記述言語：英語   出版者・発行元：Scientific Reports  

Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl−] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas—for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice by administering local spinal cord injections of bicuculline (GABAA receptor blockade) or bumetanide (lowers intracellular [Cl−] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive reconfiguration of presynaptic GABAergic input.

DOI： 10.1038/s41598-023-34701-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

DOI： 10.1038/s41598-023-33977-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cell Reports  

The relationships between tissue-resident microglia and early macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding in situ and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated or genetic labeling, we find that intraventricular CD206+ macrophages, which are abundantly observed along the inner surface of the mouse cerebral wall, frequently enter the pallium at embryonic day 12. Immunofluorescence of the tracked cells show that postinfiltrative macrophages in the pallium acquire microglial properties while losing the CD206+ macrophage phenotype. We also find that intraventricular macrophages are supplied transepithelially from the roof plate. This study demonstrates that the “roof plate→ventricle→pallium” route is an essential path for microglial colonization into the embryonic mouse brain.

DOI： 10.1016/j.celrep.2023.112092

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Each oligodendrocyte (OC) forms myelin approximately in around 10 different axons to coordinate information transfer by regulating conduction velocity in the central nervous system (CNS). In the classical view, myelin has been considered a static structure that rarely turns over under healthy conditions because myelin tightly holds axons by their laminar complex structure. However, in recent decades, the classical views of static myelin have been renewed with pioneering studies that showed plastic changes in myelin throughout life with new experiences, such as the acquisition of new motor skills and the formation of memory. These changes in myelin regulate conduction velocity to optimize the temporal pattern of neuronal circuit activity among distinct brain regions associated with skill learning and memory. Here, we introduce pioneering studies and discuss the implications of plastic myelin on neural circuits and brain function.

DOI： 10.1016/j.neures.2022.11.002

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出版者・発行元：Proceedings of SPIE - The International Society for Optical Engineering  

Optical bioimaging and optogenetics have recently made it possible to control brain functions. However, these methods have limitations, such as the inability to regulate neural activity with a high spatiotemporal resolution. To address this limitation, we have developed microscope for biological applications by integrating optogenetics and digital holographic technology. This provides precise spatiotemporal information about neural activity.

DOI： 10.1117/12.3008169

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Cellular Neuroscience  

Oligodendrocytes (OCs) form myelin around axons, which is dependent on neuronal activity. This activity-dependent myelination plays a crucial role in training and learning. Previous studies have suggested that neuronal activity regulates proliferation and differentiation of oligodendrocyte precursor cells (OPCs) and myelination. In addition, deficient activity-dependent myelination results in impaired motor learning. However, the functional response of OC responsible for neuronal activity and their pathological changes is not fully elucidated. In this research, we aimed to understand the activity-dependent OC responses and their different properties by observing OCs using in vivo two-photon microscopy. We clarified that the Ca2+ activity in OCs is neuronal activity dependent and differentially regulated by neurotransmitters such as glutamate or adenosine triphosphate (ATP). Furthermore, in 5-month-old mice models of Alzheimer’s disease, a period before the appearance of behavioral abnormalities, the elevated Ca2+ responses in OCs are ATP dependent, suggesting that OCs receive ATP from damaged tissue. We anticipate that our research will help in determining the correct therapeutic strategy for neurodegenerative diseases beyond the synapse.

DOI： 10.3389/fncel.2023.1154196

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Folia Pharmacologica Japonica  

Microglia are the only immune cells in the central nervous system. It has been shown that microglia actively regulate the number of neurons by participating in the cell death of neural stem cells during development and maturation. In addition, recent optical techniques have enabled in vivo imaging, which has revealed the function of microglia on synapses. Microglia regularly monitor synaptic activity and remove synapses that show abnormal activity in the event of brain infarction or other disorders. During development, microglia contribute to the formation of immature synapses by contacting dendrites during early synapse formation, and they are also involved in the de-synaptic process by selectively removing weakly active synapses through the use of classical complement cascade signaling. Furthermore, these abnormalities are known to contribute to the development of autism during development and to the development of Alzheimer's disease during maturation. In addition to this, microglia also contribute to plastic changes in synapses during the learning process in maturation. Furthermore, by modifying synaptic activity, microglia are known to be involved in changes in the activity of neuronal circuits. In addition to these synaptic functions, microglia are also known to be involved in the permeability of the blood-brain barrier. In this chapter, these functions will be summarized and discussed.

DOI： 10.1254/fpj.23010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuron  

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as “resting versus activated” and “M1 versus M2.” This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

DOI： 10.1016/j.neuron.2022.10.020

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記述言語：日本語   出版者・発行元：克誠堂出版(株)  

急性疼痛時や疼痛モデルマウス作製前後における大脳皮質第一次体性感覚野(S1)神経細胞の自発活動や各細胞間の活動相関性および機能的結合の経時変化を検証した。6～8週齢の雄性C57BL/6マウスおよび雄性parvalbumin-Creマウスを使用し、疼痛モデルにはcomplete Freund's adjuvantの足底注入による炎症性疼痛モデルを用いた。モデルマウス作成後の疼痛急性期から維持期では、S1神経細胞の自発活動が増加し、各細胞間の活動相関性が増加すること、疼痛の改善(作製後28日)に伴ってそれが元の状態まで低下することが分かった。疼痛急性期のS1神経細胞ではN型カルシウムイオンチャネルの発現が増加しており、拮抗薬の脳室内単回投与および徐放製剤を用いたS1局所慢性投与が疼痛改善に有効であった。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Visualized Experiments  

Recent advances in optical bioimaging and optogenetics have enabled the visualization and manipulation of biological phenomena, including cellular activities, in living animals. In the field of neuroscience, detailed neural activity related to brain functions, such as learning and memory, has now been revealed, and it has become feasible to artificially manipulate this activity to express brain functions. However, the conventional evaluation of neural activity by two-photon Ca2+ imaging has the problem of low temporal resolution. In addition, manipulation of neural activity by conventional optogenetics through the optic fiber can only simultaneously regulate the activity of neurons with the same genetic background, making it difficult to control the activity of individual neurons. To solve this issue, we recently developed a microscope with a high spatiotemporal resolution for biological applications by combining optogenetics with digital holographic technology that can modify femtosecond infrared laser beams. Here, we describe protocols for the visualization, evaluation, and manipulation of neural activity, including the preparation of samples and operation of a two-photon holographic microscope (Figure 1). These protocols provide accurate spatiotemporal information on neural activity, which may be useful for elucidating the pathogenesis of neuropsychiatric disorders that lead to abnormalities in neural activity.

DOI： 10.3791/64205

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出版者・発行元：Cold Spring Harbor Laboratory  

Summary

The relationships between microglia and macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated labeling, we found that a group of intraventricular macrophages belonging to border-associated macrophages (BAMs), which were abundantly observed along the inner surface of the mouse cerebral wall at embryonic day 12, frequently entered the brain wall. Immunohistochemistry of the tracked cells showed that postinfiltrative BAMs acquired microglial properties while losing a macrophage phenotype. We also found that the intraventricular BAMs were supplied transepithelially from the roof plate. Thus, this study demonstrates that the “roof plate→ventricle→cerebral wall” route is an essential path for microglial colonization into the embryonic mouse brain.

DOI： 10.1101/2022.07.27.501563

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Communications  

Chronic pain is a major public health problem that currently lacks effective treatment options. Here, a method that can modulate chronic pain-like behaviour induced by nerve injury in mice is described. By combining a transient nerve block to inhibit noxious afferent input from injured peripheral nerves, with concurrent activation of astrocytes in the somatosensory cortex (S1) by either low intensity transcranial direct current stimulation (tDCS) or via the chemogenetic DREADD system, we could reverse allodynia-like behaviour previously established by partial sciatic nerve ligation (PSL). Such activation of astrocytes initiated spine plasticity to reduce those synapses formed shortly after PSL. This reversal from allodynia-like behaviour persisted well beyond the active treatment period. Thus, our study demonstrates a robust and potentially translational approach for modulating pain, that capitalizes on the interplay between noxious afferents, sensitized central neuronal circuits, and astrocyte-activation induced synaptic plasticity.

DOI： 10.1038/s41467-022-31773-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Holographic structured illumination combined with optogenetics enables patterned stimulation of neurons and glial cells in an intact living brain. Moreover, in vivo functional imaging of cellular activity with recent advanced microscope technologies allows for visualization of the cellular responses during learning, emotion and cognition. Integrating these techniques can be used to verify the link between cell function and behavior output. However, there are technical limitations to stimulate multiple cells with high spatial and temporal resolution with available techniques of optogenetic stimulation. Here, we summarized a two-photon microscope combined with holographic system to stimulate multiple cells with high spatial and temporal resolution for living mice and their biological application.

DOI： 10.1016/j.neures.2021.10.012

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記述言語：英語   出版者・発行元：Neuroscience Research  

DOI： 10.1016/j.neures.2022.04.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Clinical Investigation  

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.

DOI： 10.1172/JCI154611

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Veterinary Medical Science  

Neonicotinoid pesticides (NNs) cause behavioral abnormalities in mammals, raising concerns about their effects on neural circuit activity. We herein examined the neurological effectof the NN clothianidin (CLO) by in vivo Ca2+ imaging using two-photon microscopy. Mice were fed the no-observed-adverse-effect-level (NOAEL) dose of CLO for 2 weeks and their neuronal activity in the primary somatosensory cortex (S1) was observed weekly for 2 weeks. CLO exposure caused a sustained influx of Ca2+ in neurons in the S1 2/3 layers, indicating hyperactivation of neurons. In addition, microarray gene expression analysis suggested the induction of neuroinflammation and changes in synaptic activity. These results demonstrate that exposure to the NOAEL dose of CLO can overactivate neurons and disrupt neuronal homeostasis.

DOI： 10.1292/jvms.22-0013

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Neonicotinoid pesticides are a class of insecticides that reportedly have harmful effects on bees and dragonflies, causing a reduction in their numbers. Neonicotinoids act as neuroreceptor modulators, and some studies have reported their association with neurodevelopmental disorders. However, the precise effect of neonicotinoids on the central nervous system has not yet been identified. Herein, we conducted in vivo Ca2+ imaging using a two-photon microscope to detect the abnormal activity of neuronal circuits in the brain after neonicotinoid application. The oral administration of acetamiprid (ACE) (20 mg/kg body weight (BW) in mature mice with a quantity less than the no-observed-adverse-effect level (NOAEL) and a tenth or half of the median lethal dose (LD50) of nicotine (0.33 or 1.65 mg/kg BW, respectively), as a typical nicotinic acetylcholine receptor (nAChR) agonist, increased anxiety-like behavior associated with altered activities of the neuronal population in the somatosensory cortex. Furthermore, we detected ACE and its metabolites in the brain, 1 h after ACE administration. The results suggested that in vivo Ca2+ imaging using a two-photon microscope enabled the highly sensitive detection of neurotoxicant-mediated brain disturbance of nerves.

DOI： 10.1038/s41598-022-09038-7

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その他リンク： https://www.nature.com/articles/s41598-022-09038-7

記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

<p>Visualization (or &quot;Understanding&quot; or &quot;Researchinto&quot;) of physiological and pathological phenomena has taken a leapforward by recent advanced optical bio imaging technique. Traditionally,physiological phenomena including cell division, cell function, moleculartransport and cell death were detected by biochemical methods. However, thisinformation lacked high resolution spatial and temporal information. Usingrecent optical techniques, both spatial and temporal information can beintegrated across the molecular, cellular and systems levels that allow us tofurther investigate the hierarchical interaction of brain systems thatultimately reveal the pathological mechanism. In this session, we will discussthe current and potential future state of the construction of bio-imagingcenter, and will further discuss by understanding hierarchical physiologicalsystem that leads to the creation of healthy society.</p>

DOI： 10.1254/jpssuppl.95.0_2-s17-2

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

<p>Microglia are the sole immune responding cells in the central nervous system. Their role as neuro-immune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. In addition to the pathological function of microglia, recent developments in molecular probes and optical imaging in vivo have revealed that microglia are highly motile cell in the healthy brain, extending and retracting their process that extend from a largely stationary cell soma. We used in vivo two photon microscopy to reveal their physiological and pathological function on synapse and vessels. We particularly showed the functional consequence of microglial contact on synapse and vessels to indicate their role in neurological or psychiatric brain. </p><p>In this session, we will show 1. Microglial regulation of blood brain barrier, 2. Microglial role for cross modal plasticity that indicate their pathological role in schizophrenia. </p><p></p>

DOI： 10.1254/jpssuppl.95.0_3-s31-3

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬学会  

アルツハイマー型認知機能障害、自閉スペクトラム症、統合失調症などの多岐にわたる疾患において、神経回路を決定するシナプスの異常を認める。近年の光学技術の発達に伴い、脳の免疫細胞であるミクログリアが、健常時、発達期、病態期の様々な場面で、シナプスと直接の接触を繰り返し、その新生、除去、維持、活動の制御などの多岐にわたる役割を果たすことが解明されてきた。本稿では、ミクログリアとシナプスに関する最新の知見をまとめ、今後の疾患研究への展望について議論する。

DOI： 10.14894/faruawpsj.58.9_858

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416201861

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1416201836

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記述言語：英語   出版者・発行元：(一社)日本毒性学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Oligodendrocytes, which form the myelin sheaths that insulate axons, regulate conduction velocity. Myelinated axons make up the brain's white matter and contribute to the efficiency of information processing by regulating the timing of neural activity. Traditionally, it has been thought that myelin is a static, inactive insulator around the axon. However, recent studies in humans using magnetic resonance imaging have shown that structural changes in the white matter occur during learning and training, suggesting that 1) white matter change depends on neural activity and 2) activity-dependent changes in white matter are essential for learning and behavior. Furthermore, suppression of oligodendrocytes and their progenitor cells leads to deficits in motor learning and remote fear memory consolidation, suggesting a causal relationship between glial function and the learning process. However, for technical reasons, it remains unclear how myelin-generating glia modulate neural circuitry and what underlying mechanisms they employ to affect learning and behavior. Recent advances in optical and genetic techniques have helped elucidate this mechanism. In this review, we highlight evidence that neural activities regulated by myelin plasticity play a pivotal role in learning and behavior and provide further insight into possible therapeutic targets for treating diseases accompanied by myelin impairment.

DOI： 10.1016/j.neures.2020.12.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Science Advances  

Sustained neuropathic pain from injury or inflammation remains a major burden for society. Rodent pain models have informed some cellular mechanisms increasing neuronal excitability within the spinal cord and primary somatosensory cortex (S1), but how activity patterns within these circuits change during pain remains unclear. We have applied multiphoton in vivo imaging and holographic stimulation to examine single S1 neuron activity patterns and connectivity during sustained pain. Following pain induction, there is an increase in synchronized neuronal activity and connectivity within S1, indicating the formation of pain circuits. Artificially increasing neuronal activity and synchrony using DREADDs reduced pain thresholds. The expression of N-type voltage-dependent Ca2+ channel subunits in S1 was increased after pain induction, and locally blocking these channels reduced both the synchrony and allodynia associated with inflammatory pain. Targeting these S1 pain circuits, via inhibiting N-type Ca2+ channels or other approaches, may provide ways to reduce inflammatory pain.

DOI： 10.1126/sciadv.abd8261

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掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：日本毒性学会  

<p>Neonicotionoid pesticides are insecticides which have been thought to be one of the causes of Colony Collapse Disorder. They were considered to be less toxic to mammals than insects, but some of the recent studies suggested their association with disruption of higher brain fuction in mammals. Nevertheless, it is still unclear how neonicotionoids affect on the central nervous system. Here, we propose the use of in vivo Ca²⁺ imaging with two-photon microscope to detect abnormal activity of neuronal circuits in brain with the application of neonicotionoids.</p><p>In this study, a less than the no-observed-adverse-effect level (NOAEL) of acetamiprid (20 mg/kg bw); and a tenth or half of the median lethal doses of nicotine (0.33 or 1.65 mg/kg bw respectively) were orally administered to mice. They were subjected to elevated plus maze test and Ca²⁺ imaging by two-photon microscope in the somatosensory cortex. We further detected acetamiprid and metabolites in brain and blood an hour after the administration.</p><p>Mice exposed to acetamiprid or nicotine exhibited an increase in anxiety-like behavior that associated with the altered activities of the neuronal population in the somatosensory cortex. Although the dose of acetamiprid used in the current study was below the NOAEL, both acetamiprid and nicotine affected the behavior and the neuronal activity in the somatosensory cortex. The results suggested that in vivo Ca²⁺ imaging using two-photon microscope enabled highly sensitive detection of brain neurodisruption by neurotoxicants.</p>

DOI： 10.14869/toxpt.48.1.0_p-37e

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掲載種別：研究論文（国際会議プロシーディングス）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

DOI： 10.1038/s41598-020-78294-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature  

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.

DOI： 10.1038/s41586-020-2777-8

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

記述言語：日本語   出版者・発行元：(一社)日本毒性学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Communications  

In the developing cortex, postmigratory neurons accumulate in the cortical plate (CP) to properly differentiate consolidating subtype identities. Microglia, despite their extensive surveying activity, temporarily disappear from the midembryonic CP. However, the mechanism and significance of this absence are unknown. Here, we show that microglia bidirectionally migrate via attraction by CXCL12 released from the meninges and subventricular zone and thereby exit the midembryonic CP. Upon nonphysiological excessive exposure to microglia in vivo or in vitro, young postmigratory and in vitro-grown CP neurons showed abnormal differentiation with disturbed expression of the subtype-associated transcription factors and genes implicated in functional neuronal maturation. Notably, this effect is primarily attributed to interleukin 6 and type I interferon secreted by microglia. These results suggest that “sanctuarization” from microglia in the midembryonic CP is required for neurons to appropriately fine-tune the expression of molecules needed for proper differentiation, thus securing the establishment of functional cortical circuit.

DOI： 10.1038/s41467-020-15409-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41467-019-13771-5

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：GLIA  

Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.

DOI： 10.1002/glia.23713

Web of Science

Scopus

PubMed

記述言語：日本語   出版者・発行元：日本毒性学会  

<p>　一部の化学物質は脳内の受容体に作用する事で細胞内、細胞間における情報伝達を攪乱する“シグナル毒性”を示し、予期せぬ影響を引き起こす。特に脳機能は神経細胞やグリア細胞間の複雑なシグナルネットワークが形成されており、このネットワークの攪乱は、シグナル毒性のクリティカルなエンドポイントになり得ると考えられる。しかし、シグナル毒性を起因とする“脳機能の攪乱”は、細胞死やそれに伴う脳組織変性を伴わない場合が多く、現行の神経毒性試験法では検出不可能である。そこで、本研究では、ニコチン性アセチルコリン受容体 (nAChR)のアゴニストであるネオニコチノイド(NNs)およびニコチンをモデル化合物とし、体性感覚野における神経細胞の活動変化を2光子顕微鏡で検出する事で、シグナル毒性に伴う脳機能の攪乱を検出する事を目的とした。</p><p>　まず、C57BL/6Nマウスを用い、アセタミプリド(ACE)をマウスの最小毒性量である20 mg/kgとなるように経口投与し、経時的に採血を行い、LC/MSを用いてACEおよびその代謝産物の血中濃度を定量した。また、ACEを20 mg/kgおよび7.1 mg/kgとなるように経口投与し、投与1時間後にオープンフィールド試験および高架式十字迷路試験をそれぞれ行った。さらに、C57BL/6JマウスにACEを30 mg/kgおよび典型的なnAChRアゴニストであるニコチンをLD50の半分の濃度（1.6 mg/kg）となるように経口投与し、2光子顕微鏡を用いて、体性感覚野における神経細胞の活動を経時的に観察した。</p><p>　結果について、ACEのTmaxは約25分で、主要な代謝産物であるdm-ACEでは約150分であった。ACE投与の1時間後には、マウスの活動性は抑制され、不安様行動が増加した。また、体性感覚野において、ACE投与1時間後および2時間半後に神経細胞の発火頻度が減少し、同期発火が増加した。ニコチン投与直後および30分後には、発火頻度が減少傾向を示し、同期発火が増加した。本結果は、脳神経活動の変化が行動の変化の原因であることを示唆する結果であった。</p>

DOI： 10.14869/toxpt.47.1.0_p-4s

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Communications  

Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

DOI： 10.1038/s41467-019-13812-z

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/mds.27819

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/neup.12560

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/978-981-32-9636-7_4

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/978-1-4939-9658-2_20

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/978-1-4939-9658-2_6

Web of Science

PubMed

掲載種別：研究論文（学術雑誌）  

DOI： 10.1073/pnas.1908361116

Web of Science

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1073/pnas.1811013115

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1364/OL.43.005447

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/glia.23475

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1523/ENEURO.0088-18.2018

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/j.pain.0000000000001248

Web of Science

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Biochemistry  

Electrical activity is essential for brain function. However, neurons, the electrically active cells, are less numerous than the non-electrical glial cells in the central nervous system. The non-electrical components modify the function of neural circuits, depending on the electrical neuronal activity, by wrapping synapses, myelinating axons and phagocytozing the neuronal components. Moreover, recent evidence has suggested that they contribute to neurological and psychiatric disease by regulating neuronal circuits, ultimately affecting their behaviour. In this review, we highlight the physiological functions of glial cells, particularly the electrical activity-dependent processes, to provide further insight into their role in brain function.

DOI： 10.1093/jb/mvy023

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1117/12.2323184

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS INC  

Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated. Here, we show that the reduced mastication resulted in impaired spatial memory and learning function owing to the morphological change and decreased activity in the hippocampus. We used an in vivo model for reduced masticatory stimuli, in which juvenile mice were fed with powder diet and found that masticatory stimulation during the growth period positively regulated long-term spatial memory to promote cognitive function. The functional linkage between mastication and brain was validated by the decrease in neurons, neurogenesis, neuronal activity, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These findings taken together provide in vivo evidence for a functional linkage between mastication and cognitive function in the growth period, suggesting a need for novel therapeutic strategies in masticatory function-related cognitive dysfunction.

DOI： 10.1177/0022034517708771

Web of Science

PubMed

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

J-GLOBAL

J-GLOBAL

J-GLOBAL

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

© 2019 SPIE. Multispots in three-dimensions generated by phase mode spatial light modulators (SLMs) are very useful in laser processing or light induced biological treatments, such as optogenetics. So far, the intensity of the focus spots varies depending to the distance from optical axis. In order to equalize intensities in all generated spots, simple feedback method was applied. Further, look up table was created by dividing imaging area in sectors. Experiment results show improvement in the random spots at some degree, however, further analyzation is required.

Scopus

記述言語：日本語  

J-GLOBAL

記述言語：英語   会議種別：ポスター発表  

開催地：ハワイ, 米国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：茨城  

記述言語：日本語   会議種別：ポスター発表  

開催地：大阪  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋  

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開催地：東京  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：仙台  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：横浜  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：神奈川、横浜  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岡崎  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：東京  

記述言語：英語   会議種別：ポスター発表  

開催地：千葉  

記述言語：英語   会議種別：ポスター発表  

開催地：淡路  

記述言語：英語   会議種別：ポスター発表  

開催地：San Diego, CA  

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：宇都宮  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：神戸  

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：蘇州  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：京都  

記述言語：英語   会議種別：ポスター発表  

開催地：山梨  

記述言語：日本語   会議種別：ポスター発表  

開催地：千葉  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：仙台  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：仙台  

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：Osaka; Japan  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：神戸  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：山梨  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：藤沢  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：京都  

記述言語：英語   会議種別：口頭発表（招待・特別）  

開催地：福岡  

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：神戸  

記述言語：英語   会議種別：ポスター発表  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大阪  

記述言語：英語   会議種別：ポスター発表  

開催地：シュパイヤー  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：大阪  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：淡路  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：シュパイヤー  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：筑波大学東京キャンパス文京校舎,東京  

記述言語：英語   会議種別：ポスター発表  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：淡路  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：香川  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：愛知  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：千葉  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：新潟  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：金沢  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：東京  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：札幌  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：札幌  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：中央  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京  

記述言語：日本語   会議種別：ポスター発表  

開催地：大阪  

記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：兵庫  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：小牧  

記述言語：日本語   会議種別：ポスター発表  

開催地：山梨  

記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：兵庫  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：兵庫  

記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：京都  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：愛知  

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：和歌山  

記述言語：日本語   会議種別：ポスター発表  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：愛知  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大阪  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：和歌山  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：秋田  

記述言語：英語   会議種別：ポスター発表  

開催地：神戸  

記述言語：日本語   会議種別：ポスター発表  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：京都  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（招待・特別）  

開催地：東京  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：東京  

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：横浜  

記述言語：英語   会議種別：ポスター発表  

開催地：新潟