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Last Updated :2024/07/25

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Master

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Pharmacology

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Pharmacology

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Profile and Settings

Profile and Settings

  • Name (Japanese)

    Sato

  • Name (Kana)

    Masaaki

  • Name

    201101059686497780

Alternate Names

Achievement

Research Interests

  • イメージング   二光子レーザー顕微鏡   社会行動   自閉症   発達障害   バーチャルリアリティー   神経回路   記憶・学習   可塑性   

Research Areas

  • Life sciences / Basic brain sciences
  • Life sciences / Neuroscience - general
  • Life sciences / Pharmacology

Research Experience

  • 2021 - Today Hokkaido University Research and Education Center for Brain Science
  • 2020 - Today Hokkaido University Graduate School of Medicine
  • 2016 - 2020 Saitama University Graduate School of Science and Engineering
  • 2014 - 2016 Japan Science and Technology Agency PRESTO researcher
  • 2012 - 2014 Japan Science and Technology Agency
  • 2009 - 2014 RIKEN

Published Papers

  • Kaoru Inokuchi, Khaled Ghandour, Tatsuya Haga, Noriaki Ohkawa, Chi Chung Alan FUNG, Masanori Nomoto, Mostafa R. Fayed, Hirotaka Asai, Masaaki Sato, Tomoki Fukai
    bioRxiv 2024/07/01 
    Every day, we experience new daily episodes and store new memories. Although memories are stored in corresponding engram cells, how different sets of engram cells are selected for current and next episodes, and how they create their memories, remains unclear. We report that in mice, hippocampal CA1 neurons show an organized synchronous activity in prelearning home cage sleep that correlates with the learning ensembles only in engram cells, termed preconfigured ensembles. Moreover, after learning, a subset of nonengram cells develops population activity, which is constructed during postlearning offline periods through synaptic depression and scaling, and then emerges to represent engram cells for new learning. Together, our findings indicate that during offline periods there are two parallel processes occurring: conserving of past memories through reactivation, and preparation for upcoming ones through offline synaptic plasticity mechanisms.
  • Masaaki Sato, Haruki Kuronuma, Kosei Matsumoto
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 159 (4) 229 - 234 2024/06 
    The development of genetically-encoded fluorescent probes for the detection of intracellular calcium ions and various neurotransmitters has progressed significantly in recent years, and there is a growing need for techniques that rapidly and efficiently image these signals in the living brain for pharmacological studies of the central nervous system. In this article, we discuss one-photon fluorescence microscopy techniques used for brain activity imaging, particularly wide-field imaging and head-mounted miniaturized microscopy, and introduce their basic principles, recent advances, and applications in pharmacological research. Wide-field calcium imaging is suitable for mesoscopic observation of cortical activity during behavioral tasks in head-fixed awake mice, while head-mounted miniaturized microscopes can be attached to the animal's head to image brain activity associated with naturalistic behaviors such as social behavior and sleep. One-photon microscopy allows for the development of a simple and cost-effective imaging system using an affordable excitation light source such as a light-emitting diode. Its excitation light illuminates the entire field of view simultaneously, making it easy to perform high-speed imaging using a high-sensitivity camera. In contrast, the short wavelength of the excitation light limits the field of observation to areas on or near the brain surface due to its strong light scattering. Moreover, the out-of-focus fluorescence makes it difficult to obtain images with a high signal-to-noise ratio and spatial resolution. The use of one-photon microscopy in brain activity imaging has been limited compared to two-photon microscopy, but its advantages have recently been revisited. Therefore, this technique is expected to become a useful method for pharmacologists to visualize the activity of the living brain.
  • Masaaki Sato, Eric Overton, Shuhei Fujima, Toru Takumi
    bioRxiv 2024/04
  • Multiphoton imaging of hippocampal neural circuits: techniques and biological insights into region-, cell-type-, and pathway-specific functions (invited review)
    Kotaro Mizuta, Masaaki Sato*
    Neurophotonics 11 (3) 033406  2024 [Refereed][Invited]
  • Masaaki Sato, Takuya Terai
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 159 (1) 12 - 12 2024
  • Masaaki Sato, Nobuhiro Nakai, Shuhei Fujima, Katrina Y Choe, Toru Takumi
    Molecular psychiatry 2023/08/24 [Refereed][Invited]
     
    Social behaviors, how individuals act cooperatively and competitively with conspecifics, are widely seen across species. Rodents display various social behaviors, and many different behavioral paradigms have been used for investigating their neural circuit bases. Social behavior is highly vulnerable to brain network dysfunction caused by neurological and neuropsychiatric conditions such as autism spectrum disorders (ASDs). Studying mouse models of ASD provides a promising avenue toward elucidating mechanisms of abnormal social behavior and potential therapeutic targets for treatment. In this review, we outline recent progress and key findings on neural circuit mechanisms underlying social behavior, with particular emphasis on rodent studies that monitor and manipulate the activity of specific circuits using modern systems neuroscience approaches. Social behavior is mediated by a distributed brain-wide network among major cortical (e.g., medial prefrontal cortex (mPFC), anterior cingulate cortex, and insular cortex (IC)) and subcortical (e.g., nucleus accumbens, basolateral amygdala (BLA), and ventral tegmental area) structures, influenced by multiple neuromodulatory systems (e.g., oxytocin, dopamine, and serotonin). We particularly draw special attention to IC as a unique cortical area that mediates multisensory integration, encoding of ongoing social interaction, social decision-making, emotion, and empathy. Additionally, a synthesis of studies investigating ASD mouse models demonstrates that dysfunctions in mPFC-BLA circuitry and neuromodulation are prominent. Pharmacological rescues by local or systemic (e.g., oral) administration of various drugs have provided valuable clues for developing new therapeutic agents for ASD. Future efforts and technological advances will push forward the next frontiers in this field, such as the elucidation of brain-wide network activity and inter-brain neural dynamics during real and virtual social interactions, and the establishment of circuit-based therapy for disorders affecting social functions.
  • Nobuhiro Nakai, Masaaki Sato*, Okito Yamashita, Yukiko Sekine, Xiaochen Fu, Junichi Nakai, Andrew Zalesky, Toru Takumi*
    Cell reports 112258 - 112258 2023/03/28 [Refereed]
     
    Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain to be elucidated. To investigate FC dynamics in locomoting mice, we develop mesoscopic Ca2+ imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. By using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in individuals with autism. Our VR-based real-time imaging system provides crucial information to understand FC dynamics linked to behavioral abnormality of neuropsychiatric disorders.
  • Masaaki Sato, Hiroaki Norimoto
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 158 (2) 138 - 138 2023
  • Masaaki Sato, Miki Kimura, Ai Ueda, Yuya Miyamoto
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 158 (2) 139 - 143 2023 
    The symptoms and behavioral abnormalities of brain diseases are thought to be caused by the dysfunction of neural circuits formed by numerous neurons. Virtual reality (VR) is used for behavioral tasks under head fixation and has the advantage of precise control of experimental conditions. In this review, we first overview the application of VR in rodent neuroscience, introduce our research on two-photon calcium imaging of the hippocampus of autism spectrum disorder (ASD) model mice navigating a VR environment, and then discuss how hippocampal dysfunction can relate to ASD phenotypes. By combining a VR system with two-photon microscopy, we clarified the formation of hippocampal CA1 place cell maps in mice undergoing spatial learning in VR. As mice learned, the number of place cells increased, and the density of cells that responded to places with behaviorally relevant features such as rewards and landmarks increased more than cells active elsewhere. Furthermore, many stable place cells responded at landmark and reward locations. Shank2-deficient ASD model mice spent more time running and received more rewards. In their hippocampal maps, the proportion of cells active at landmarks did not increase, whereas the proportion of cells active at rewards excessively increased. Individuals with ASD are known to show unique tendencies in their perception and cognition of the world around them, but the detailed brain mechanisms remain unclear. It is thus possible that some ASD cases involve cognitive mapping abnormalities, such as the distortion of hippocampal information representation that our study revealed.
  • Hitomi Sasamori, Toshiaki Asakura, Chiaki Sugiura, Youcef Bouchekioua, Naoya Nishitani, Masaaki Sato, Takayuki Yoshida, Miwako Yamasaki, Akira Terao, Masahiko Watanabe, Yu Ohmura, Mitsuhiro Yoshioka
    Scientific Reports 12 (1) 6014  2022/04/10 [Refereed][Not invited]
     
    Abstract Major psychiatric disorders such as attention-deficit/hyperactivity disorder and schizophrenia are often accompanied by elevated impulsivity. However, anti-impulsive drug treatments are still limited. To explore a novel molecular target, we examined the role of dopamine D5 receptors in impulse control using mice that completely lack D5 receptors (D5KO mice). We also measured spontaneous activity and learning/memory ability because these deficits could confound the assessment of impulsivity. We found small but significant effects of D5 receptor knockout on home cage activity only at specific times of the day. In addition, an analysis using the q-learning model revealed that D5KO mice displayed lower behavioral adjustment after impulsive actions. However, our results also showed that baseline impulsive actions and the effects of an anti-impulsive drug in D5KO mice were comparable to those in wild-type littermates. Moreover, unlike previous studies that used other D5 receptor-deficient mouse lines, we did not observe reductions in locomotor activity, working memory deficits, or severe learning deficits in our line of D5KO mice. These findings demonstrate that D5 receptors are dispensable for impulse control. Our results also indicate that time series analysis and detailed analysis of the learning process are necessary to clarify the behavioral functions of D5 receptors.
  • Takashi Takekawa, Masanori Nomoto, Hirotaka Asai, Noriaki Ohkawa, Reiko Okubo-Suzuki, Khaled Ghandour, Masaaki Sato, Masamichi Ohkura, Junichi Nakai, Shin-ichi Muramatsu, Yasunori Hayashi, Kaoru Inokuchi, Tomoki Fukai
    2022/04/07 
    Currently, calcium imaging allows for the long-term recording of large-scale neuronal activity in diverse states. However, it remains difficult to extract neuronal dynamics from recorded imaging data. In this study, we propose an improved CNMF-based algorithm and an effective method for extracting cell shapes with fewer false positives and false negatives caused by image processing. We also showed that the values obtained during image processing can be combined and used for false positive determination of cells. For the CNMF algorithm, we combined cell-by-cell regularization and baseline shrinkage estimation, which greatly improved its stability and robustness. We applied these methods to artificial and real data and confirmed their effectiveness. Our method is simpler and faster, detects more cells with lower firing rates and signal-to-noise ratios, and enhance the quality of the extracted cell signals. These advances can improve the standard of downstream analysis and contribute to progress in neuroscience.
  • Youcef Bouchekioua, Mao Nebuka, Hitomi Sasamori, Naoya Nishitani, Chiaki Sugiura, Masaaki Sato, Mitsuhiro Yoshioka, Yu Ohmura
    Translational Psychiatry 12 (1) 58  2022/02/11 [Refereed][Not invited]
     
    Previous findings have proposed that drugs targeting 5-HT2C receptors could be promising candidates in the treatment of trauma- and stress-related disorders. However, the reduction of conditioned freezing observed in 5-HT2C receptor knock-out (KO) mice in previous studies could alternatively be accounted for by increased locomotor activity. To neutralize the confound of individual differences in locomotor activity, we measured a ratio of fear responses during versus before the presentation of a conditioned stimulus previously paired with a footshock (as a fear measure) by utilizing a conditioned licking suppression paradigm. We first confirmed that 5-HT2C receptor gene KO attenuated fear responses to distinct types of single conditioned stimuli (context or tone) independently of locomotor activity. We then assessed the effects of 5-HT2C receptor gene KO on compound fear responses by examining mice that were jointly conditioned to a context and a tone and later re-exposed separately to each. We found that separate re-exposure to individual components of a complex fear memory (i.e., context and tone) failed to elicit contextual fear extinction in both 5-HT2C receptor gene KO and wild-type mice, and also abolished differences between genotypes in tone-cued fear extinction. This study delineates a previously overlooked role of 5-HT2C receptors in conditioned fear responses, and invites caution in the future assessment of molecular targets and candidate therapies for the treatment of PTSD.
  • Risa Takamura, Kotaro Mizuta, Yukiko Sekine, Tanvir Islam, Takashi Saito, Masaaki Sato, Masamichi Ohkura, Junichi Nakai, Toshio Ohshima, Takaomi C. Saido, Yasunori Hayashi
    The Journal of Neuroscience 41 (24) 5315 - 5329 0270-6474 2021/06/16 [Refereed]
  • Elena Cid, Angel Marquez-Galera, Manuel Valero, Beatriz Gal, Daniel C. Medeiros, Carmen M. Navarron, Luis Ballesteros-Esteban, Rita Reig-Viader, Aixa V. Morales, Ivan Fernandez-Lamo, Daniel Gomez-Dominguez, Masaaki Sato, Yasunori Hayashi, Àlex Bayés, Angel Barco, Jose P. Lopez-Atalaya, Liset M. de la Prida
    Cell Reports 35 (10) 109229  2211-1247 2021/06 [Refereed]
     
    Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.
  • Kotaro Mizuta, Junichi Nakai, Yasunori Hayashi, Masaaki Sato*
    Hippocampus 31 (3) 235 - 243 2021/03 [Refereed][Not invited]
     
    In the hippocampus, spatial and nonspatial information are jointly represented as a neural map in which locations associated with salient features are over-represented by increased densities of relevant place cells. Although we recently demonstrated that experience-dependent establishment of these disproportionate maps is governed by selective stabilization of salient place cells following their conversion from non-place cells, the underlying mechanism for pre-established map reorganization remained to be understood. To this end, we investigated the changes in CA1 functional cellular maps imaged using two-photon calcium imaging in mice performing a reward-rearrangement task in virtual reality. Mice were pre-trained on a virtual linear track with a visual landmark and a reward in two distinct locations. Then, they were re-trained on the same track with the exception that the location of reward was shifted to match the landmark location. We found that, in contrast to de novo map formation, robust map reorganization occurred through parallel coordination of new place field formation, lateral shifting of existing place fields, and selective stabilization of place fields encoding salient locations. Our findings demonstrate that intricate interplay between multiple forms of cellular dynamics enables rapid updating of information stored in hippocampal maps.
  • Isamu Miura#, Masaaki Sato#, Eric T N Overton, Nobuo Kunori, Junichi Nakai, Takakazu Kawamata, Nobuhiro Nakai, Toru Takumi (# co-first authors)
    PLOS biology 18 (9) e3000584  2020/09/21 [Refereed][Not invited]
     
    The insular cortex (IC) participates in diverse complex brain functions, including social function, yet their cellular bases remain to be fully understood. Using microendoscopic calcium imaging of the agranular insular cortex (AI) in mice interacting with freely moving and restrained social targets, we identified 2 subsets of AI neurons-a larger fraction of "Social-ON" cells and a smaller fraction of "Social-OFF" cells-that change their activity in opposite directions during social exploration. Social-ON cells included those that represented social investigation independent of location and consisted of multiple subsets, each of which was preferentially active during exploration under a particular behavioral state or with a particular target of physical contact. These results uncover a previously unknown function of AI neurons that may act to monitor the ongoing status of social exploration while an animal interacts with unfamiliar conspecifics.
  • Isamu Miura, Eric T N Overton, Nobuhiro Nakai, Takakazu Kawamata, Masaaki Sato, Toru Takumi
    Neurologia medico-chirurgica 60 (9) 429 - 438 2020/09/15 [Refereed][Not invited]
     
    Social behavior includes a variety of behaviors that are expressed between two or more individuals. In humans, impairment of social function (i.e., social behavior and social cognition) is seen in neurodevelopmental and neurological disorders including autism spectrum disorders (ASDs) and stroke, respectively. In basic neuroscience research, fluorescence monitoring of neural activity, such as immediate early gene (IEG)-mediated whole-brain mapping, fiber photometry, and calcium imaging using a miniaturized head-mounted microscope or a two-photon microscope, and non-fluorescence imaging such as functional magnetic resonance imaging (fMRI) are increasingly used to measure the activity of many neurons and multiple brain areas in animals during social behavior. In this review, we overview recent rodent studies that have investigated the dynamics of brain activity during social behavior at the whole-brain and local circuit levels and studies that explored the neural basis of social function in healthy, in brain-injured, and in autistic human subjects. A synthesis of such findings will advance our understanding of brain mechanisms underlying social behavior and facilitate the development of pharmaceutical and functional neurosurgical interventions for brain disorders affecting social function.
  • Masaaki Sato*, Kotaro Mizuta, Tanvir Islam, Masako Kawano, Yukiko Sekine, Takashi Takekawa, Daniel Gomez-Dominguez, Alexander Schmidt, Fred Wolf, Karam Kim, Hiroshi Yamakawa, Masamichi Ohkura, Min Goo Lee, Tomoki Fukai, Junichi Nakai, Yasunori Hayashi (* lead contact)
    Cell Reports 32 (1) 107864  2211-1247 2020/07 [Refereed][Not invited]
  • Alessandro Luchetti, Ayaka Bota, Adam Weitemier, Kotaro Mizuta, Masaaki Sato, Tanvir Islam, Thomas J. McHugh, Ayumu Tashiro, Yasunori Hayashi
    The Journal of Neuroscience 40 (25) 4936 - 4944 0270-6474 2020/06 [Refereed][Not invited]
  • An aspherical microlens assembly for deep brain fluorescence microendoscopy
    Sato M*, Sano S, Watanabe H, Kudo Y, Nakai J*
    Biochem. Biophys. Res. Commun. 527 (2) 447 - 452 2020/06 [Refereed][Not invited]
  • Sugimito K, Sato M, Nakai J, Kawakami K
    FEBS Open Bio 10 (6) 1031 - 1043 2020/06 [Refereed][Not invited]
     
    The ATP1A2 coding α2 subunit of Na,K-ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+ ) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G-CaMP7 in cortical neurons and astrocytes (Atp1a2+/- ), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/- were higher than those in wild-type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/- may contribute to FHM2 pathophysiology.
  • Yuki Motegi, Masaaki Sato*, Kazuhide Horiguchi, Masamichi Ohkura, Keiko Gengyo-Ando, Yuji Ikegaya, Yasuyuki Fusamae, Yoshie Hongo, Minoru Suzuki, Koichi Ogawa, Miyako Takaki*, Junichi Nakai*
    Neuroscience research 151 53 - 60 2020/02 [Refereed][Not invited]
     
    Most imaging studies of the enteric nervous system (ENS) that regulates the function of the gastrointestinal tract are so far performed using preparations isolated from animals, thus hindering the understanding of the ENS function in vivo. Here we report a method for imaging the ENS cellular network activity in living mice using a new transgenic mouse line that co-expresses G-CaMP6 and mCherry in the ENS combined with the suction-mediated stabilization of intestinal movements. With confocal or two-photon imaging, our method can visualize spontaneous and pharmacologically-evoked ENS network activity in living animals at cellular and subcellular resolutions, demonstrating the potential usefulness for studies of the ENS function in health and disease.
  • Khaled Ghandour, Noriaki Ohkawa, Chi Chung Alan Fung, Hirotaka Asai, Yoshito Saitoh, Takashi Takekawa, Reiko Okubo-Suzuki, Shingo Soya, Hirofumi Nishizono, Mina Matsuo, Makoto Osanai, Masaaki Sato, Masamichi Ohkura, Junichi Nakai, Yasunori Hayashi, Takeshi Sakurai, Takashi Kitamura, Tomoki Fukai, Kaoru Inokuchi
    Nature communications 10 (1) 2637 - 2637 2019/06/14 [Refereed][Not invited]
     
    The brain stores and recalls memories through a set of neurons, termed engram cells. However, it is unclear how these cells are organized to constitute a corresponding memory trace. We established a unique imaging system that combines Ca2+ imaging and engram identification to extract the characteristics of engram activity by visualizing and discriminating between engram and non-engram cells. Here, we show that engram cells detected in the hippocampus display higher repetitive activity than non-engram cells during novel context learning. The total activity pattern of the engram cells during learning is stable across post-learning memory processing. Within a single engram population, we detected several sub-ensembles composed of neurons collectively activated during learning. Some sub-ensembles preferentially reappear during post-learning sleep, and these replayed sub-ensembles are more likely to be reactivated during retrieval. These results indicate that sub-ensembles represent distinct pieces of information, which are then orchestrated to constitute an entire memory.
  • Takuma Kobayashi, Tanvir Islam, Masaaki Sato, Masamichi Ohkura, Junichi Nakai, Yasunori Hayashi, Hitoshi Okamoto
    Scientific reports 9 (1) 8366 - 8366 2019/06/10 [Refereed][Not invited]
     
    Wearable technologies for functional whole brain imaging in freely moving animals would advance our understanding of cognitive processing and adaptive behavior. Fluorescence imaging can visualize the activity of individual neurons in real time, but conventional microscopes have limited sample coverage in both the width and depth of view. Here we developed a novel head-mounted laser camera (HLC) with macro and deep-focus lenses that enable fluorescence imaging at cellular resolution for comprehensive imaging in mice expressing a layer- and cell type-specific calcium probe. We visualized orientation selectivity in individual excitatory neurons across the whole visual cortex of one hemisphere, and cell assembly expressing the premotor activity that precedes voluntary movement across the motor cortex of both hemispheres. Including options for multiplex and wireless interfaces, our wearable, wide- and deep-imaging HLC technology could enable simple and economical mapping of neuronal populations underlying cognition and behavior.
  • Nobuhiro Nakai, Toru Takumi, Junichi Nakai, Masaaki Sato*
    Frontiers in Neuroscience 12 412  1662-453X 2018/06/19 [Refereed][Not invited]
     
    In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings.
  • Kimura K.D, Sato, M, Sakura, M
    Lecture Notes in Computer Science (Springer) 10922 65 - 81 2018/05 [Refereed][Invited]
  • Sato M, Mizuta K, Islam T, Kawano M, Takekawa T, Gomez-Dominguez D, Kim K, Yamakawa H, Ohkura M, Fukai T, Nakai J, Hayashi Y
    2018/02 [Refereed][Not invited]
  • Takekawa T, Asai H, Ohkawa N, Nomoto M, Okubo-Suzuki R, Ghandour K, Sato M, Hayashi Y, Inokuchi K, Fukai T
    bioRxiv 2017/11 [Not refereed][Not invited]
  • Masaaki Sato*, Yuki Motegi, Shogo Yagi, Keiko Gengyo-Ando, Masamichi Ohkura, Junichi Nakai*
    BIOMEDICAL OPTICS EXPRESS 8 (9) 4049 - 4060 2156-7085 2017/09 [Refereed][Not invited]
     
    Fluorescence microendoscopy is becoming a promising approach for deep brain imaging, but the current technology for visualizing neurons on a single focal plane limits the experimental efficiency and the pursuit of three-dimensional functional neural circuit architectures. Here we present a novel fast varifocal two-photon microendoscope system equipped with a gradient refractive index (GRIN) lens and an electrically tunable lens (ETL). This microendoscope enables quasi-simultaneous imaging of the neuronal network activity of deep brain areas at multiple focal planes separated by 85-120 mu m at a fast scan rate of 7.5-15 frames per second per plane, as demonstrated in calcium imaging of the mouse dorsal CA1 hippocampus and amygdala in vivo. (C) 2017 Optical Society of America
  • Masaaki Sato
    FRONTIERS IN CELLULAR NEUROSCIENCE 11 62  1662-5102 2017/03 [Refereed][Not invited]
     
    The human Ube3a gene encodes an E3 ubiquitin ligase and exhibits brain-specific genomic imprinting. Genetic abnormalities that affect the maternal copy of this gene cause the neurodevelopmental disorder Angelman syndrome (AS), which is characterized by severe mental retardation, speech impairment, seizure, ataxia and some unique behavioral phenotypes. In this review article, I highlight the evolution of the Ube3a gene and its imprinting to provide evolutionary insights into AS. Recent comparative genomic studies have revealed that Ube3a is most phylogenetically similar to HECTD2 among the human HECT (homologous to the E6AP carboxyl terminus) family of E3 ubiquitin ligases, and its distant evolutionary origin can be traced to common ancestors of fungi and animals. Moreover, a gene more similar to Ube3a than HECTD2 is found in a range of eukaryotes from amoebozoans to basal metazoans, but is lost in later lineages. Unlike in mice and humans, Ube3a expression is biallelic in birds, monotremes, marsupials and insects. The imprinting domain that governs maternal expression of Ube3a was formed from non-imprinted elements following multiple chromosomal rearrangements after diversification of marsupials and placental mammals. Hence, the evolutionary origins of Ube3a date from long before the emergence of the nervous system, although its imprinted expression was acquired relatively recently. These observations suggest that exogenous expression and functional analyses of ancient Ube3a orthologs in mammalian neurons will facilitate the evolutionary understanding of AS.
  • Masaaki Sato*, Masako Kawano, Kotaro Mizuta, Tanvir Islam, Min Goo Lee, Yasunori Hayashi
    eNeuro 4 (3) 2373-2822 2017 [Refereed][Not invited]
     
    The demonstration of the ability of rodents to navigate in virtual reality (VR) has made it an important behavioral paradigm for studying spatially modulated neuronal activity in these animals. However, their behavior in such simulated environments remains poorly understood. Here, we show that encoding and retrieval of goal location memory in mice head-fixed in VR depends on the postsynaptic scaffolding protein Shank2 and the dorsal hippocampus. In our newly developed virtual cued goal location task, a head-fixed mouse moves from one end of a virtual linear track to seek rewards given at a target location along the track. The mouse needs to visually recognize the target location and stay there for a short period of time to receive the reward. Transient pharmacological blockade of fast glutamatergic synaptic transmission in the dorsal hippocampus dramatically and reversibly impaired performance of this task. Encoding and updating of virtual cued goal location memory was impaired in mice deficient in the postsynaptic scaffolding protein Shank2, a mouse model of autism that exhibits impaired spatial learning in a real environment. These results highlight the crucial roles of the dorsal hippocampus and postsynaptic protein complexes in spatial learning and navigation in VR.
  • Masaaki Sato*, Masako Kawano, Yuchio Yanagawa, Yasunori Hayashi
    NEUROBIOLOGY OF LEARNING AND MEMORY 135 146 - 151 1074-7427 2016/11 [Refereed][Not invited]
     
    Imaging studies of the subcortical striatum in vivo have been technically challenging despite its functional importance in movement control and procedural learning. Here, we report a method for imaging striatal neuronal circuits in mice in vivo using two-photon microscopy. Cell bodies and intermingled dendrites of GABAergic neurons labeled with fluorescent proteins were imaged in the dorsal striatum through an imaging window implanted in the overlying cortex. This technique could be highly useful for studying the structure and function of striatal networks at cellular and subcellular resolutions in normal mice, as well as in mouse models of neurological disorders. (C) 2016 The Authors. Published by Elsevier Inc.
  • Satoshi Manita, Takayuki Suzuki, Chihiro Homma, Takashi Matsumoto, Maya Odagawa, Kazuyuki Yamada, Keisuke Ota, Chie Matsubara, Ayumu Inutsuka, Masaaki Sato, Masamichi Ohkura, Akihiro Yamanaka, Yuchio Yanagawa, Junichi Nakai, Yasunori Hayashi, Matthew E. Larkum, Masanori Murayama
    NEURON 86 (5) 1304 - 1316 0896-6273 2015/06 [Refereed][Not invited]
     
    A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. In vivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit.
  • Masaaki Sato*, Masako Kawano, Masamichi Ohkura, Keiko Gengyo-Ando, Junichi Nakai, Yasunori Hayashi
    PLOS ONE 10 (5) e0125354  1932-6203 2015/05 [Refereed][Not invited]
     
    The spatiotemporally controlled expression of G-CaMP fluorescent calcium indicator proteins can facilitate reliable imaging of brain circuit activity. Here, we generated a transgenic mouse line that expresses G-CaMP7 under a tetracycline response element. When crossed with a forebrain-specific tetracycline-controlled transactivator driver line, the mice expressed G-CaMP7 in defined cell populations in a tetracycline-controlled manner, notably in pyramidal neurons in layer 2/3 of the cortex and in the CA1 area of the hippocampus; this expression allowed for imaging of the in vivo activity of these circuits. This mouse line thus provides a useful genetic tool for controlled G-CaMP expression in vivo.
  • Masaaki Sato*, Michael P. Stryker*
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (12) 5611 - 5616 0027-8424 2010/03 [Refereed][Not invited]
     
    A defect in the maternal copy of a ubiqutin ligase gene Ube3a can produce a neurodevelopmental defect in human children known as Angelman syndrome. We investigated the role of the maternally expressed Ube3a gene in experience-dependent development and plasticity of the mouse visual system. As demonstrated by optical imaging, rapid ocular dominance (OD) plasticity after brief monocular deprivation (MD) was severely impaired during the critical period (CP) in the visual cortex (VC) of Ube3a maternal-deficient (m-/p+) mice. Prolonged MD elicited significant plasticity in m-/p+ mice that never matched the level seen in control animals. In older animals after the CP, 7-day MD elicited mild OD shifts in both control and m-/p+ mice; however, the OD shifts in m-/p+ mice lacked the strengthening of visual responses to the two eyes characteristic of normal adult plasticity. Anatomic effects of the maternal deficiency include reduced spine density on basal, but not apical, dendrites of pyramidal neurons in the binocular region of the VC. Imprinting of Ube3a expression was not fully established in the early postnatal period, consistent with the normal development of cortical retinotopy and visual acuity that we observed in m-/p+ mice, but was fully established by the onset of the CP. These results demonstrate that paternal and maternal genomes are not functionally equivalent for cortical plasticity, and that maternally expressed Ube3a is required for normal experience-dependent modification of cortical circuits during and after the CP.
  • Masaaki Sato, Michael P. Stryker
    JOURNAL OF NEUROSCIENCE 28 (41) 10278 - 10286 0270-6474 2008/10 [Refereed][Not invited]
     
    Sensory experience profoundly shapes neural circuitry of juvenile brain. Although the visual cortex of adult rodents retains a capacity for plasticity in response to monocular visual deprivation, the nature of this plasticity and the neural circuit changes that accompany it remain enigmatic. Here, we investigate differences between adult and juvenile ocular dominance plasticity using Fourier optical imaging of intrinsic signals in mouse visual cortex. This comparison reveals that adult plasticity takes longer than in the juvenile mouse, is of smaller magnitude, has a greater contribution from the increase in response to the open eye, and has less effect on the hemisphere ipsilateral to the deprived eye. Binocular deprivation also causes different changes in the adult. Adult plasticity is similar to juvenile plasticity in its dependence on signaling through NMDA receptors. We propose that adult ocular dominance plasticity arises from compensatory mechanisms that counterbalance the loss of afferent activity caused by visual deprivation.
  • M Sato, K Suzuki, S Nakanishi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 341 (2) 304 - 309 0006-291X 2006/03 [Refereed][Not invited]
     
    With the aid of microarray and PCR analysis, this investigation sought expression profiles of BDNF-regulated genes in Cultured mouse cerebellar granule cells and addressed their relevance to gene regulation in developing granule cells in vivo. Many of the BDNF-upregulated and downregulated genes identified were upregulated and downregulated, respectively, during cerebellar development. This developmental change was, at least partly, prevented in the TrkB receptor-deficient cerebellum. The BDNF-upregulated genes were distributed in either postmigratory or both premigratory and postinigratory granule cells at postnatal day 8 (P8) and were still present in mature granule cells at P21. In contrast, the BDNF-downregulated genes were predominantly expressed in premigratory granule cells at P8 and disappeared at P21. Furthermore, many of the BDNF-Upregulated gene products are implicated in signaling cascades of N-methyl-D-aspartate receptors and MAP kinase. The results indicate that BDNF signaling plays a pivotal role in promoting gene expression in granule cell development and maturation. (c) 2006 Elsevier Inc. All rights reserved.
  • K Suzuki, M Sato, Y Morishima, S Nakanishi
    JOURNAL OF NEUROSCIENCE 25 (41) 9535 - 9543 0270-6474 2005/10 [Refereed][Not invited]
     
    In the developing cerebellum, switching of subunit composition of NMDA receptors occurs in granule cells from NR2B subunit-containing receptors to NR2C subunit-containing receptors. This switching of subunit composition plays an important role in the establishment of functional mossy fiber-granule cell synaptic transmission in the mature cerebellar network. The mechanism underlying NR2C upregulation in developing granule cells, however, has to date remained to be determined. In granule cells cultured in low ( 5 mM) KCl, brain-derived neurotrophic factor (BDNF) upregulated NR2CmRNA via the TrkB-extracellular signal-regulated kinase (ERK) 1/2 cascade and promoted the formation of an NR2C-containing NMDA receptor complex. In granule cells cultured in high (25mM) KCl, depolarization stimulated voltage-sensitive Ca2+ channels. The resultant increase in intracellular Ca2+ activated Ca2+/calmodulin-dependent calcineurin phosphatase and blocked NR2C mRNA upregulation. Interestingly, the depolarization-induced Ca2+ increase simultaneously upregulated BDNFmRNA via Ca2+ calmodulin-dependent protein kinase ( CaMK). Consequently, when calcineurin was inhibited by its inhibitor FK506 under the depolarizing condition, the CaMK-mediated increase in BDNF became a stimulatory signal, and the endogenous BDNF autocrine system was capable of upregulating NR2C mRNA via the common TrkB-ERK cascade. The importance of the BDNF-TrkB pathway was further supported by a significant reduction in NR2C in normally migrated granule cells of TrkB(-/-) knock-out mice in vivo. The convergent mechanism of the BDNF and Ca2+ signaling cascades thus plays an important regulatory role in NR2C induction in granule cells during cerebellar development.
  • M Sato, K Suzuki, H Yamazaki, S Nakanishi
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 (16) 5874 - 5879 0027-8424 2005/04 [Refereed][Not invited]
     
    Primary culture of postnatal cerebellar granule cells provides a model system that recapitulates many molecular events of developing granule cells in vivo. Depolarization of cultured granule cells increases intracellular Ca2+ and activates Ca2+/calmodulin-dependent calcineurin (CaN) phosphatase. This Ca2+ signaling mimics some of the signaling events for proliferation, migration, and differentiation of granule cellsin vivo. We investigated the genome-wide expression profiles of depolarization- and CaN-regulated genes in cultured mouse granule cells and addressed their relevance to gene regulation in developing granule cells in vivo. Granule cells were cultured under a nondepolarization condition (5 mM KCI) and a depolarization condition (25 mM KCI) with and without the CaN inhibitor FK506. Gene expression profiles between depolarization and nondepolarization and between FK506 treatment and untreatment were analyzed by microarray techniques. Both depolarization and FK506 treatment influence expression levels of a large number of genes, most of which are overlapping, however, are conversely regulated by these two treatments. Importantly, many of the FK506-responsive genes are up- or down-regulated in parallel with gene expression in postnatal granule cells in vivo. The FK506-down-regulated genes are highly expressed in proliferating/premigratory granule cells and many of these genes encode cellular components involved in cell proliferation, migration, and differentiation. In contrast, the FK506-up-regulated genes are predominantly expressed in post-migratory granule cells, including many functional molecules implicated in synaptic transmission and modulation. This investigation demonstrates that the CaN signaling plays a pivotal role in development and synaptic organization of granule cells during the postnatal period.
  • M Sato, T Tabata, K Hashimoto, K Nakamura, K Nakao, M Katsuki, J Kitano, K Moriyoshi, M Kano, S Nakanishi
    EUROPEAN JOURNAL OF NEUROSCIENCE 20 (4) 947 - 955 0953-816X 2004/08 [Refereed][Not invited]
     
    mGluR1 and mGluR5 of the metabotropic glutamate receptor family are coupled to inositol trisphosphate-Ca2+ signal cascades and evoke distinct Ca2+ responses in neural cells and heterologously expressing cells. In heterologous cells, stimulation of recombinant mGluR1 evokes a single-peaked Ca2+ response whereas mGluR5 elicits an oscillatory Ca2+ response. The distinct Ca2+ responses are interchangeable by single amino substitution of aspartate for threonine at the corresponding position of the carboxy-terminal cytoplasmic regions of mGluR1 and mGluR5, respectively. In this investigation, we generated knock-in mice, termed mGluR1 D854T mice, in which aspartate of mGluR1 was replaced with threonine. We examined the effect of this D854T substitution on Ca2+ and current responses mediated by mGluR1 in cultured cerebellar Purkinje cells. Stimulation of mGluR1 D854T by a group 1 mGluR agonist, 3,5-dihydroxyphenylglycine (DHPG) evoked, as in wild-type mGluR1, only single-peaked Ca2+ responses as measured by Ca2+ fluorometric analysis. We then examined mGluR1-induced inward currents carried by nonselective cation channels during whole-cell recordings from cultured Purkinje cells. The mGluR1 D854T mutation abolished the responsiveness of mGluR1 to low concentrations of DHPG (0.5-500 nM) and reduced its desensitization during prolonged agonist application. mGluR1 D854T homozygous mutants showed no apparent behavioural abnormality as analysed by motor movement tests. These results indicate that, although additional modulatory mechanisms seem to be required to produce oscillatory Ca2+ responses of mGluR1, the single amino acid substitution at position 854 of mGluR1 is capable of influencing the kinetics of neuronal mGluR1 responses, most probably through PKC-mediated phosphorylation.
  • M Sato, K Suzuki, S Nakanishi
    JOURNAL OF NEUROSCIENCE 21 (11) 3797 - 3805 0270-6474 2001/06 [Refereed][Not invited]
     
    In three alternative splice variants of Homer 1 transcripts, Homer 1a mRNA has been shown to be upregulated selectively and rapidly by neural stimulation and represents a member of the immediate early gene (IEG) family. We investigated the mechanism underlying Homer 1a mRNA induction in cerebellar granule cell culture. All Homer 1 variants were expressed in cultured granule cells as analyzed by RNA blotting and immunochemical characterization. Glutamate stimulation of granule cells selectively upregulated Homer 1a mRNA via NMDA receptor-mediated influx of extracellular calcium. The induction of Homer 1a mRNA was much slower (peaked at 4 hr) and sustained longer than that of the typical IEG c-fos mRNA. Actinomycin D and cycloheximide experiments have revealed that, despite the presence of the mRNA-destabilizing AU-rich motif, transcriptional activation is a main determinant for selective Homer 1a mRNA induction. Inhibitor analysis as well as immunochemical characterization has indicated that the MEK (MAPK/ERK kinase)-ERK (extracellular signal-regulated kinase) cascade plays an indispensable role in glutamate-stimulated induction of Homer 1a mRNA. Consistent with this observation, brain-derived neurotrophic factor, which is known to activate the ERK cascade, similarly upregulated Homer 1a mRNA. These results demonstrate that MAPK (mitogen-activated protein kinase) is a key mediator that links distinct extracellular stimuli to the transcriptional activation of Homer 1a mRNA.
  • T Imura, S Shimohama, M Sato, H Nishikawa, K Madono, A Akaike, J Kimura
    JOURNAL OF NEUROSCIENCE 19 (22) 9768 - 9779 0270-6474 1999/11 [Refereed][Not invited]
     
    Small heat shock proteins (sHSPs), a family of HSPs, are known to accumulate in the CNS, mainly in astrocytes, in several pathological conditions such as Alexander's disease, Alzheimer's disease, and Creutzfeldt-Jakob disease. sHSPs may act not only as molecular chaperones, protecting against various stress stimuli, but may also play a physiological role in regulating cell differentiation and proliferation. In the present study, we have demonstrated that transient focal ischemia in rats dramatically induced HSP27 but not alpha B-crystallin (alpha BC), both of which are members of sHSPs, in reactive astrocytes. In contrast, in vitro chemical ischemic stress induced both HSP27 and alpha BC in cultured glial cells to the same extent. Dibutyryl cAMP (dBcAMP) and isoproterenol, a beta-adrenergic receptor (beta AR) agonist, enhanced HSP27 expression but suppressed aBC, and changed the shape of the cells to a stellate form. dBcAMP and isoproterenol inhibited cell proliferation under normal conditions. An increase in beta AR-like immunoreactivity was also observed in reactive astrocytes in vivo. These results, together with recent findings that beta AR plays an important role in glial scar formation in vivo, raise the possibility that beta AR activation modulates sHSP expression after focal ischemia and is involved in the transformation of astrocytes to their reactive form.
  • S Takami, H Nishikawa, M Minami, A Nishiyori, M Sato, A Akaike, M Satoh
    NEUROSCIENCE LETTERS 227 (3) 173 - 176 0304-3940 1997/05 [Refereed][Not invited]
     
    The distribution and cell source of macrophage inflammatory protein-1 alpha (MIP-1 alpha) mRNA induced by transient and permanent middle cerebral artery occlusion (MCAO) were investigated by a double in situ hybridization technique. The distribution and time course of the induction of MIP-1 alpha mRNA were similar in the two MCAO models. MIP-1 alpha mRNA was not detected in the sham-operated rat brain. MIP-1 alpha mRNA was induced by MCAO with the peak of expression at 4-6 h after the onset of occlusion, and the signals of MIP-1 alpha mRNA were observed in the ischemic core region at an earlier time point, and thereafter intensely in the penumbra of the ischemic area. The signals of MIP-1 alpha mRNA were evident on Mac-1 alpha mRNA-positive cells, but not on glial fibrillary acidic protein (GFAP) mRNA-positive cells, indicating that MIP-1 alpha mRNA was induced in microglia/macrophages of the rat brain after focal cerebral ischemia. (C) 1997 Elsevier Science Ireland Ltd.

MISC

Association Memberships

  • Society for Neuroscience   日本顕微鏡学会   日本生理学会 評議員   日本神経精神薬理学会   日本神経科学学会   日本薬理学会 学術評議員 薬理学エデュケーター   

Research Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2024/04 -2029/03 
    Author : 佐藤 正晃
  • 日本学術振興会：科学研究費助成事業 基盤研究(B)
    Date (from‐to) : 2023/04 -2027/03 
    Author : 佐藤 正晃
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2021/04 -2024/03 
    Author : 吉岡 充弘, 西谷 直也, 大村 優, 佐藤 正晃
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2020/04 -2023/03 
    Author : 佐藤 正晃
     
    ナビゲーションや空間記憶に重要な役割を果たす海馬の錐体細胞は、動物が特定の場所を通過するときに活性化する「場所細胞」としての性質をもつ。我々は過去の研究で、シナプスタンパク質の一つShank2を欠損した自閉症モデルマウスがバーチャルリアリティ空間で空間学習の異常を示すこと、また、その海馬ではランドマーク地点をコードするセルアセンブリ (協調的に働く複数の細胞の集団)の形成に特異的な異常が観察されることを明らかにした。このような機能回路の異常を理解するためには、生後の発達過程の神経回路活動を解析し、その形成と成熟のメカニズムを明らかにすることが必要である。そこで、本研究は、生後発達期の海馬の活動を二光子カルシウムイメージングで明らかにすることを目的としている。 本年度は以下の研究を行った。生後初期のG-CaMP7トランスジェニックマウスのイメージングのために、小型化したチタン製のヘッドプレートおよびヘッドプレートホルダーを設計して作成した。しかし生後直後のマウスは小さくて扱いにくかったため、マウスよりも大きいラットを用いた実験系を立ち上げた。生後間もないラットの脳に蛍光カルシウムセンサータンパク質を発現するAAVベクターを注入し、１-２週間の後に切片を作成して発現を確認したところ、いくつかの候補のうちの特定のプロモーターのみが、生後ラットの海馬で外来遺伝子の良好な発現を引きおこすことを明らかにした。生後2-３週のラットの頭部にヘッドプレートを装着してバーチャルリアリティ環境に置いたところ、トレッドミル上で問題なく自発歩行できることが確認できた。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2020/07 -2022/03 
    Author : Sato Masaaki
     
    Hippocampal pyramidal cells play an essential role in memory formation and have the property of "place cells" that exhibit location-specific activity. However, it is unclear by what synaptic activity the location specificity of their responses emerges. To establish a method for calcium imaging of the dendritic spine activity of hippocampal pyramidal cells, a spine-specific fluorescent calcium sensor protein was expressed in the pyramidal cells in the dorsal hippocampal CA1 area using adeno-associated viral vectors and transgenic mice, and its usefulness in in vivo imaging was investigated.
  • 文部科学省：科学研究費補助金(新学術領域(研究領域提案型))
    Date (from‐to) : 2019 -2020 
    Author : 佐藤正晃
  • 文部科学省：科学研究費補助金(新学術領域研究(研究領域提案型))
    Date (from‐to) : 2017 -2018 
    Author : 佐藤正晃
  • 文部科学省：科学研究費補助金（挑戦的萌芽研究）
    Date (from‐to) : 2016 -2017 
    Author : 佐藤正晃
  • 科学技術振興機構：さきがけ「細胞機能の構成的な理解と制御」
    Date (from‐to) : 2012 -2016 
    Author : 佐藤正晃
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010/04 -2015/03 
    Author : HAYASHI Yasunori, SATO Masaaki, UEDA Yoshibumi
     
    Hippocampus is involved in the encoding an episodic experience into a physical trace in brain. However, how an episode is represented at cellular resolution, how long it lasts, and whether the same representation is reinstated upon recall are still not fully elucidated due to the lack of method to longitudinally observe representation. We performed two-photon microscopic Ca2+-imaging of ~1000 CA1 pyramidal neurons from mouse dorsal hippocampus during a familiar episodic event under virtual reality over two weeks. The hippocampal representation consists of a group of neurons firing sequentially during the event; ~2% of the cells fire at specific time point consistently while ~20% join the representation on each day and turn over in a few days. A change in the episode sequence largely eliminates both components, even the animal is behaviorally recalling the episode indicating the retrieval of a familiar episodic sequence can take place without a reinstatement of the same representation.
  • 文部科学省：科学研究費補助金(新学術領域研究(研究領域提案型))
    Date (from‐to) : 2014 -2015 
    Author : 佐藤 正晃
     
    本課題は、海馬における記憶情報表現の動的な性質を理解するために、マウスをバーチャルリアリティ下の空間学習課題で訓練した時の海馬場所地図の可塑的変化をin vivoカルシウムイメージングで明らかにすることを目的としている。本年度は、仮想直線路を走るマウスのCA1野の場所細胞地図を、異なるセッションで間で比較することで、海馬の場所地図の安定性を定量的に解析した。昨年度までに得られた結果で、仮想直線路内に設定された視覚的手がかりや報酬の存在する場所は、他の場所よりも多くの場所細胞によってコードされること（過剰表現）が明らかになった。このメカニズムを解析する目的で、場所細胞の安定性が上記のような行動上重要な場所とそうでない中立的な場所とで差があるかどうか検討したところ、前者の安定性の方が後者のものより高いことが明らかとなった。一方で、新しい場所細胞が形成される確率や、中立的な場所をコードする細胞が行動上重要な場所をコードする細胞に変化する確率には差が見られなかったことから、場所細胞の選択的な安定化が過剰表現の形成のメカニズムであることが示された。 また、上記の場所地図の形成に関わる回路メカニズムを明らかにする目的で、対物レンズを上下動することで焦点を変化させることのできるピエゾアクチュエータを二光子顕微鏡に取り付け、上昇層に存在する抑制性介在細胞と錐体細胞層に存在する興奮性錐体細胞の２つの細胞タイプを、ほぼ同時にイメージングする３次元カルシウムイメージングを試みた。しかし、ピエゾアクチュエータは対物レンズの位置を物理的に動かすため、特に重い対物レンズの場合は高速かつ正確に動作を制御することが難しく、この問題を解決する一つの方法として、対物レンズを上下動させることなく焦点を変化させることのできる可変焦点レンズの使用を検討した。この手法の最適化は今後の課題である。
  • 文部科学省：科学研究費補助金(新学術領域研究(研究領域提案型))
    Date (from‐to) : 2013 -2014 
    Author : 佐藤 正晃
     
    本年度はShank2ノックアウトマウスを用いて、前年度に確立したバーチャルリアリティ環境下の仮想空間学習課題における行動実験とカルシウムイメージングを行うことを目的とした。Shank2は興奮性シナプスのシナプス後肥厚部に存在するタンパク質複合体に含まれる足場タンパク質の一つであり、ヒトの自閉症家系におけるその変異の存在が報告されている。またShank2ノックアウトマウスが行動レベルにおいてはヒト自閉症に似た社会性の低下を示し、シナプスレベルではNMDA受容体機能の低下を示すことなどが既に報告されている。本年度の研究でShank2ノックアウトマウスの仮想空間学習課題の成績を評価したところ、仮想空間での場所認識を必要としない非遅延課題では野生型と有意な行動の差がなかったが、視覚的手がかりを用いて標的地点に遅延時間の間滞在することで報酬が得られる遅延課題においては、野生型に比べ標的地点における滞在時間が有意に低下した。また、仮想直線路上の標的地点を移動させて行う再学習訓練においても、Shank2ノックアウトマウスは野生型に比べ、新しい標的地点における滞在時間が有意に低下していた。このことは、Shank2ノックアウトマウスにおいて空間学習と再学習が障害されていることを示しており、自閉症に見られる学習障害や、特定の行動に固執する傾向との類似を示唆するものであった。その後、この行動課題を遂行しているShank2ノックアウトマウスの海馬神経回路活動のカルシウムイメージングを行った。今後は取得したイメージングデータの定量的な解析を行う予定である。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2012 -2013 
    Author : SATO Masaaki
     
    It has been thought that acquisition, retension and recall of memories are mediated by activity of groups of neurons that are formed and reorganized by learning and experience. In this study, we imaged hippocampal CA1 neuronal circuit activity in head-fixed mice performing spatial behavior in virtual reality by using two-photon deep brain imaging of transgenic mice expressing genetically-encoded calcium indicators in the brain. We computationally extracted activity time-series of hundreds of neurons from images and confirmed that a subpopulation of CA1 pyramidal neurons exhibited virtual place-specific activity. We also observed that neurons with different virtual place fields were anatomically intermingled each other in hippocampal CA1 local circuits.
  • Ministry of Education, Culture, Sports, Science and Technology：Grants-in-Aid for Scientific Research(若手研究(スタートアップ), 研究活動スタート支援)
    Date (from‐to) : 2009 -2010 
    Author : Masaaki SATO
     
    To establish chronic in vivo two-photon calcium imaging, we generated transgenic mice that stably express a genetically-encoded calcium sensor GCaMP4 in layer 5 of cortex and CA1 of hippocampus. Our in vivo two-photon imaging confirmed that the fluorescence of GCaMP4 in hippocampal CA1 pyramidal cells of these mice increased rapidly and substantially in response to pharmacologically-induced elevation of neuronal circuit activity. These transgenic mice will thus become a valuable tool for longitudinal imaging studies of learning-induced neuronal circuit plasticity in the brain.

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