Sasaki, Verónica C. Piatti, Ernie Hwaun, Siavash Ahmadi, John E. Lisman, Stefan Leutgeb, Jill K. Leutgeb

Nature Neuroscience　21　(2)　258-269　2018/02/01
Publisher: Nature Publishing Group
DOI： 10.1038/s41593-017-0061-5 　

ISSN： 1546-1726 1097-6256
Temporally coordinated spiking activity of human induced pluripotent stem cell-derived neurons co-cultured with astrocytes Peer-reviewed

Tasuku Kayama, Ikuro Suzuki, Aoi Odawara, Takuya Sasaki, Yuji Ikegaya

Biochemical and Biophysical Research Communications　495　(1)　1028-1033　2018/01/01
Publisher: Elsevier B.V.
DOI： 10.1016/j.bbrc.2017.11.115 　

ISSN： 1090-2104 0006-291X
Monitoring brain neuronal activity with manipulation of cardiac events in a freely moving rat Peer-reviewed

Yu Shikano, Yuji Ikegaya, Takuya Sasaki

Neuroscience Research　136　56-62　2018
Publisher: Elsevier Ireland Ltd
DOI： 10.1016/j.neures.2018.02.004 　

ISSN： 1872-8111 0168-0102
Characterization of Peripheral Activity States and Cortical Local Field Potentials of Mice in an Elevated Plus Maze Test. International-journal Peer-reviewed

Toya Okonogi, Ryota Nakayama, Takuya Sasaki, Yuji Ikegaya

Frontiers in behavioral neuroscience　12　62-62　2018
Publisher: Frontiers Media S.A.
DOI： 10.3389/fnbeh.2018.00062 　

ISSN： 1662-5153
Spatial Representation of Hippocampal Place Cells in a T-Maze with an Aversive Stimulation Peer-reviewed

Sakura Okada, Hideyoshi Igata, Takuya Sasaki, Yuji Ikegaya

FRONTIERS IN NEURAL CIRCUITS　11　101　2017/12

DOI： 10.3389/fncir.2017.00101 　

ISSN： 1662-5110
Representation of time by hippocampal neurons Peer-reviewed

Yu Shikano, Takuya Sasaki, Yuji Ikegaya

Brain and Nerve　69　(11)　1233-1239　2017/11/01
Publisher: Igaku-Shoin Ltd
ISSN： 1881-6096
Selective attenuation of electrophysiological activity of the dentate gyrus in a social defeat mouse model Peer-reviewed

Yuki Aoki, Yuya Nishimura, Timm Hondrich, Ryota Nakayama, Hideyoshi Igata, Takuya Sasaki, Yuji Ikegaya

JOURNAL OF PHYSIOLOGICAL SCIENCES　67　(4)　507-513　2017/07

DOI： 10.1007/s12576-016-0481-0 　

ISSN： 1880-6546

eISSN： 1880-6562
Simultaneous Recordings of Central and Peripheral Bioelectrical Signals in a Freely Moving Rodent Peer-reviewed

Takuya Sasaki, Yuya Nishimura, Yuji Ikegaya

BIOLOGICAL & PHARMACEUTICAL BULLETIN　40　(5)　711-715　2017/05

DOI： 10.1248/bpb.b17-00070 　

ISSN： 0918-6158
cAMP-Dependent Calcium Oscillations of Astrocytes: An Implication for Pathology Peer-reviewed

Sakiko Ujita, Takuya Sasaki, Akiko Asada, Kenta Funayama, Mengxuan Gao, Katsuhiko Mikoshiba, Norio Matsuki, Yuji Ikegaya

CEREBRAL CORTEX　27　(2)　1602-1614　2017/02

DOI： 10.1093/cercor/bhv310 　

ISSN： 1047-3211

eISSN： 1460-2199
A new device for the simultaneous recording of cerebral, cardiac, and muscular electrical activity in freely moving rodents Peer-reviewed

Sakura Okada, Hideyoshi Igata, Tetsuya Sakaguchi, Takuya Sasaki, Yuji Ikegaya

JOURNAL OF PHARMACOLOGICAL SCIENCES　132　(1)　105-108　2016/09

DOI： 10.1016/j.jphs.2016.06.001 　

ISSN： 1347-8613

eISSN： 1347-8648
Homeostatic changes in neuronal network oscillations in response to continuous hypoperfusion in the mouse forebrain Peer-reviewed

Yuya Nishimura, Reimi Abe, Takuya Sasaki, Yuji Ikegaya

NEUROSCIENCE RESEARCH　109　28-34　2016/08

DOI： 10.1016/j.neures.2016.02.007 　

ISSN： 0168-0102

eISSN： 1872-8111
Subcellular calcium dynamics during juvenile development in mouse hippocampal astrocytes Peer-reviewed

Ryota Nakayama, Takuya Sasaki, Kenji F. Tanaka, Yuji Ikegaya

EUROPEAN JOURNAL OF NEUROSCIENCE　43　(7)　923-932　2016/04

DOI： 10.1111/ejn.13188 　

ISSN： 0953-816X

eISSN： 1460-9568
Early Failures Benefit Subsequent Task Performance Peer-reviewed

Hideyoshi Igata, Takuya Sasaki, Yuji Ikegaya

SCIENTIFIC REPORTS　6　21293　2016/02

DOI： 10.1038/srep21293 　

ISSN： 2045-2322
Memory formation and retrieval of neuronal silencing in the auditory cortex Peer-reviewed

Hiroshi Nomura, Kojiro Hara, Reimi Abe, Natsuko Hitora-Imamura, Ryota Nakayama, Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　112　(31)　9740-9744　2015/08

DOI： 10.1073/pnas.1500869112 　

ISSN： 0027-8424
Spatial and memory circuits in the medial entorhinal cortex Peer-reviewed

Takuya Sasaki, Stefan Leutgeb, Jill K. Leutgeb

CURRENT OPINION IN NEUROBIOLOGY　32　16-23　2015/06

DOI： 10.1016/j.conb.2014.10.008 　

ISSN： 0959-4388

eISSN： 1873-6882
Probing neuronal activity using genetically encoded red fluorescent calcium indicators Peer-reviewed

Takuya Sasaki

Optogenetics: Light-Sensing Proteins and their Applications　149-158　2015/01/01
Publisher: Springer Japan
DOI： 10.1007/978-4-431-55516-2_10 　
Astrocyte calcium signalling orchestrates neuronal synchronization in organotypic hippocampal slices

Takuya Sasaki, Tomoe Ishikawa, Reimi Abe, Ryota Nakayama, Akiko Asada, Norio Matsuki, Yuji Ikegaya

Journal of Physiology　592　(13)　2771-2783　2014/07/01
Publisher: Blackwell Publishing Ltd
DOI： 10.1113/jphysiol.2014.272864 　

ISSN： 1469-7793 0022-3751
Astrocyte calcium signalling orchestrates neuronal synchronization in organotypic hippocampal slices Peer-reviewed

Takuya Sasaki, Tomoe Ishikawa, Reimi Abe, Ryota Nakayama, Akiko Asada, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHYSIOLOGY-LONDON　592　(13)　2771-2783　2014/07

DOI： 10.1113/jphysiol.2014.272864 　

ISSN： 0022-3751

eISSN： 1469-7793
In Vivo Visualization of Subtle, Transient, and Local Activity of Astrocytes Using an Ultrasensitive Ca2+ Indicator Peer-reviewed

Kazunori Kanemaru, Hiroshi Sekiya, Ming Xu, Kaname Satoh, Nami Kitajima, Keitaro Yoshida, Yohei Okubo, Takuya Sasaki, Satoru Moritoh, Hidetoshi Hasuwa, Masaru Mimura, Kazuki Horikawa, Ko Matsui, Takeharu Nagai, Masamitsu Iino, Kenji F. Tanaka

CELL REPORTS　8　(1)　311-318　2014/07

DOI： 10.1016/j.celrep.2014.05.056 　

ISSN： 2211-1247
Interneuron firing precedes sequential activation of neuronal ensembles in hippocampal slices Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

EUROPEAN JOURNAL OF NEUROSCIENCE　39　(12)　2027-2036　2014/06

DOI： 10.1111/ejn.12554 　

ISSN： 0953-816X

eISSN： 1460-9568
Large-scale imaging of subcellular calcium dynamics of cortical neurons with G-CaMP6-actin Peer-reviewed

Chiaki Kobayashi, Masamichi Ohkura, Junichi Nakai, Norio Matsuki, Yuji Ikegaya, Takuya Sasaki

NEUROREPORT　25　(7)　501-506　2014/05

DOI： 10.1097/WNR.0000000000000126 　

ISSN： 0959-4965

eISSN： 1473-558X
Optogenetic Countering of Glial Acidosis Suppresses Glial Glutamate Release and Ischemic Brain Damage Peer-reviewed

Kaoru Beppu, Takuya Sasaki, Kenji F. Tanaka, Akihiro Yamanaka, Yugo Fukazawa, Ryuichi Shigemoto, Ko Matsui

NEURON　81　(2)　314-320　2014/01

DOI： 10.1016/j.neuron.2013.11.011 　

ISSN： 0896-6273

eISSN： 1097-4199
Interpyramid Spike Transmission Stabilizes the Sparseness of Recurrent Network Activity Peer-reviewed

Yuji Ikegaya, Takuya Sasaki, Daisuke Ishikawa, Naoko Honma, Kentaro Tao, Naoya Takahashi, Genki Minamisawa, Sakiko Ujita, Norio Matsuki

CEREBRAL CORTEX　23　(2)　293-304　2013/02

DOI： 10.1093/cercor/bhs006 　

ISSN： 1047-3211
The axon as a unique computational unit in neurons Peer-reviewed

Takuya Sasaki

NEUROSCIENCE RESEARCH　75　(2)　83-88　2013/02

DOI： 10.1016/j.neures.2012.12.004 　

ISSN： 0168-0102
Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation Peer-reviewed

Takuya Sasaki, Kaoru Beppu, Kenji F. Tanaka, Yugo Fukazawa, Ryuichi Shigemoto, Ko Matsui

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　109　(50)　20720-20725　2012/12

DOI： 10.1073/pnas.1213458109 　

ISSN： 0027-8424
Genetically Encoded Green Fluorescent Ca2+ Indicators with Improved Detectability for Neuronal Ca2+ Signals Peer-reviewed

Masamichi Ohkura, Takuya Sasaki, Junko Sadakari, Keiko Gengyo-Ando, Yuko Kagawa-Nagamura, Chiaki Kobayashi, Yuji Ikegaya, Junichi Nakai

PLOS ONE　7　(12)　e51286　2012/12

DOI： 10.1371/journal.pone.0051286 　

ISSN： 1932-6203
Heterogeneity and independency of unitary synaptic outputs from hippocampal CA3 pyramidal cells Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHYSIOLOGY-LONDON　590　(19)　4869-4880　2012/10

DOI： 10.1113/jphysiol.2012.237685 　

ISSN： 0022-3751
Preinspiratory calcium rise in putative pre-Botzinger complex astrocytes Peer-reviewed

Yasumasa Okada, Takuya Sasaki, Yoshitaka Oku, Naoya Takahashi, Megumi Seki, Sakiko Ujita, Kenji F. Tanaka, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHYSIOLOGY-LONDON　590　(19)　4933-4944　2012/10

DOI： 10.1113/jphysiol.2012.231464 　

ISSN： 0022-3751
GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy Peer-reviewed

Ryuta Koyama, Kentaro Tao, Takuya Sasaki, Junya Ichikawa, Daisuke Miyamoto, Rieko Muramatsu, Norio Matsuki, Yuji Ikegaya

NATURE MEDICINE　18　(8)　1271-+　2012/08

DOI： 10.1038/nm.2850 　

ISSN： 1078-8956
Expanding the Repertoire of Optogenetically Targeted Cells with an Enhanced Gene Expression System Peer-reviewed

Kenji F. Tanaka, Ko Matsui, Takuya Sasaki, Hiromi Sano, Shouta Sugio, Kai Fan, Rene Hen, Junichi Nakai, Yuchio Yanagawa, Hidetoshi Hasuwa, Masaru Okabe, Karl Deisseroth, Kazuhiro Ikenaka, Akihiro Yamanaka

CELL REPORTS　2　(2)　397-406　2012/08

DOI： 10.1016/j.celrep.2012.06.011 　

ISSN： 2211-1247
An Improved Genetically Encoded Red Fluorescent Ca2+ Indicator for Detecting Optically Evoked Action Potentials Peer-reviewed

Masamichi Ohkura, Takuya Sasaki, Chiaki Kobayashi, Yuji Ikegaya, Junichi Nakai

PLOS ONE　7　(7)　e39933　2012/07

DOI： 10.1371/journal.pone.0039933 　

ISSN： 1932-6203
Targeted axon-attached recording with fluorescent patch-clamp pipettes in brain slices Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

NATURE PROTOCOLS　7　(6)　1228-1234　2012/06

DOI： 10.1038/nprot.2012.061 　

ISSN： 1754-2189

eISSN： 1750-2799
Effects of Axonal Topology on the Somatic Modulation of Synaptic Outputs Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROSCIENCE　32　(8)　2868-2876　2012/02

DOI： 10.1523/JNEUROSCI.5365-11.2012 　

ISSN： 0270-6474
Locally Synchronized Astrocytes Peer-reviewed

Takuya Sasaki, Nahoko Kuga, Shigehiro Namiki, Norio Matsuki, Yuji Ikegaya

CEREBRAL CORTEX　21　(8)　1889-1900　2011/08

DOI： 10.1093/cercor/bhq256 　

ISSN： 1047-3211
Large-Scale Calcium Waves Traveling through Astrocytic Networks In Vivo Peer-reviewed

Nahoko Kuga, Takuya Sasaki, Yuji Takahara, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROSCIENCE　31　(7)　2607-2614　2011/02

DOI： 10.1523/JNEUROSCI.5319-10.2011 　

ISSN： 0270-6474
Action-Potential Modulation During Axonal Conduction Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

SCIENCE　331　(6017)　599-601　2011/02

DOI： 10.1126/science.1197598 　

ISSN： 0036-8075
Fluorescent pipettes for optically targeted patch-clamp recordings Peer-reviewed

Daisuke Ishikawa, Naoya Takahashi, Takuya Sasaki, Atsushi Usami, Norio Matsuki, Yuji Ikegaya

NEURAL NETWORKS　23　(6)　669-672　2010/08

DOI： 10.1016/j.neunet.2010.02.004 　

ISSN： 0893-6080
Circuit topology for synchronizing neurons in spontaneously active networks Peer-reviewed

Naoya Takahashi, Takuya Sasaki, Wataru Matsumoto, Norio Matsuki, Yuji Ikegaya

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　107　(22)　10244-10249　2010/06

DOI： 10.1073/pnas.0914594107 　

ISSN： 0027-8424
Reverse Optical Trawling for Synaptic Connections In Situ Peer-reviewed

Takuya Sasaki, Genki Minamisawa, Naoya Takahashi, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROPHYSIOLOGY　102　(1)　636-643　2009/07

DOI： 10.1152/jn.00012.2009 　

ISSN： 0022-3077
Regional Difference in Stainability with Calcium-Sensitive Acetoxymethyl-Ester Probes in Mouse Brain Slices Peer-reviewed

Shigehiro Namiki, Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

INTERNATIONAL JOURNAL OF NEUROSCIENCE　119　(2)　214-226　2009

DOI： 10.1080/00207450802330819 　

ISSN： 0020-7454
Fast and accurate detection of action potentials from somatic calcium fluctuations Peer-reviewed

Takuya Sasaki, Naoya Takahashi, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROPHYSIOLOGY　100　(3)　1668-1676　2008/09

DOI： 10.1152/jn.00084.2008 　

ISSN： 0022-3077
Oseltamivir enhances hippocampal network synchronization Peer-reviewed

Atsushi Usami, Takuya Sasaki, Nobuhiro Satoh, Takahiro Akiba, Satoshi Yokoshima, Tohru Fukuyama, Kenzo Yamatsugu, Motomu Kanai, Masakatsu Shibasaki, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHARMACOLOGICAL SCIENCES　106　(4)　659-662　2008/04

DOI： 10.1254/jphs.SC0070467 　

ISSN： 1347-8613

eISSN： 1347-8648
Long-range axonal calcium sweep induces axon retraction Peer-reviewed

Ryuji X. Yamada, Takuya Sasaki, Junya Ichikawa, Ryuta Koyama, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROSCIENCE　28　(18)　4613-4618　2008/04

DOI： 10.1523/JNEUROSCI.0019-08.2008 　

ISSN： 0270-6474
Pharmacologic action of oseltamivir on the nervous system. Peer-reviewed

Kenichi Ishii, Hiroshi Hamamoto, Takuya Sasaki, Yuji Ikegaya, Kenzo Yamatsugu, Motomu Kanai, Masakatsu Shibasaki, Kazuhisa Sekimizu

Drug Discoveries & Therapeutics　2　(1)　24-34　2008/02

ISSN： 1881-7831

eISSN： 1881-784X
Active Hippocampal Networks Undergo Spontaneous Synaptic Modification Peer-reviewed

Masako Tsukamoto-Yasui, Takuya Sasaki, Wataru Matsumoto, Ayako Hasegawa, Takeshi Toyoda, Atsushi Usami, Yuichi Kubota, Taku Ochiai, Tomokatsu Hori, Norio Matsuki, Yuji Ikegaya

PLOS ONE　2　(11)　e1250　2007/11

DOI： 10.1371/journal.pone.0001250 　

ISSN： 1932-6203
Watching neuronal circuit dynamics through functional multineuron calcium imaging (fMCI) Peer-reviewed

Naoya Takahashi, Takuya Sasaki, Atsushi Usami, Norio Matsuki, Yuji Ikegaya

NEUROSCIENCE RESEARCH　58　(3)　219-225　2007/07

DOI： 10.1016/j.neures.2007.03.001 　

ISSN： 0168-0102
A low-cost method for brain slice cultures Peer-reviewed

Ryuta Koyama, Rieko Muramatsu, Takuya Sasaki, Ric Kimura, Chihiro Ueyama, Makoto Tamura, Naohiro Tamura, Junya Ichikawa, Naoya Takahashi, Atsush Usami, Maki K. Yamada, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHARMACOLOGICAL SCIENCES　104　(2)　191-194　2007/06

DOI： 10.1254/jphs.SC0070119 　

ISSN： 1347-8613
Metastability of active CA3 networks Peer-reviewed

Takuya Sasaki, Norio Matsuki, Yuji Ikegaya

JOURNAL OF NEUROSCIENCE　27　(3)　517-528　2007/01

DOI： 10.1523/JNEUROSCI.4514-06.2007 　

ISSN： 0270-6474
Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model Peer-reviewed

Takuya Sasaki, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Koichi Ishiguro, Kohji Fukunaga

BRAIN RESEARCH　1108　(1)　98-106　2006/09

DOI： 10.1016/j.brainres.2006.06.009 　

ISSN： 0006-8993
Integrative spike dynamics of rat CA1 neurons: a multineuronal imaging study Peer-reviewed

Takuya Sasaki, Rie Kimura, Masako Tsukamoto, Norio Matsuki, Yuji Ikegaya

JOURNAL OF PHYSIOLOGY-LONDON　574　(1)　195-208　2006/07

DOI： 10.1113/jphysiol.2006.108480 　

ISSN： 0022-3751

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Misc. 7

内受容感覚を伝達する経路と脳情報処理

佐々木拓哉

実験医学　2024/05
内臓信号が神経回路演算に及ぼす影響の考察

佐々木拓哉

神経回路学会誌　2023/10
学習時の個性

久我奈穂子, 佐々木拓哉

生体の科学　2023/10
求心性迷走神経を介した脳末梢連環の意義

佐々木拓哉

ファルマシア, 最前線　2023/09
最新脳科学と応用(5) ~学習・記憶・意思決定~

佐々木拓哉

Yano E plus　2023/08
齧歯目における分オーダーの時間認知

鹿野悠, 佐々木拓哉, 池谷裕二

CLINICAL NEUROSCIENCE,　2023/02
脳虚血性細胞死における脂肪酸結合タンパク質(FABP)の役割

郭青云, 川畑伊知郎, 佐々木拓哉, 福永浩司

脳循環代謝(Web)　33　(1)　2021

ISSN： 2188-7519

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Research Projects 21

ブレイン-ボディテックを実現する末梢計測デバイスと信号解析技術の開発

佐々木拓哉

Offer Organization: 科学技術振興機構(JST)

System: 経済安全保障重要技術育成プログラム(K Program)

2025/08 - 2030/07
多様なこころを脳と身体性機能に基づいてつなぐ「自在ホンヤク機」の開発

筒井健一郎、佐々木拓哉

Offer Organization: 科学技術振興機構(JST)

System: ムーンショット型研究開発事業

Institution: 東北大学

2022 - 2028/03

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さまざまな場面でコミュニケーションを支援する「自在ホンヤク機」を開発し、多様な人々を包摂する社会をもたらします。神経科学・分子生命科学と、VR/AR・ロボット工学の分野の研究者が協力して、こころの状態を定量化する技術を研究するとともに、知覚・認知や運動機能への介入法を研究します。これらの成果を融合して開発する「自在ホンヤク機」は、個人、個人間、あるいは、数人から数十人程度の小グループを対象としてコミュニケーション支援を行います。
Analysis of gene expression profiles in neurons encoding emotion

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Research (Exploratory)

Institution: Tohoku University

2024/06/28 - 2026/03/31
Neuronal circuit dynamics for memory state transition

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Transformative Research Areas (A)

Institution: Tohoku University

2021/09/10 - 2026/03/31
Cell type census of adaptive neuronal circuits: biological mechanisms of structural and functional organization

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Transformative Research Areas (A)

Institution: Tokyo Medical and Dental University

2021/09/10 - 2026/03/31
Elucidation and application of neural mechanisms that induce hibernation-like hypometabolic state

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (S)

Institution: University of Tsukuba

2021/07/05 - 2026/03/31
多様な迷走神経情報から創発する内受容感覚の脳統合

佐々木拓哉

Offer Organization: 科学技術振興機構

System: 戦略的な研究開発の推進戦略的創造研究推進事業 CREST

Institution: 東北大学

2021 - 2026/03

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脳は、内臓など身体内部の生理状態の感覚(内受容感覚)を統合します。求心性迷走神経は、各臓器からの局所情報を脳へ伝達する重要な末梢神経です。本研究では、マウス・ヒトを対象として、複数臓器の生理活動が、どのように求心性迷走神経の内受容感覚情報に局所変換され、どのように迷走神経-脳神経回路によって伝達、統合されて、脳機能の創発に至るのかを体系的に理解できるような統合的理論の導出を目指します。
Analysis of deep brain regions in stress response

Sasaki Takuya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Challenging Research (Exploratory)

Institution: Tohoku University

2021/07/09 - 2023/03/31

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In this study, we investigated the regulatory mechanisms of stress susceptibility in male mice, spanning from gene expression to neuronal population dynamics within the ventral hippocampus (vHC). Knockdown of the Calb1 gene in the vHC resulted in increased stress resilience and a lack of the typical post-stress increase in ventral hippocampal sharp wave ripple (SWR) activity. Following stress exposure, SWRs in the vHC facilitated synchronous reactivation of neuronal ensembles involved in stress memory encoding and enhanced information transfer to the amygdala. Importantly, suppression of post-stress vHC SWRs through real-time feedback stimulation or physical activity prevented deficits in social behavior. These findings collectively demonstrate that the internal reactivation of negative stress-related memories, facilitated by ventral hippocampal SWRs, plays a critical role in determining stress susceptibility at a neurophysiological level.
Realtime manipulation of hippocampal spike sequences in rats

Sasaki Takuya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research (B)

Institution: Tohoku University

2020/04/01 - 2023/03/31

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This study investigated how awake synchronous events during a new experience contribute to the formation of reactivation patterns in the hippocampal neuronal circuits. The researchers found that the disruption of awake sharp-wave ripples prevented the experience-induced changes in neuronal contributions during post-experience synchronous events. Additionally, the hippocampal place cells that participated more in reward-related synchronous events exhibited stronger reactivation during post-experience synchronous events. The combined effects of awake synchronous neuronal patterns and place-selective firing patterns determined the ensembles of cells that showed significant increases or decreases in their correlated spikes. Overall, awake synchronous events play a crucial role in identifying the hippocampal neuronal ensembles that will be involved in synchronous reactivation during subsequent offline states, thus promoting memory consolidation.
病気につながる血管周囲の微小炎症を標的とする量子技術、ニューロモデュレーション医療による未病時治療法の開発

村上正晃

Offer Organization: 内閣府(CAO)

System: ムーンショット型研究開発制度

2020/04 - 2023/03
Roles of memory consolidation in psychiatric disease

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: Tohoku University

2021/04/01 - 2022/03/31
長時空間において進行する心身機能老化の超マルチスケール解析 Competitive

佐々木拓哉

Offer Organization: AMED

System: 革新的先端研究開発支援事業 PRIME

2018/10 - 2021/03
Individual differences in the relationship between memory and stress responses Competitive

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: The University of Tokyo

2019 - 2020
末梢光変調による精神機能調節の解明 Competitive

佐々木拓哉

Offer Organization: 科学技術振興機構

System: 戦略的創造研究推進事業さきがけ

Institution: 東京大学

2017 - 2020

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生物の精神機能の中枢は脳ですが、生命システムには、末梢活動が精神機能を制御する潜在的な仕組みも多数存在します。しかし、その生理学的な意義はほとんど未解明です。この課題に挑むために、本研究では、末梢部位の活動を正確に制御する光操作法を開発します。新しい末梢光操作法と全身計測法を融合することで、末梢中枢連関の問題に挑み、精神機能調節における末梢活動の位置付けや因果関係を検証します。
目的志向型の適応行動における海馬回路表象の解析 Competitive

佐々木拓哉

Offer Organization: 文部科学省

System: 科学研究費補助金(新学術領域研究(研究領域提案型))

2017 - 2018
Analysis of neuronal activity in the brain underlying individuality Competitive

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Institution: The University of Tokyo

2017 - 2018
大規模計測と光操作の融合による海馬ニューロンの神経相関と投射構造の解明 Competitive

佐々木拓哉

Offer Organization: 文部科学省

System: 科学研究費補助金（挑戦的萌芽研究）

2016 - 2017
Neuronal network dynamics in reponse to mental stress Competitive

Sasaki Takuya

Offer Organization: Japan Society for the Promotion of Science

System: Grants-in-Aid for Scientific Research

Category: Grant-in-Aid for Young Scientists (A)

Institution: The University of Tokyo

2015 - 2017

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Chronic social defeat is a widely used animal model with high etiological and discriminative validity that evokes profound behavioral phenotypes. In this study, we examined how social defeat stress alters physiological activity in freely moving rats. Our recording system integrates local field potential signals from the cortex, heartbeat signals, and skeletal muscle signals into an electrical interface board that is mounted on an animal’s head. After receiving a physical attack from the resident rat, the heart rate of the intruder animals was transiently increased and then decreased when they started to show freezing behavior. During the freezing period, brain local field potential power was prominently reduced. The evidence will advance the understanding of the neurophysiological correlate of mind-body associations during mental stress exposure.
行動適応における海馬場所細胞の再生パターンの解析 Competitive

佐々木拓哉

Offer Organization: 文部科学省

System: 科学研究費補助金(新学術領域研究(研究領域提案型))

Category: 新学術領域研究(研究領域提案型)

Institution: 東京大学

2015 - 2016

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記憶・学習に重要な海馬には、動物がある特定の場所を通過したときに活動する場所細胞が存在する。場所細胞の発見で動物の行動と神経活動とを結びつけて考えられるようになり、海馬では過去の行動の記憶が再生されていることが知られている。さらに近年では、海馬の神経活動が将来の行動設計にも関わっていることが示唆されているが、その性質はまだ詳しく知られていない。そこで本研究では、経路設計が必要な空間ナビゲーション課題を構築して、課題遂行中のラットの海馬の神経活動を記録し、解析を行った。本研究では、状況依存的にラットが目的地までの２つのうち一方の経路へと選択を変える必要がある行動課題を構築した。課題開始の合図の音と、光による手がかり刺激（cue）が提示され、ラットは与えられたcueに応じて、スタートからゴールまで特定の経路を走ると報酬が得られる。これまでの迷路課題とは異なり、道なりに進むような課題ではないため、ラットはこれから通るべき経路を想起する必要がある。この行動課題を遂行しているラットの海馬CA1野から、マルチユニット記録法により、神経細胞の発火を記録した。海馬神経細胞の経路選択性とcue選択性の相関を調べたが、相関関係はあるとはいえなかった。すなわち、経路選択的な細胞が、そのcue提示時に選択的に活動するわけではないということである。よって、cueにより、海馬神経ネットワークの状態が変化し、同じ神経回路が別の働きをするようなメカニズムが存在することが示唆された。
成体動物を用いた多ニューロン画像法で海馬病態システムに迫る

佐々木拓哉

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 特別研究員奨励費

2010 - 2012

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蛍光電極を用いた軸索パッチクランプ法を詳細に記述した論文を執筆し、本研究成果はNature Protocols誌およびNeuroscience Research誌に掲載された。ニューロンでは、細胞体で脱分極が起こった際、活動電位の幅が増大するが、この増幅がどのように軸索を伝播していくかを解析した。海馬CA3野の錐体細胞より軸索パッチクランプ記録を行い、軸索の長さと分枝数に依存して、伝播する活動電位の幅が減衰して正常に戻ることを見出した。本研究成果はJournal o fNeuroscience誌およびJournal o fPhysiology誌に掲載された。また、光感受性チャネルタンパク質を発現する遺伝子改変動物の導入に取り組んだ。本研究では、チャネルロドプシン2をアストロサイトに選択的に発現した遺伝子改変マウスを用いて、これらのアストロサイトを光刺激すると、神経活動が誘発されたことを明らかにした。また、スライス標本を用いた解析から、グリア細胞の光刺激により、グルタミン酸が放出され、小脳プルキンエ細胞のAMPA受容体を活性化させることが明らかになった。また、平行線維-プルキンエ細胞間のシナプスにおいては、グリア細胞の光刺激により、長期的な可塑性が観察された。さらに個体行動の解析から、グリア細胞の光刺激により誘発された神経活動は、小脳依存性の運動学習を制御するのに十分であることが示された。以上の結果から、グリア細胞が神経活動や個体行動を制御し、脳内の情報処理において重要な役割を担っていることが示唆された。さらに、平成22年度に所属した埼玉大学との共同研究により、高感度の蛍光カルシウムセンサータンパク質の開発に成功し、PLoS ONE誌に2報の論文を掲載した。
多ニューロン画像法を用いて海馬回路の演算様式を解明する

佐々木拓哉

Offer Organization: 日本学術振興会

System: 科学研究費助成事業

Category: 特別研究員奨励費

Institution: 東京大学

2007 - 2009

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1.昨年度に引き続き、多ニューロンカルシウム画像法の改良に取り組んだ。今期は、海馬のみならず、多数の脳領域において画像法の効率を検討した(Namiki et al.2009)。大脳皮質や嗅球では、カルシウム蛍光指示薬の導入効率が高いことを見出した。 2.さらに、画像法を応用し、神経回路内の多数のシナプス結合を検出するための新規光学実験技法を開発した(ROTing法)。これにより、脳スライス標本内の数百個のシナプス結合の同定が可能となり、神経回路の作動原理を追究する上で、有用な技法になると期待される(Sasaki et al.2009)。 3.蛍光イメージング下でパッチクランプ記録を効率的に実現するため、蛍光パッチクランプ電極の開発を試みた(Ishikawa et al.2010)。この電極の開発に成功し、神経細胞の樹状突起や軸索など、細かい構造体からのパッチクランプ記録が容易に実現可能となった。この発明は、現在特許申請中である。 4.軸索周辺に存在するアストロサイトが、活動電位の軸索伝播、およびその下流のシナプス伝達をどのように調節するか検討している(現在進行中)。これまでに、軸索近傍のアストロサイトの活動が、軸索を伝播する活動電位の幅を増大させ、その下流で生じるシナプス伝達を増強させることが明らかになった。この結果は、アストロサイトが軸索を伝播する活動電位の幅を調節することで、従来考えられていたより広範な影響を及ぼすことが示唆された。これは、グリア-ニューロン相互作用を介した神経回路の調節メカニズムに関する新たな知見であると考えられる。

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