Language：English   Publisher：Pharmacological Research  

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase–activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry “double-hit” mutations in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen‑based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase–targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC. Moreover, fasudil (3–20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

DOI： 10.1016/j.phrs.2022.106589

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease and related tauopathies and has gained prominence in the development of therapies for Alzheimer’s disease. Neuroinflammation plays an important role in the progression of neurodegenerative disorders, and activated astrocytes and microglia strongly influence Aβ and tau pathologies. Numerous transgenic mouse models that recapitulate critical Alzheimer’s disease-like pathology have been developed to examine the pathogenic mechanisms underlying Alzheimer’s disease and evaluate therapeutic approaches targeting tau, but the relevant mechanisms remain unknown. In this study, we investigated changes in gene expression related to neuroinflammation in glial cells of rTg4510 mice, an animal model of non-Alzheimer’s disease tauopathy. First, we analyzed 4- and 6-month-old rTg4510 mice in terms of cognition and behaviors that mimic the behavioral and psychological problems of dementia. Deterioration of executive functions and impairment of daily life activities are early signs of Alzheimer’s disease. In the present study, nest-building behavior, which represents active interaction with the environment, evaluated the executive functions that are the basis of daily life activities. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a greater amount of time in the open arm of the plus-maze test than control mice. We also used magnetic-activated cell sorting to analyze the expressions of genes related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Axl, Cd11c, and CD68 expression levels were increased in microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocytes were also increased in 6-month-old rTg4510 mice compared with control mice. In conclusion, neuroinflammation may be related to neuronal degeneration and abnormal behavior in rTg4510 mice.</p>

DOI： 10.1254/jpssuppl.97.0_2-b-p-037

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Language：English   Publisher：Communications Biology  

Transgenic animals expressing fluorescent proteins are widely used to label specific cells and proteins. By using a split Cre recombinase fused with mCherry-binding nanobodies or designed ankyrin repeat proteins, we created Cre recombinase dependent on red fluorescent protein (RFP) (Cre-DOR). Functional binding units for monomeric RFPs are different from those for polymeric RFPs. We confirmed selective target RFP-dependent gene expression in the mouse cerebral cortex using stereotaxic injection of adeno-associated virus vectors. In estrogen receptor-beta (Esr2)-mRFP1 mice and gastrin-releasing peptide receptor (Grpr)-mRFP1 rats, we confirmed that Cre-DOR can be used for selective tracing of the neural projection from RFP-expressing specific neurons. Cellular localization of RFPs affects recombination efficiency of Cre-DOR, and light and chemical-induced nuclear translocation of an RFP-fused protein can modulate Cre-DOR efficiency. Our results provide a method for manipulating gene expression in specific cells expressing RFPs and expand the repertory of nanobody-based genetic tools.

DOI： 10.1038/s42003-022-03944-2

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Language：English   Publisher：European Journal of Pharmacology  

Current antipsychotics used to treat schizophrenia have associated problems, including serious side effects and treatment resistance. We recently identified a significant association of schizophrenia with exonic copy number variations in the Rho GTPase activating protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice, Arhgap10 gene variations result in RhoA/Rho-kinase pathway activation. We evaluated the pharmacokinetics of fasudil and hydroxyfasudil using liquid chromatography-tandem mass spectrometry in mice. The antipsychotic effects of fasudil on hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits were also investigated in a MK-801-treated pharmacological mouse schizophrenia model. Fasudil and its major metabolite, hydroxyfasudil, were detected in the brain at concentrations above their respective Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 fasudil. Fasudil improved the hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits in MK-801-treated mice in a dose-dependent manner. Following oral administration of fasudil, brain hydroxyfasudil was detected at concentration above the Ki value for Rho-kinase whilst fasudil was undetectable. MK-801-induced hyperlocomotion was also improved by oral fasudil administration. These results suggest that fasudil has antipsychotic-like effects on the MK-801-treated pharmacological mouse schizophrenia model. There are two isoforms in Rho-kinase, and further investigation is needed to clarify the isoforms involved in the antipsychotic-like effects of fasudil in the MK-801-treated mouse schizophrenia model.

DOI： 10.1016/j.ejphar.2022.175207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Pharmacological Sciences  

Vancomycin is a glycopeptide antibiotic that is a primary treatment for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended. Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician's experience and expertise. In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. Although small training sets were used, we established a predictive model with a target attainment rate comparable to those of experts, another ML model, and commonly used vancomycin dosing software. Our strategy will help develop an expert-like predictive model that aids in decision making for initial vancomycin dosing, particularly in settings where dose planning consultations are unavailable.

DOI： 10.1016/j.jphs.2022.02.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Reelin is an extracellular matrix protein that is mainly produced in Cajal-Retzius cells and controls neuronal migration, which is important for the proper formation of cortical layers in the developmental stage of the brain. In the adult brain, Reelin plays a crucial role in the regulation of N-methyl-D-aspartate receptor-dependent synaptic function, and its expression decreases postnatally. Clinical studies showed reductions in Reelin protein and mRNA expression levels in patients with psychiatric disorders; however, the causal relationship remains unclear. Reelin-deficient mice exhibit an abnormal neuronal morphology and behavior, while Reelin supplementation ameliorates learning deficits, synaptic dysfunctions, and spine loss in animal models with Reelin deficiency. These findings suggest that the neuronal deficits and brain dysfunctions associated with the down-regulated expression of Reelin are attenuated by enhancements in its expression and functions in the brain. In this review, we summarize findings on the role of Reelin in neuropsychiatric disorders and discuss potential therapeutic approaches for neuropsychiatric disorders associated with Reelin dysfunctions.

DOI： 10.3390/ijms23031829

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Behavioural Brain Research  

The Reelin gene (RELN) encodes a large extracellular protein, which has multiple roles in brain development and adult brain function. It activates a series of neuronal signal transduction pathways in the adult brain that function in synaptic plasticity, dendritic morphology, and cognitive function. To further investigate the roles of Reln in brain function, we generated a mouse line using the C57BL/6 J strain with the specific Reln deletion identified from a Japanese patient with schizophrenia (Reln-del mice). These mice exhibited abnormal sociality, but the pathophysiological significance of the Reln deletion for higher brain functions, such as learning and behavioral flexibility remains unclear. In this study, cognitive function in Reln-del mice was assessed using touchscreen-based visual discrimination (VD) and reversal learning (RL) tasks. Reln-del mice showed normal learning in the simple VD task, but the learning was delayed in the complex VD task as compared to their wild-type (WT) littermates. In the RL task, sessions were divided into early perseverative phase (sessions with <50% correct) and later learning phase (sessions with ≥50% correct). Reln-del mice showed normal perseveration but impaired relearning ability in both simple RL and complex RL task as compared to WT mice. These results suggest that Reln-del mice have impaired learning ability, but the behavioral flexibility is unaffected. Overall, the observed behavioral abnormalities in Reln-del mice suggest that this mouse model is a useful preclinical tool for investigating the neurobiological mechanism underlying cognitive impairments in schizophrenia and a therapeutic strategy.

DOI： 10.1016/j.bbr.2021.113569

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Orexin neurons in the hypothalamus regulate physiological functions, including energy homeostasis and wakefulness, and are also related to motivation. Here, we examined the roles of orexin neurons in motivated behaviors. We measured the activities of orexin neurons using fiber photometry under a free-moving condition, in which the rats were subjected to the fixed ratio (FR) or progressive ratio (PR) schedule of a touchscreen-based automated operant task. To measure the activities of orexin neurons, AAV-FLEX-GCaMP7s was injected into the hypothalamus of Orexin-Cre rats. We found that under FR5 conditions in which rats were able to obtain a food pellet by touching the screen consecutively five times, the activity in orexin neurons was increased after the fifth screen touch (after which one food pellet is delivered). The activity peaked before rats obtained reward, and then decreased after food intake. Next, we included non-reward trials in the FR5 test in which the rat was not able to earn reward even after touching the screen five times. The orexin activities in non-reward trials were also increased after the fifth screen touch, but the decrease after food intake was diminished compared to those in reward-trials. In the PR schedule test, the orexin activities were gradually increased. Together, these observations suggest that the orexin activities are associated with motivational behaviors, and that orexin neurons may be involved in craving and reward prediction, and satisfaction.</p>

DOI： 10.1254/jpssuppl.95.0_1-ss-08

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Interferon-induced transmembrane protein-3 (IFITM3) belongs to the IFITM family, which comprises five and seven subtypes in humans and mice, respectively. IFITM proteins participate in various biological processes such as the immune response, including suppression of viral infection. While the immune response is associated with the pathology and development of Alzheimer's disease (AD), it is unknown whether this response is beneficial or harmful. Recently, IFITM3 was found to be a γ-secretase modulatory protein, a type of protein associated with the generation of amyloid b (Aβ). However, further research is needed to determine whether IFITM3 is associated with abnormal behaviors, including cognitive impairment in AD, and whether it may be a new molecular target for AD therapy. Since our final goal is to clarify the role of IFITM3 in an animal model of AD, in this study we used <i>App-KI </i>mice, which overproduce Aβ-42 without overexpressing amyloid precursor protein, to examine changes in IFITM3 expression. The cortex, dentate gyrus (DG), and CA3 regions of 4- and 8-month-old <i>App-KI</i> mice exhibited Aβ accumulation and also increased IFITM3 expression. Expressions of astrocytes and microglia were age-dependently increased around Aβ plaques. Notably, IFITM3 expression colocalized with astrocytes, which were situated near Aβ in all brain regions of 8-month-old <i>App-KI </i>mice. These results suggest that IFITM3 is increased in astrocytes and is accompanied by Aβ accumulation.</p>

DOI： 10.1254/jpssuppl.96.0_1-b-p-333

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

DOI： 10.3390/ijms22115549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurochemistry International  

Reelin, an extracellular matrix protein, is secreted by Cajal-Retzius cells and plays crucial roles in the development of brain structures and neuronal functions. Reductions in Reelin cause the brain dysfunctions associated with mental disorders, such as schizophrenia. A recent genome-wide copy number variation analysis of Japanese schizophrenia patients identified a novel deletion in RELN encoding Reelin. To clarify the pathophysiological role of the RELN deletion, we developed transgenic mice carrying the RELN deletion (Reln-del) and found abnormalities in their brain structures and social behavior. In the present study, we performed an in vitro analysis of Reelin expression, intracellular Reelin signaling, and the morphology of primary cultured cortical neurons from wild-type (WT) and Reln-del mice. Reelin protein levels were lower in Reln-del neurons than in WT neurons. Dab1 expression levels were significantly higher in Reln-del neurons than in WT neurons, suggesting that Reelin signaling was decreased in Reln-del neurons. Reelin was mainly expressed in γ-aminobutyric acid (GABA)-ergic inhibitory neurons, but not in parvalbumin (PV)-positive neurons. A small proportion of Ca2+/calmodulin-dependent protein kinase II α subunit (CaMKIIα)-positive excitatory neurons also expressed Reelin. In comparisons with WT neurons, significant decreases were observed in neurite lengths and branch points as well as in the number of postsynaptic density protein 95 (PSD95) immunoreactive puncta in Reln-del neurons. A disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3) is a protease that inactivates Reelin by cleavage at the N-t site. The knockdown of ADAMTS-3 by short hairpin RNAs suppressed Reelin cleavage in conditioned medium and reduced Dab1 expression, indicating that Reelin signaling was enhanced in the primary cultured cortical neurons of WT and heterozygous Reln-del. Accordingly, the inhibition of ADAMTS-3 may be a potential candidate in the clinical treatment of schizophrenia by enhancing Reelin signaling in the brain.

DOI： 10.1016/j.neuint.2020.104954

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Science  

The neural mechanisms underlying memory regulation during sleep are not yet fully understood.We found that melanin concentrating hormone-producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs.Wake- and REM sleep- active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state-dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep-active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

DOI： 10.1126/science.aax9238

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurochemistry International  

The ventral pallidum (VP) is a critical component of the basal ganglia neurocircuitry regulating learning and decision making; however, its precise role in controlling associative learning of environmental stimuli conditioned to appetitive or aversive outcomes is still unclear. Here, we investigated the expression of preproenkephalin, a polypeptide hormone previously shown to be expressed in nucleus accumbens neurons controlling aversive learning, within GABAergic and glutamatergic VP neurons. Next, we explored the behavioral consequences of chemicogenetic inhibition or excitation of preproenkephalin-expressing VP neurons on associative learning of reward- or aversion-paired stimuli in autoshaping and inhibitory avoidance tasks, respectively. We reveal for the first time that preproenkephalin is expressed predominantly in GABAergic rather than glutamatergic VP neurons, and that excitation of these preproenkephalin-expressing VP neurons was sufficient to impair inhibitory avoidance learning. These findings indicate the necessity for inhibition of preproenkephalin-expressing VP neurons for avoidance learning, and suggest these neurons as a potential therapeutic target for psychiatric disorders associated with maladaptive aversive learning.

DOI： 10.1016/j.neuint.2019.02.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Psychological stresses such as social loss and separation during childhood induce hardship, referred to as emotional pain. These experiences are well-documented risk factors for the development of physical pain in adulthood. However, the underlying neuronal mechanisms of this exacerbation of pain are largely unknown, and consequently there is no effective pharmacotherapy. In this study, we sought to determine whether infant maternal separation (MS) contributes to aggravation of neuropathic pain in adult mice. MS increased anxiety- and depression-like behavioral responses to adult stress. In MS animals, chronic constriction injury (CCI) heightened the sensory dimension of chronic pain relative to that of control mice. However, MS mice treated with fluoxetine for 4 weeks after MS did not exhibit augmentation of allodynia, and their emotional response was attenuated. Microglia were more abundant in the spinal cord in MS/CCI mice than in control/CCI mice. These results suggest that emotional impairment is related to augmentation of neuropathic pain, and that dysfunction of microglial activation contributes to heightened pain sensitivity.

DOI： 10.1016/j.bbr.2018.06.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Patients suffering from neuropsychiatric disorders such as substance use and addiction disorders show impaired decision-making, which may be associated with their psychiatric disorders. Previously, using a gambling test for rodents, we demonstrated that methamphetamine-dependent rats showed alterations in their decision-making strategy. In this study, we investigated the effect of nicotine on impaired decision-making strategy in rats which have been treated repeatedly with methamphetamine. Nicotine has previously been shown to have therapeutic effects on attentional and cognitive abnormalities in psychosis. Rats were administered methamphetamine subcutaneously (sc) at 4 mg/kg once a day, for 30 days, and their decision-making was then assessed with a rodent gambling task. We found that methamphetamine-treated rats preferred the high-risk/high-return actions, which is consistent with our previous findings. Methamphetamine-induced impairment of decision-making was reversed by daily nicotine treatment (0.3 mg/kg, sc). This effect was associated with the reduction of lose-shift behavior after negative reward prediction error. Repeated treatment with nicotine had no effects on arm-choice behavior in naïve rats. Varenicline, an α4β2-nicotinic acetylcholine receptor partial agonist, also ameliorated the altered decision-making in methamphetamine-treated rats. Our findings suggest that nicotine treatment is useful for ameliorating the altered decision-making caused by methamphetamine treatment, and that the α4β2-nicotinic acetylcholine receptor is a therapeutic target for poor decision-making.

DOI： 10.1016/j.bbr.2018.06.016

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Language：Japanese   Publisher：The Japanese Pharmacological Society  

<p>Decision-making is a key activity process that influences many aspects of daily living and both mental and physical health. In general, healthy participants reveal rational choice, but patients with neuropsychiatric disorders reveal irrational and risky choice in decision-making. Addiction is one of typical diseases revealed risky decision-making, addicts select risky action and options that confer short-term rewards at the cost of long-term disadvantages. Thus, irrational and risky decision-making is recognized as a core problem in patients with neuropsychiatric disorders, and a better understanding of the mechanisms underlying altered decision-making would provide insights into potential therapeutic approaches for these diseases. However, the neural pathway and substrates underlying these deficits are particularly unknown. Recently, we found that insular cortex is one of key regions for risky decision-making in an animal model of methamphetamine addiction, by using the designer receptor exclusively activated by designer drug (DREADD) technology, and that GABAergic dysfunction in insular cortex is involved in evaluating the subjective value of reward and reward prediction error. These brain dysfunctions would be related to risk taking behavior in addiction. In this review, we introduced the possible neural pathway related to risky decision-making and behavioral changes in choice strategy using adeno associated virus (AAV).</p>

DOI： 10.1254/fpj.153.224

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Alzheimer's disease (AD) is a progressive disease characterized by loss of memory and other important mental functions. Accumulation of amyloid beta (Aβ) and fibrillary tangles are the main pathological hallmarks of this disease. Emerging data suggest that the disease process begins years before clinical diagnostic confirmation; thus, methods to improve early detection would provide opportunities for early intervention to delay progressive cognitive decline and disease onset. In our research we assessed the cognitive abilities of <i>APP</i>^{<i>NL-G-F/NL-G-F</i>} knock-in (<i>APP-</i>KI) mice with a touch screen-based automated test battery and water maze test. These tests are mainly dependent on the brain regions that are prone to Aβ accumulation at the earliest stages of the disease. We subjected male 6- and 11-months old <i>APP-</i>KI mice in water maze test where only older mice showed significantly worsened behavior than wild-type mice. However, using touchscreen based behavioral test it was possible to detect cognitive impairment in <i>APP-</i>KI mice at an early (4 months) stage while classical behavioral tests shows comparable results between wild-type and disease model mice. </p>

DOI： 10.1254/jpssuppl.92.0_1-p-041

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Decision making in complex and uncertain situations is a fundamental adaptive process resulting from the integration of several executive functions. Impaired decision-making is a symptomatic feature of a number of psychiatric disorders. In general, patients with psychiatric disorders show a propensity to prefer actions associated with large short-term gains but long-term losses preferentially to those associated with small but long-term gains. They are more likely to select risky options and show an altered temporal horizon of risks and benefits. Moreover, clinical studies report that dopamine therapy induce impaired decision-making in patients with dopaminergic dysfunction such as Parkinson's disease and Redox-less syndrome. Thus, to establish and optimize the animal model of impaired decision-making is important for development of new therapeutic strategy in these disorders.</p><p>To clarify the underlying neurobiology of decision-making, we conducted a study in healthy mice by using a mouse gambling operant test based on uncertainty and conflicting choices. Mice chose the low-risk / low-reward option on the reward amount- and provability-dependent manner. Our findings suggest that healthy mice prefer risk-aversive choice in this operant test as dose man in Iowa gambling test.</p>

DOI： 10.1254/jpssuppl.92.0_1-p-023

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Language：Japanese   Publisher：The Japanese Psychological Association  

DOI： 10.4992/pacjpa.82.0_ss-029

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DOI： 10.1016/j.jns.2017.08.2013

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Language：Japanese   Publisher：公益社団法人 日本薬学会  

前頭前皮質は高次の学習記憶を司る脳部位であり，ニコチン性アセチルコリン受容体(nAChR)を介したアセチルコリン神経の投射・支配を受けている．統合失調症などの精神疾患患者は，前頭前皮質の機能が低下(hypofrontality)しており，また，喫煙率が高い傾向がある．最近，ゲノムワイド関連解析により，nAChRのα5サブユニットを司るヒト<i>CHRNA5</i>遺伝子に一塩基多型(SNP)が存在することが分かり，この変異が喫煙や統合失調症のリスクを高める可能性が報告された．基礎研究においても，マウスのα5サブユニット遺伝子を欠損させると，前頭前皮質の形態学的変化や行動に異常が生じることが報告されているが，ヒト遺伝子多型が，細胞活性あるいは神経回路にどのような影響をもたらすのか，さらには統合失調症患者で観察されるような行動障害や，hypofrontalityを引き起こすかは不明である．<br>本稿では，ヒトα5サブユニット変異体(α5SNP)を発現するマウスを用いて，α5SNPがもたらす皮質機能障害について検討したKoukouliらの研究を紹介する．<br>なお，本稿は下記の文献に基づいて，その研究成果を紹介するものである.<br>1) Tobacco and Genetics Consortium., <i>Nat</i>. <i>Genet</i>., <b>42</b>, 441–447(2010).<br>2) Schizophrenia Working Group of the Psychiatric Genomics Consortium., <i>Nature</i>, <b>511</b>, 421–427(2014).<br>3) Proulx E. <i>et</i> <i>al</i>., <i>Cell</i>. <i>Mol</i>. <i>Life</i> <i>Sci</i>., <b>71</b>, 1225-1244(2014).<br>4) Koukouli F. <i>et</i> <i>al</i>., <i>Nat</i>. <i>Med</i>., <b>23</b>, 347–354(2017).

DOI： 10.14894/faruawpsj.53.9_923

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Language：English   Publisher：Neurobiology of Aging  

Emerging evidence suggests that axonal degeneration is a disease mechanism in various neurodegenerative diseases and that the paranodes at the nodes of Ranvier may be the initial site of pathogenesis. We investigated the pathophysiology of the disease process in the central and peripheral nervous systems of a Caspr mutant mouse, shambling (shm), which is affected by disrupted paranodal structures and impaired nerve conduction of myelinated nerves. The shm mice manifest a progressive neurological phenotype as mice age. We found extensive axonal degeneration and a loss of neurons in the central nervous system and peripheral nervous system in aged shm mice. Axonal alteration of myelinated nerves was defined by abnormal distribution and expression of neurofilaments and derangements in the status of phosphorylated and non/de-phosphorylated neurofilaments. Autophagy-related structures were also accumulated in degenerated axons and neurons. In conclusion, our results suggest that disrupted axon-glia interactions at the paranode cause the cytoskeletal alteration in myelinated axons leading to neuronal cell death, and the process involves detrimental autophagy and aging as factors that promote the pathogenesis.

DOI： 10.1016/j.neurobiolaging.2016.03.020

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DOI： 10.1681/ASN.2014121196

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

DOI： 10.1073/pnas.1418014112

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We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele. Accordingly, we generated a mouse model (Arhgap10 S490P/NHEJ mice) carrying a missense variant and a coexisting frameshift mutation. We examined the spatiotemporal expression of Arhgap10 mRNA in the brain and found the highest expression levels in the cerebellum, striatum, and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in Arhgap10 S490P/NHEJ mice compared with wild-type littermates. Arhgap10 S490P/NHEJ mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination learning between Arhgap10 S490P/NHEJ and wild-type mice, but a significant impairment of visual discrimination was evident in Arhgap10 S490P/NHEJ mice but not wild-type mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of Arhgap10 S490P/NHEJ mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality of neurons in the striatum and NAc, which may be associated with vulnerability of cognition to methamphetamine treatment.

DOI： 10.1186/s13041-021-00735-4

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

DOI： 10.1186/s40478-020-01099-x

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Brain  

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline with accumulation of amyloid beta (Aβ) and neurofibrillary tangles that usually begins 15–30 years before clinical diagnosis. Rodent models that recapitulate aggressive Aβ and/or the pathology of neurofibrillary tangles are essential for AD research. Accordingly, non-invasive early detection systems in these animal models are required to evaluate the phenotypic changes, elucidate the mechanism of disease progression, and facilitate development of novel therapeutic approaches. Although many behavioral tests efficiently reveal cognitive impairments at the later stage of the disease in AD models, it has been challenging to detect such impairments at the early stage. To address this issue, we subjected 4–6-month-old male AppNL−G−F/NL−G−F knock-in (App-KI) mice to touchscreen-based location discrimination (LD), different object–location paired-associate learning (dPAL), and reversal learning tests, and compared the results with those of the classical Morris water maze test. These tests are mainly dependent on the brain regions prone to Aβ accumulation at the earliest stages of the disease. At 4–6 months, considered to represent the early stage of disease when mice exhibit initial deposition of Aβ and slight gliosis, the classical Morris water maze test revealed no difference between groups, whereas touchscreen-based LD and dPAL tasks revealed significant impairments in task performance. Our report is the first to confirm that a systematic touchscreen-based behavioral test battery can sensitively detect the early stage of cognitive decline in an AD-linked App-KI mouse model. This system could be applied in future translational research.

DOI： 10.1186/s13041-020-00690-6

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurochemistry International  

Methamphetamine is a widely abused psychostimulant. It reverses transport through the dopamine transporter, thereby increasing the extracellular level of dopamine in the brain, which is associated with the rewarding effect. Repeated intake of methamphetamine leads to drug addiction, a chronically relapsing disorder characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. The molecular and cellular mechanisms of drug addiction are not well understood, but have been proposed to involve neural plasticity and the remodeling of specific brain circuits. Accumulating evidence also indicates that patients addicted to methamphetamine exhibit impaired cognitive functions such as executive function, attention, social cognition, flexibility, and working memory. Furthermore, decision-making is altered in patients with drug addiction, including methamphetamine abusers. Cognitive impairment as well as altered decision-making in methamphetamine abusers may contribute to the high rate of relapse even after long-term withdrawal with psychosocial support. In this article, we review the effect of methamphetamine on cognition and decision-making in rodents. We also discuss possible mechanisms underlying cognition and decision-making impairments, including neuronal circuits, molecular and cellular events, and action control, as well as potential therapeutic targets.

DOI： 10.1016/j.neuint.2018.12.019

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neurobiolaging.2016.03.020.

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor β (TRβ) gene. TRβ is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.

DOI： 10.1016/j.psyneuen.2014.05.021

Language：English   Publishing type：Research paper (scientific journal)  

Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.

DOI： 10.1371/journal.pone.0103458

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease is a progressive neurodegenerative disorder. Amyloid β, a neurotoxic protein, causes disruption of hippocampal synaptic plasticity, and induces cognitive impairment in Alzheimer's disease. We previously revealed that fingolimod, a new oral immunosuppressant used to treat multiple sclerosis, ameliorates oligomeric amyloid β-induced neuronal damage via up-regulation of neuronal brain-derived neurotrophic factor (BDNF). Here, we showed that oral administration of fingolimod ameliorated the impairment in object recognition memory and associative learning in mice injected with amyloid β. This effect was associated with restoration of normal BDNF expression levels in the cerebral cortices and hippocampi, suggesting that neuroprotection was mediated by up-regulation of neuronal BDNF levels. Therefore, fingolimod may provide therapeutic effects in patients with Alzheimer's disease.

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors, which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy.

Language：English   Publishing type：Research paper (scientific journal)  

Interferon-induced transmembrane protein 3 (IFITM3) ıplays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long-lasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)-induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:C-ACM-induced neurodevelopmental abnormalities were alleviated by ifitm3(-/-) astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3(-) (/) (-) mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

DOI： 10.1002/glia.22461

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ(1-40) or the control peptide Aβ(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.

Language：English   Publishing type：Research paper (scientific journal)  

Several clinical studies have demonstrated a consistent relationship between changes in meteorological factors, particularly barometric pressure, and pain intensity in subjects with chronic pain. We have previously demonstrated that exposure to artificially low barometric pressure (LP) intensifies pain-related behaviors in rats with neuropathic pain. In the present study, guinea pigs with unilateral L5 spinal nerve ligation (SNL) were placed in a pressure-controlled chamber and subjected to LP of 10 or 27hPa below the ambient pressure. The SNL surgery led to increased hindpaw withdrawal frequencies to 34-, 59-, and 239-mN von Frey filaments (VFFs). When the SNL animals were subjected to both LP exposures consecutively, the hindpaw withdrawal frequencies further increased; the effect was most significant when the animals were exposed to LP 27hPa below ambient pressure. In contrast, no change was seen in a group of sham-operated control animals. These results indicate that fluctuations in LP within the range of natural weather patterns can potentiate neuropathic pain in guinea pigs.

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese  

Authorship：Lead author   Language：Japanese  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

AIM:To examine the effect of irsogladine, a novel antiulcer drug, on the mucosal ulcerogenic response to monochloramine (NH(2)Cl) in rat stomach, in comparison with rebamipide, another antiulcer drug with cytoprotective a ctivity.METHODS AND RESULTS:Oral administration of NH(2)Cl-(120mM) produced severe hemorrhagic lesions in unanesthetized rat stomachs.Both irsogladine (1mg/kg-10mg/ kg,po) and rebamipide (30mg/kg-100mg/kg, po) dose dependently prevented the development of these lesions in response to NH(2)Cl, the effect of irsogladine was significant at 3mg/kg or greater, and that of rebamipide only at 100mg/kg. The protective effect of irsogladine on NH(2)Cl induced gastric lesions was significantly reduced by N( G) nitro L arginine methyl ester (L-NAME) but not by indomethacin, while that of rebamipide was significantly mitigated by indomethacin but not by L-NAME. Topical application of NH(2)Cl-(20mM)caused a marked reduction of potential difference (PD) in exvivo stomachs. This PD reduction was not affected by mucosal application of irso-gladine, but significantly prevented by rebamipide. The mucosal exposure to NH(4)OH (120mM) also caused a marked PD reduction in the ischemic stomach (bleeding from the carotid artery), resulting in gastric lesions. These ulcerogenic and PD responses caused by NH(4)OH plus ischemia were also significantly mitigated by rebamipide, in an indomethacin sensitive manner, while irsogladine potently prevented such lesions without affecting the PD response, in a L-NAME sensitive manner.CONCLUSION:These results suggest that (1)NH(2)Cl gen-erated either exogenously or endogenously damages the gastric mucosa, (2)both irsogladine and rebamipide protect the stomach against injury caused by NH(2)Cl,and (3)the mechanism underlying the protective action of irsogladine is partly mediated by endogenous nitric oxide, while that of rebamipide is in part mediated by endogenous prostaglandins.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1681/ASN.2014121196

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：NATL ACAD SCIENCES  

Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders exhibit altered decision-making patterns, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. Using a gambling test, we demonstrated that methamphetamine (METH)-treated rats chose a high-risk/high-reward option more frequently and assigned higher value to high returns than control rats, suggestive of changes in decision-making choice strategy. Immunohistochemical analysis following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-treated animals. Pharmacological studies, together with in vivo microdialysis, showed that the insular neural system played a crucial role in decision-making. Moreover, manipulation of INS activation using designer receptor exclusively activated by designer drug technology resulted in alterations to decision-making. Our findings suggest that the INS is a critical region involved in decision-making and that insular neural dysfunction results in risk-taking behaviors associated with altered decision-making.

DOI： 10.1073/pnas.1418014112

Web of Science

Event date： 2021.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：Web会議（津）  

Event date： 2021.12

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Event date： 2021.6

Language：English   Presentation type：Oral presentation (general)  

Event date： 2021.3

Language：Japanese  

Event date： 2020.10 - 2020.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Event date： 2020.8 - 2020.9

Language：Japanese  

Event date： 2020.7 - 2020.8

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Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2017.9

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Venue：横浜   Country：Japan  

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Venue：京都市   Country：Japan  

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Venue：京都   Country：Japan  

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Venue：千葉市   Country：Japan  

Event date： 2017.7

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Venue：千葉   Country：Japan  

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Venue：名古屋   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

Event date： 2014.12

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Country：Japan  

Event date： 2014.11

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Venue：名古屋   Country：Japan  

Event date： 2014.9

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Venue：京都   Country：Japan  

Event date： 2014.9

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Venue：奈良   Country：Japan  

Event date： 2014.7

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Venue：北九州   Country：Japan  

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Venue：北九州   Country：Japan  

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Venue：東京   Country：Japan  

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Venue：福岡   Country：Japan  

Event date： 2012.10

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Country：United States  

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Venue：札幌   Country：Japan  

Event date： 2012.9

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Country：Japan  

Event date： 2012.9

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Venue：名古屋   Country：Japan  

Event date： 2012.9

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Country：Japan  

Event date： 2012.7

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Country：Spain  

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Country：Spain  

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Country：Spain  

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Venue：京都   Country：Japan  

Event date： 2012.3

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Venue：京都   Country：Japan  

Event date： 2012.2

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Venue：名古屋   Country：Japan  

Event date： 2012.2

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Venue：名古屋   Country：Japan  

Event date： 2011.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都   Country：Japan  

Event date： 2011.10

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Event date： 2011.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2011.10

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Country：Japan  

Event date： 2011.9

Language：English   Presentation type：Oral presentation (general)  

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Venue：名古屋   Country：Japan  

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Venue：豊中   Country：Japan  

Event date： 2010.11

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Country：United States  

Event date： 2010.11 - 2011.11

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Venue：東京   Country：Japan  

Event date： 2010.10

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Venue：北九州   Country：Japan  

Event date： 2010.7

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Event date： 2010.1

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Venue：岡崎   Country：Japan  

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Venue：四日市   Country：Japan  

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Venue：つくば   Country：Japan  

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Venue：名古屋   Country：Japan  

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Venue：Chicago   Country：United States  

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Venue：新潟   Country：Japan  

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Venue：金沢   Country：Japan  

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Venue：東京   Country：Japan  

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Event date： 2008.9

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Country：Japan  

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Country：Japan  

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Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.11

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Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

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Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.11

Language：English   Presentation type：Poster presentation  

Country：United States  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.9

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.9

Language：English   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.7

Language：Japanese  

Country：Japan  

Event date： 2007.7

Language：English   Presentation type：Oral presentation (general)  

Event date： 2007.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.7

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.7

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.6

Language：Japanese   Presentation type：Poster presentation  

Country：Japan  

Event date： 2007.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.3

Language：Japanese  

Country：Japan  

Event date： 2007.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.3

Language：English  

Country：Japan  

Event date： 2007.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.12

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.10

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.7

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2006.2

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.12

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.11

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.11

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.8

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.7

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.6

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.6

Language：English   Presentation type：Oral presentation (general)  

Event date： 2005.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.3

Language：Japanese   Presentation type：Oral presentation (general)  

Event date： 2005.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2005.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.6

Language：Japanese  

Country：Japan  

Event date： 2004.5

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.2

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2004.2

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.8

Language：English   Presentation type：Oral presentation (general)  

Event date： 2003.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.7

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.5

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.3

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2003.2

Language：Japanese  

Country：Japan  

Event date： 2002.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2002.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2002.10

Language：Japanese  

Country：Japan  

Event date： 2002.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2002.10

Language：English   Presentation type：Oral presentation (general)  

Event date： 2002.8

Language：Japanese  

Country：Japan  

Event date： 2002.4

Language：Japanese  

Country：Japan  

Event date： 2002.3

Language：English  

Event date： 2002.3

Language：English  

Country：Japan  

Event date： 2002.2

Language：Japanese  

Event date： 2001.9

Language：Japanese  

Country：Japan  

Event date： 2001.7

Language：Japanese  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都市  

Language：English   Presentation type：Symposium, workshop panel (nominated)  

Venue：千葉市  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：千葉  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Poster presentation  

Venue：京都  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸  

脳科学と疾患の授業（2コマ）を行った。