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FURUYASHIKI TomoyukiGraduate School of Medicine / Faculty of Medical SciencesProfessor
Research activity information
■ Award- Oct. 2024 神戸大学, 学長表彰
- May 2024 CINP (International College of Neuropsychopharmacology), CINP Sumitomo Pharma Brain Health Basic Research Award
- Oct. 2023 神戸大学, 学長表彰
- Oct. 2022 神戸大学, 学長表彰
- Oct. 2021 神戸大学, 学長表彰
- Oct. 2020 神戸大学, 学長表彰
- Oct. 2019 神戸大学, 学長表彰
- Oct. 2018 Kobe University, President's award
- Nov. 2015 Astellas Foundation for Research on Metabolic Disorders, Best President’s Award
- Mar. 2012 The Japanese Pharmacological Society, 27th Young Investigator Award
- Feb. 2025, Journal of Pharmacological SciencesScientific journal
- Chronic stress induces neural dysfunctions and risks mental illnesses. Clinical and preclinical studies have established the roles of brain regions underlying emotional and cognitive functions in stress and depression. However, neural pathways to perceive sensory stimuli as stress to cause behavioral disturbance remain unknown. Using whole-brain imaging of Arc-dVenus neuronal response reporter mice and machine learning analysis, here we unbiasedly demonstrated different patterns of contribution of widely distributed brain regions to neural responses to acute and chronic social defeat stress (SDS). Among these brain regions, multiple sensory cortices, especially the piriform (olfactory) cortex, primarily contributed to classifying neural responses to chronic SDS. Indeed, SDS-induced activation of the piriform cortex was augmented with repetition of SDS, accompanied by impaired odor discrimination. Axonal tracing and chemogenetic manipulation showed that excitatory neurons in the piriform cortex directly project to the lateral septum and activate it in response to chronic SDS, thereby inducing behavioral disturbance. These results pave the way for identifying a spatially defined sequence of neural consequences of stress and the roles of sensory pathways in perceiving chronic stress in mental illness pathology.Dec. 2024, Neuropsychopharmacology, English, International magazineScientific journal
- Atrial fibrillation (AF) is strongly associated with strokes, heart failure, and increased mortality. This study aims to identify the monocyte-macrophage heterogeneity and interactions of these cells with non-immune cells, and to identify functional biomarkers in patients with AF. Therefore, we assess the single cell landscape of left atria (LA), using a combination of single cell and nucleus RNA-seq. Myeloid cells in LA tissue are categorized into five macrophage clusters, three monocyte clusters, and others. Cell-Chat analysis revealed that monocytes and IL1B+ macrophages send epidermal growth factor (EGF) signals to fibroblasts. Amphiregulin (AREG) is the most upregulated gene in monocytes and IL1B+ macrophages in the AF group, compared with healthy controls from other groups. Serum AREG levels are higher in patients with persistent AF. These data suggested that EGF signaling pathway could be a therapeutic target for AF and serum AREG levels provide an effective biomarker for predicting persistent AF.Dec. 2024, Communications biology, 7(1) (1), 1601 - 1601, English, International magazineScientific journal
- Nov. 2024, Neuroscience research, English, International magazine
- Mental disorders have become one of the most burdensome health concerns. We have previously demonstrated that whey-derived β-lactolin (glycine-thereonine-tryptophan-tyrosine tetrapeptide) activates dopaminergic systems and improves psychiatric function in rodents. However, the effects of β-lactolin on human mood states have not been investigated. This randomized, double-blind, placebo-controlled study aimed to evaluate the effects of supplementation with β-lactolin-rich whey peptide on human mood states. Sixty healthy adults (aged 45-64 years) with relatively low psychological health were randomly allocated to receive either whey peptide (containing β-lactolin 1.6 mg/day) or placebo for 6 weeks. Mood states (primary outcomes) were evaluated using self-reporting questionnaires. Health-related quality of life (QOL), salivary stress marker and lipid mediator levels were evaluated as secondary outcomes. Compared with placebo, supplementation with β-lactolin improved changes in trait anxiety (p = 0.046), as assessed using the state-trait anxiety inventory, and in subjective stress (p = 0.043), as assessed using the Perceived Stress Scale. In the assessment of QOL, changes in the vitality subscale and mental health summary score of the 36-Item Short-Form Health Survey were improved in the β-lactolin group. The levels of salivary immunoglobulin A were significantly higher in the β-lactolin group. In a subgroup analysis by median age (54.5 years), subjective stress and salivary prostaglandin levels were significantly decreased by β-lactolin supplementation in the 45-54 -year-old subgroup. In conclusion, supplementation with β-lactolin improves trait anxiety, subjective stress, and psychological QOL, which may be associated with immunologic responses detected via salivary analysis.Oct. 2024, Scientific reports, 14(1) (1), 23444 - 23444, English, International magazineScientific journal
- There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B+ inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B+ inflammatory macrophages differentiated from S100A8/9/12+ classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.Jun. 2024, Scientific reports, 14(1) (1), 14893 - 14893, English, International magazineScientific journal
- BACKGROUND: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS. METHODS: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45+ immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis. RESULTS: CD4+ T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7+ (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3)+ regulatory CD4+ T cells. The proportion of central memory CD4+ T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4+ T cells into effector CD4+ T cells and that from naive CD4+ T cells into central memory CD4+ T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4+ T cells. CONCLUSIONS: For the first time, we revealed single cell-level characteristics of CD4+ T cells in patients with ACS. CD4+ T cells could be therapeutic targets of ACS. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN000040747.May 2024, Arteriosclerosis, thrombosis, and vascular biology, 44(5) (5), 1135 - 1143, English, International magazineScientific journal
- Despite the importance of lipid mediators in stress and depression and their link to inflammation, the influence of stress on these mediators and their role in inflammation is not fully understood. This study used RNA-seq, LC-MS/MS, and flow cytometry analyses in a mouse model subjected to chronic social defeat stress to explore the effects of acute and chronic stress on lipid mediators, gene expression, and cell population in the bone marrow and spleen. In the bone marrow, chronic stress induced a sustained transition from lymphoid to myeloid cells, accompanied by corresponding changes in gene expression. This change was associated with decreased levels of 15-deoxy-d12,14-prostaglandin J2, a lipid mediator that inhibits inflammation. In the spleen, chronic stress also induced a lymphoid-to-myeloid transition, albeit transiently, alongside gene expression changes indicative of extramedullary hematopoiesis. These changes were linked to lower levels of 12-HEPE and resolvins, both critical for inhibiting and resolving inflammation. Our findings highlight the significant role of anti-inflammatory and pro-resolving lipid mediators in the immune responses induced by chronic stress in the bone marrow and spleen. This study paves the way for understanding how these lipid mediators contribute to the immune mechanisms of stress and depression.Apr. 2024, Journal of pharmacological sciences, 154(4) (4), 279 - 293, English, Domestic magazineScientific journal
- Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation.Feb. 2024, Scientific reports, 14(1) (1), 4178 - 4178, English, International magazineScientific journal
- "Preprocessing" is the first step required in brain image analysis that improves the overall quality and reliability of the results. However, it is computationally demanding and time-consuming, particularly to handle and parcellate complicatedly folded cortical ribbons of the human brain. In this study, we aimed to shorten the analysis time for data preprocessing of 1410 brain images simultaneously on one of the world's highest-performing supercomputers, "Fugaku." The FreeSurfer was used as a benchmark preprocessing software for cortical surface reconstruction. All the brain images were processed simultaneously and successfully analyzed in a calculation time of 17.33 h. This result indicates that using a supercomputer for brain image preprocessing allows big data analysis to be completed shortly and flexibly, thus suggesting the possibility of supercomputers being used for expanding large data analysis and parameter optimization of preprocessing in the future.Jan. 2024, Scientific reports, 14(1) (1), 2233 - 2233, English, International magazineScientific journal
- The dentate gyrus (DG) of the hippocampus regulates stress-related emotional behaviors and ensures neurogenesis throughout life. Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation, survival, and synaptic formation in both the peripheral and central nervous systems. NT-3 is expressed in the adult DG of the hippocampus; several chronic stress conditions enhance NT-3 expression in rodents. However, functional modulation of the adult DG by NT-3 signaling remains unclear. To directly investigate the impact of NT-3 on DG function, NT-3 was overexpressed in the hippocampal ventral DG by an adeno-associated virus carrying NT-3 (AAV-NT-3). Four weeks following the AAV-NT-3 injection, high NT-3 expression was observed in the ventral DG. We examined the influence of NT-3 overexpression on the neuronal responses and neurogenic processes in the ventral DG. NT-3 overexpression significantly increased the expression of the mature DG neuronal marker calbindin and immediate early genes, such as Fos and Fosb, thereby suggesting DG neuronal activation. During neurogenesis, the number of proliferating cells and immature neurons in the subgranular zone of the DG significantly decreased in the AAV-NT-3 group. Among the neurogenesis-related factors, Vegfd, Lgr6, Bmp7, and Drd1 expression significantly decreased. These results demonstrated that high NT-3 levels in the hippocampus regulate the activation of mature DG neurons and suppress the early phase of neurogenic processes, suggesting a possible role of NT-3 in the regulation of adult hippocampal function under stress conditions.Frontiers Media SA, Jul. 2023, Frontiers in Neuroscience, 17, 1178555 - 1178555, English, International magazineScientific journal
- Inflammation has been associated with depression, and innate immune receptors, such as the Toll-like receptor (TLR) 2/4 in the medial prefrontal cortex (mPFC), are crucial for chronic stress-induced depression-related behaviors in mice. HMGB1, a putative ligand for TLR2/4, has been suggested to promote depression-related behaviors under acute stress. However, the roles of endogenous HMGB1 under chronic stress remain to be investigated. Here, we found that the cerebroventricular infusion of HMGB1 proteins blocked stress-induced social avoidance and that HMGB1-neutralizing antibodies augmented repeated social defeat stress-induced social avoidance in mice, suggesting the antidepressive-like effect of HMGB1 in the brain. By contrast, the infusion of HMGB1-neutralizing antibodies to the mPFC and HMGB1 knockout in α-CaMKII-positive forebrain neurons attenuated the social avoidance, suggesting the pro-depressive-like effect of HMGB1 released from prefrontal neurons under chronic stress. In addition, repeated social defeat stress induced HMGB1 nuclear export selectively in mPFC neurons, which was abolished in the mice lacking RAGE, one of HMGB1 receptors, suggesting the positive feedback loop of HMGB1-RAGE signaling under chronic stress. These findings pave the way for identifying multiple roles of HMGB1 in the brain for chronic stress and depression.MDPI AG, Jul. 2023, Cells, 12(13) (13), 1789 - 1789, English, International magazineScientific journal
- BACKGROUND AND PURPOSE: High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well-known that angiotensin II (Ang II)-AT1 and prostaglandin E2 (PGE2)-EP1 systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear. EXPERIMENTAL APPROACH: Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II-AT1 and PGE2-EP1 systems in HS-induced hypertension and neuronal and behavioral impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. KEY RESULTS: We demonstrated that hypertension and impaired social behavior and object recognition memory following HS intake could be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 gene knockout. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the interaction of Ang II-AT1 and PGE2-EP1 systems could be novel therapeutic targets for hypertension-induced cognitive impairment.Apr. 2023, British journal of pharmacology, 180(18) (18), 2393 - 2411, English, International magazineScientific journal
- 日本臨床分子医学会, Apr. 2023, 日本臨床分子医学会学術総会プログラム・抄録集, 58回, 56 - 56, Japanese脳内炎症は骨格筋のC/EBP経路を介してストレス性筋萎縮を促進する
- Microglia are crucial for tissue homeostasis and its disturbance. However, microglial heterogeneity and its relationship with microglial activation in physiological conditions remain elusive. Using single-cell RNA sequencing, we identified microglial subpopulations with distinct transcriptome signatures in the resting brain. The distribution of two major, continuous subpopulations varied across brain regions, especially between cerebral cortices and the hypothalamus. Lipopolysaccharide and chronic social defeat stress, both of which involve the innate immune receptor TLR4, upregulate the marker genes of selective microglial subpopulations. These findings suggest that microglial subpopulations contribute to the heterogeneity of microglial transcriptome and responsiveness within and across brain regions.Mar. 2023, Journal of pharmacological sciences, 151(3) (3), 142 - 147, English, Domestic magazineScientific journal
- N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.Feb. 2023, International journal of molecular sciences, 24(4) (4), English, International magazineScientific journal
- The transcription profile of microglia related to fear conditioning remains unclear. Here, we used Illumina MouseWG-6v2 microarrays to investigate the gene transcription changes in microglia and peripheral monocytes after contextual fear conditioning of C57BL/6 J mice. Mice were trained with or without a single minimized footshock stimulation (0-s or 2-s, 0.4 mA) and re-exposed to the training context without footshock for three different durations 24 h later: 0 min (FS0), 3 min (FS3), or 30 min (FS30). Whole brain microglia and peripheral monocytes were prepared 24 h after re-exposure using a neural tissue dissociation kit, including non-footshock controls for two re-exposure durations (Con3 and Con30). The data can be valuable for researchers interested in glial cells and neurotransmission studies and are related to the research article "Contextual fear conditioning regulates synapse-related gene transcription in mouse microglia".Feb. 2023, Data in brief, 46, 108862 - 108862, English, International magazineScientific journal
- Japanese Pharmacological Society, 2023, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 97, 3 - BScientific journal
- Individual variability of stress susceptibility led to the concept of stress resilience to adapt well upon stressors. However, the neural mechanisms of stress resilience and its relevance to antidepressant actions remain elusive. In rodents, chronic stress induces dendritic atrophy and decreases dendritic spine density in the medial prefrontal cortex (mPFC), recapitulating prefrontal alterations in depressive patients, and the mPFC promotes stress resilience. Whereas dopamine neurons projecting to the nucleus accumbens potentiated by chronic stress promote stress susceptibility, dopamine neurons projecting to the mPFC activated upon acute stress contribute to dendritic growth of mPFC neurons via dopamine D1 receptors, leading to stress resilience. Rodent studies have also identified the roles of prefrontal D1 receptors as well as D1 receptor-expressing mPFC neurons projecting to multiple subcortical areas and dendritic spine formation in the mPFC for the sustained antidepressant-like effects of low-dose ketamine. Thus, understanding the cellular and neural-circuit mechanism of prefrontal D1 receptor actions paves the way for bridging the gap between stress resilience and the sustained antidepressant-like effects. The mechanistic understanding of stress resilience might be exploitable for developing antidepressants based on a naturally occurring mechanism, thus safer than low-dose ketamine.Elsevier BV, Dec. 2022, Neuroscience Research, English, International magazineScientific journal
- Abstract Severe and prolonged social stress induces mood and cognitive dysfunctions and precipitates major depression. Neuroinflammation has been associated with chronic stress and depression. Rodent studies showed crucial roles of a few inflammation-related lipid mediators for chronic stress-induced depressive-like behaviors. Despite an increasing number of lipid mediators identified, systematic analyses of synthetic pathways of lipid mediators in chronic stress models have not been performed. Using LC–MS/MS, here we examined the effects of chronic social defeat stress on multiple synthetic pathways of lipid mediators in brain regions associated with stress susceptibility in mice. Chronic social defeat stress increased the amounts of 12-lipoxygenase (LOX) metabolites, 12-HETE and 12-HEPE, specifically in the nucleus accumbens 1 week, but not immediately, after the last stress exposure. The increase was larger in stress-resilient mice than stress-susceptible mice. The S isomer of 12-HETE was selectively increased in amount, indicating the role of 12S-LOX activity. Among the enzymes known to have 12S-LOX activity, only Alox12 mRNA was reliably detected in the brain and enriched in brain endothelial cells. These findings suggest that chronic social stress induces a late increase in the amounts of 12S-LOX metabolites derived from the brain vasculature in the nucleus accumbens in a manner associated with stress resilience.Springer Science and Business Media LLC, Dec. 2022, Scientific Reports, 12(1) (1), 11385 - 11385, English, International magazineScientific journal
- Microglia have been suggested to be involved in the underlying mechanism of conditional fear memory formation by regulating inflammatory cytokines. However, the mechanism linking microglia and neuronal activity related to fear conditioning remains unclear. This study characterized the transcription profile of microglia in a fear memory conditional mouse model. Compared with those in control mice microglia, the most significantly induced genes were synapse-related, whereas immune-related genes were reduced due to fear memory consolidation. Whilst the increased expression of synapse-related genes was reversed after fear memory extinction, that of immunological genes was not, strongly suggesting a connection between microglia, neurons, and a dysregulated immune response following contextual fear conditioning. Furthermore, in the hippocampal microglia, we found that the expression of neurotransmitter release regulators, γ-aminobutyric acid (GABA) receptor GABRB3 and synapsin 1/2, increased under fear memory consolidation and restored (decreased) after extinction. In addition, compared with the transcription profile in peripheral monocytes, few overlapping genes were not enriched in biological processes. Taken together, the identified conditional fear stress-induced changes in mouse microglial transcription profiles suggest that microglia-neuron communication mediates contextual fear conditioning.Aug. 2022, Brain research bulletin, 189, 57 - 68, English, International magazineScientific journal
- (一社)日本筋学会, Aug. 2022, 日本筋学会学術集会プログラム・抄録集, 8回, 78 - 78, Japaneseストレスは骨格筋のC/EBP経路を介して筋萎縮を促進する
- Fractalkine is one of the CX3C chemokine family, and it is widely expressed in the brain including the hypothalamus. In the brain, fractalkine is expressed in neurons and binds to a CX3C chemokine receptor 1 (CX3CR1) in microglia. The hypothalamus regulates energy homeostasis of which dysregulation is associated with obesity. Therefore, we examined whether fractalkine-CX3CR1 signalling involved in regulating food intake and hypothalamic inflammation associated with obesity pathogenesis. In the present study, fractalkine significantly reduced food intake induced by several experimental stimuli and significantly increased brain-derived neurotrophic factor (BDNF) mRNA expression in the hypothalamus. Moreover, tyrosine receptor kinase B (TrkB) antagonist impaired fractalkine-induced anorexigenic actions. In addition, compared with wild-type mice, CX3CR1-deficient mice showed a significant increase in food intake and a significant decrease in BDNF mRNA expression in the hypothalamus. Mice fed a high-fat diet (HFD) for 16 weeks showed hypothalamic inflammation and reduced fractalkine mRNA expression in the hypothalamus. Intracerebroventricular administration of fractalkine significantly suppressed HFD-induced hypothalamic inflammation in mice. HFD intake for 4 weeks caused hypothalamic inflammation in CX3CR1-deficient mice, but not in wild-type mice. These findings suggest that fractalkine-CX3CR1 signalling induces anorexigenic actions via activation of the BDNF-TrkB pathway and suppresses HFD-induced hypothalamic inflammation in mice.Jul. 2022, Scientific reports, 12(1) (1), 12604 - 12604, English, International magazineScientific journal
- Microglia have diverse physiological and pathological functions. However, the transcriptional mechanisms remain elusive. Here we sought new transcription factors relevant to microglial functions from the microglial transcriptome of stressed mice and evaluated their roles in primary microglia. TLR2 and TLR4 agonists increased Rel, Atf3, and Cebpb and decreased Hhex in primary microglia as repeated social defeat stress. Although Hhex was not studied in microglia, TLR2 and TLR4 agonists decreased Hhex, and Hhex overexpression attenuated TLR4-increased expression of inflammation-related genes. These findings suggest that Hhex negatively regulates inflammation-related genes in microglia and that TLR2/4 activation reduces Hhex, facilitating TLR4-mediated neuroinflammation.Jul. 2022, Journal of pharmacological sciences, 149(3) (3), 166 - 171, English, Domestic magazineScientific journal
- The evolution of mass spectrometry (MS) and analytical techniques has led to the demand for proteome analysis with high proteome coverage in single-shot measurements. Focus has been placed on data-independent acquisition (DIA)-MS and ion mobility spectrometry as techniques for deep proteome analysis. We aimed to expand the proteome coverage by single-shot measurements using optimizing high-field asymmetric waveform ion mobility spectrometry parameters in DIA-MS. With our established proteome analysis system, more than 10,000 protein groups were identified from HEK293 cell digests within 120 min of MS measurement time. Additionally, we applied our approach to the analysis of host proteins in mouse feces and detected as many as 892 host protein groups (771 upregulated/121 downregulated proteins) in a mouse model of repeated social defeat stress (R-SDS) used in studying depression. Interestingly, 285 proteins elevated by R-SDS were related to mental disorders. The fecal host protein profiling by deep proteome analysis may help us understand mental illness pathologies noninvasively. Thus, our approach will be helpful for an in-depth comparison of protein expression levels for biological and medical research because it enables the analysis of highly proteome coverage in a single-shot measurement.Jun. 2022, Journal of proteome research, 21(6) (6), 1418 - 1427, English, International magazineScientific journal
- May 2022, Circulation, 145(18) (18), 1434 - 1436, English, International magazine
- (一社)日本内分泌学会, Apr. 2022, 日本内分泌学会雑誌, 98(1) (1), 273 - 273, Japanese
- (一社)日本糖尿病学会, Apr. 2022, 糖尿病, 65(Suppl.1) (Suppl.1), S - 185, JapaneseストレスはC/EBP-KLF15経路を介して筋萎縮を促進する
- (一社)日本肥満学会, Mar. 2022, 肥満研究, 27(Suppl.) (Suppl.), 328 - 328, JapaneseC/EBP-KLF15経路はストレスによる筋萎縮に関与する
- Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.2022, Neural plasticity, 2022, 7503553 - 7503553, English, International magazineScientific journal
- Despite the growing attention toward the effects of dairy intake on stress and mental health, its relationship to psychological constructs that affect mental health remains poorly understood. We conducted a cross-sectional study (Study 1) and a longitudinal study (Study 2) to examine the association between food intake and stress resilience in Japanese middle and high school students. In Study 1, 865 participants (412 males and 453 females) completed the questionnaires. In Study 2, 109 students (51 males and 58 females) participated each year from 2016 to 2018. Dietary intake was assessed using a brief self-administered diet history questionnaire. Stress resilience was evaluated using a 13-item sense of coherence (SOC) questionnaire. Correlation coefficients were calculated in Study 1 to investigate the relationship between food group intake and SOC. In Study 2, a cross-lagged panel model was tested using structural equation modeling to investigate the effect of dairy product consumption on SOC. Study 1 revealed that only dairy product intake positively correlated with SOC and other food intake indicated no significant relationship. Study 2 indicated that augmented dairy product intake was positively associated with SOC. Among all foods, only dairy products were associated with SOC in adolescents. Although the association was weak, the longitudinal study confirmed that dairy consumption was associated with SOC. Randomized controlled trials are necessary to examine the causal relationship.2022, PloS one, 17(12) (12), e0279232, English, International magazineScientific journal
- Chronic social stress induces neuronal dysfunctions in the medial prefrontal cortex (mPFC) for emotional and cognitive disturbances. However, the subcellular mechanism remains elusive. Here we examined ultrastructural and multi-omics changes in the mPFC in a mouse model of social defeat stress. Acute stress induced dendritic membrane deformation with mitochondrial swelling in mPFC neurons, leading to dendritic atrophy after chronic stress. Synaptic, but not bulk tissue, proteomes in the mPFC differentiated naïve and stressed mice and further uncovered two distinct states in stressed mice. Proteins involved in mitochondrial metabolic functions mostly decreased with chronic stress regardless of the synaptic proteomic state. By contrast, proteins responsible for mitochondrial homeostasis increased in stressed mice with a specific synaptic proteomic state associated with behavioral resilience to chronic stress. These findings suggest that the balance between mitochondrial metabolic dysfunction and its maintenance at mPFC synapses determines stress susceptibility in mice.Japanese Pharmacological Society, 2022, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 95, 1-SS-13, Japanese
- Chronic social stress induces emotional and cognitive disturbances and is a risk for mental illness. Reduced neuronal activity in the medial prefrontal cortex (mPFC) underlies these behavioral abnormalities. However, the subcellular origin and process of this neuronal change remain elusive. Here we examined ultrastructural and multi-omics changes in the mPFC with social stress in mice. Social stress caused the loss of dendritic branches with morphological alterations of mitochondria and induced synaptic shrinkage selectively at mitochondria-containing synapses. Social stress deteriorated mitochondrial functions at synapses with altered mitochondrial proteome and central metabolism in the mPFC. Pharmacological manipulation targeting mitochondria attenuated the synaptic shrinkage and depression-related behaviors. These findings show that chronic social stress alters the central metabolism at mPFC synapses, leading to neuronal pathology and depression-related behaviors.Japanese Pharmacological Society, 2022, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 95, 1-YIA-11, Japanese
- 2020年初頭からの新型コロナウイルス感染症(COVID-19)の増加に伴い,大学教育は従来型の一斉授業から遠隔授業へと教育形態が変貌した.慣れない中で遠隔授業が普及したが,学会員間での新たな教育形態の情報共有のため,日本生理学会と日本薬理学会が共同で「COVID-19に対する各大学の対応と生理学及び薬理学教育への影響に関する緊急合同調査」を実施した.本稿ではこの全国アンケート調査の結果を報告する.薬理学会では2020年8月から9月にかけて,メールにてアンケートを依頼し,202大学の薬学部,医学部,歯学部,獣医学部等の薬理学講座より回答をいただいた(回答率89%).講義の方法を変更した講座は85%,実習の方法の変更は70%であった.講義では,対面での講義に代わり,ライブ講義とオンデマンド講義の使用が各30%,ライブとオンデマンドの併用が40%であった.実習ではライブあるいはライブとオンデマンドの併用が25%,オンデマンドによる実習が45%であった.ライブの長所には,質問を受け入れやすい双方向性のやり取りが,オンデマンドの長所には,聴講時間に関する自由度の高さと復習のしやすさが挙げられた.オンラインの短所には,学生の理解度,視聴の状況,学生の反応が把握できない点,通信環境の不具合が挙げられた.また,学修水準の二極化を危惧する声もあった.実習では,リアリティの欠如や動物実験に関する長所・短所が挙げられた.60%以上の講座では,COVID-19収束後も新たに導入した教育形態の活用を希望していた.自由意見では,学生のメンタルヘルス不調や生活リズムの乱れなどの懸念や,オンライン教育の質の担保,著作権の問題などが挙げられた.With/Afterコロナの世界におけるNew Normalとして遠隔教育をどのように導入し改良していくか,大学の薬理学教育は大きな転換点を迎えている.(著者抄録)(公社)日本薬理学会, Nov. 2021, 日本薬理学雑誌, 156(6) (6), 324 - 329, Japanese
- Stress due to adverse and demanding conditions alters immune functions. How innate and adaptive immune systems respond to stress and affect neural processes remains unclear. Rodent studies have demonstrated crucial roles of stress-induced immune responses for depressive- and anxiety-like behaviors. In the periphery, stress evokes the mobilization of neutrophils and monocytes to the circulation via sympathetic nerves and glucocorticoids. These myeloid cells are thought to promote depressive- and anxiety-like behaviors by infiltrating the brain's perivascular space, releasing cytokines, and affecting vascular endothelial functions. In the brain, stress activates microglia via innate immune receptors TLR2/4. The activated microglia in the medial prefrontal cortex secrete cytokines and alter neuronal morphology and activity in their vicinity. In subcortical brain areas, prostaglandin (PG) E2 released from the activated microglia attenuates the dopaminergic projection to the medial prefrontal cortex via PGE receptor EP1. These multiple actions of microglia promote depressive-like behavior in concert. These rodent findings may be translatable to depression that clinical studies have associated with brain and peripheral inflammations. Understanding causal relationships between immune and neural alterations under stress might be exploitable to develop inflammation-targeting therapeutics for mental illness.Oct. 2021, Neuroscience research, English, International magazine[Refereed]Scientific journal
- The mobilization efficiency of hematopoietic stem/progenitor cells from bone marrow (BM) to circulation by granulocyte colony-stimulating factor (G-CSF) is dramatically dispersed in humans and mice with no mechanistic lead for poor mobilizers. The regulatory mechanism for mobilization efficiency by dietary fat was assessed in mice. Fat-free diet (FFD) for 2 weeks greatly increased mobilization compared to normal diet (ND). The BM mRNA level of peroxisome proliferator-activated receptor δ (PPARδ), a receptor for lipid mediators, was markedly up-regulated by G-CSF in mice fed with ND and displayed strong positive correlation with widely scattered mobilization efficiency. It was hypothesized that BM fat ligand for PPARδ might inhibit mobilization. The PPARδ agonist inhibited mobilization in mice fed with ND and enhanced mobilization by FFD. Treatment with the PPARδ antagonist and chimeric mice with PPARδ+/- BM showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that BM PPARδ expression was enhanced by G-CSF mainly in mature/immature neutrophils. BM lipid mediator analysis revealed that G-CSF treatment and FFD resulted in the exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA). EPA induced the up-regulation of genes downstream of PPARδ, such as carnitine palmitoyltransferase-1α and angiopoietin-like protein 4 (Angptl4), in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with FFD in vivo. Treatment of wild-type mice with the anti-Angptl4 antibody enhanced mobilization together with BM vascular permeability. Collectively, PPARδ signaling in BM mature/immature neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.Jun. 2021, Haematologica, 106(6) (6), 1671 - 1683, English, International magazine, Co-authored internationallyScientific journal
- Springer Science and Business Media LLC, Apr. 2021, Translational psychiatry, 11(1) (1), 236 - 236, English, International magazine
Abstract Hyperdopaminergic activities are often linked to positive symptoms of schizophrenia, but their neuropathological implications on negative symptoms are rather controversial among reports. Here, we explored the regulatory role of the resting state-neural activity of dopaminergic neurons in the ventral tegmental area (VTA) on social interaction using a developmental rat model for schizophrenia. We prepared the model by administering an ammonitic cytokine, epidermal growth factor (EGF), to rat pups, which later exhibit the deficits of social interaction as monitored with same-gender affiliative sniffing. In vivo single-unit recording and microdialysis revealed that the baseline firing frequency of and dopamine release from VTA dopaminergic neurons were chronically increased in EGF model rats, and their social interaction was concomitantly reduced. Subchronic treatment with risperidone ameliorated both the social interaction deficits and higher frequency of dopaminergic cell firing in this model. Sustained suppression of hyperdopaminergic cell firing in EGF model rats by DREADD chemogenetic intervention restored the event-triggered dopamine release and their social behaviors. These observations suggest that the higher resting-state activity of VTA dopaminergic neurons is responsible for the reduced social interaction of this schizophrenia model.Scientific journal - Correlation Between Lactic Acid Bacteria Beverage Intake and Stress Resilience.We investigated the effect of lactic acid bacteria-containing beverage intake on the level of resilience against stress in male university students. Forty male university students were recruited into the study and randomly assigned into two groups. They were instructed to consume lactic acid bacteria-containing beverage or water twice a day for 28 days. The level of stress resilience, stress reaction, and anxiety were evaluated by a series of questionnaires conducted at three time points (T1: day 0, T2: day 14, and T3: day 28). The stress response was also assessed by measuring their salivary amylase levels. The variance analysis of each group showed a significant increase in stress resilience at T3 compared with T1 in the group of participants who consumed the lactic acid bacteria-containing beverage. Our results suggest that lactic acid bacteria-containing beverage intake could affect resilience against stress positively.Apr. 2021, The Kobe journal of medical sciences, 67(1) (1), E1-E6, English, Domestic magazineScientific journal
- With the spread of new coronavirus infections (COVID-19), universities/colleges have transformed their educational format from conventional group education to distance learning. In order to share information on the new educational format among the members of the society, the Physiological Society of Japan and the Japanese Pharmacological Society (JPS) jointly conducted the "Emergency Joint Survey on Responses of Universities to COVID-19 and Its Impact on Physiology and Pharmacology Education". The JPS surveyed pharmacology departments/divisions at schools of pharmacy, medicine, dentistry, and veterinary medicine in 202 universities (response rate 89%) from August to September 2020. 85% of the universities changed the lecture method, and 70% changed the practical training. 30%, 30%, and 40% of the lectures were live, on-demand, and mixed (combination of live and on-demand) lectures, respectively. 25% of the practical training was live or a combination of live and on-demand lectures, and 45% was on-demand delivery. There are many problems to do online methods such as stable network environment, lack of the reality for students and difficulty of the check of their understanding. On the other hand, there are unexpected benefits in online methods such as anytime learning, an increase in questions from students and repeatable learning. More than 60% considered employing the newly introduced educational styles even after the pandemic. Students' mental health problems and disruption of daily rhythms, quality assurance of online education, and copyright issues were also concerned. Pharmacology education faces a significant turning point in introducing and improving distance learning with or post the COVID-19 pandemic.2021, Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 156(6) (6), 324 - 329, Japanese, Domestic magazineScientific journal
- As daily lifestyle is closely associated with mental illnesses, diet-based preventive approaches are receiving attention. Supplementation with hop bitter acids such as iso-α-acids (IAA) and mature hop bitter acids (MHBA) improves mood states in healthy older adults. However, the underlying mechanism remains unknown. Since acute oral consumption with IAA increases dopamine levels in hippocampus and improves memory impairment via vagal nerve activation, here we investigated the effects of chronic administration of hop bitter acids on the dopaminergic activity associated with emotional disturbance in a mouse model of repeated social defeat stress (R-SDS). Chronic administration of IAA and MHBA significantly increased dopaminergic activity based on the dopamine metabolite to dopamine ratio in the hippocampus and medial prefrontal cortex following R-SDS. Hippocampal dopaminergic activity was inversely correlated with the level of R-SDS-induced social avoidance with or without IAA administration. Therefore, chronic treatment with hop bitter acids enhances stress resilience-related hippocampal dopaminergic activity.Dec. 2020, International journal of molecular sciences, 21(24) (24), English, International magazineScientific journal
- BACKGROUND AND PURPOSE: Inflammation has been associated with stress-related mental disturbances. Rodent studies have reported that blood-borne cytokines are crucial for stress-induced changes in emotional behaviours. However, the roles and regulation of leukocytes in chronic stress remain unclear. EXPERIMENTAL APPROACH: Adult male C57BL/6N mice were subjected to repeated social defeat stress (R-SDS) with two protocols which differed in stress durations, stress cycles, and housing conditions, followed by the social interaction test. The numbers of leukocyte subsets in the bone marrow, spleen, and blood were determined by flow cytometry shortly after or several days after R-SDS. These leukocyte changes were studied in two strains of mice with different stress susceptibility, C57BL/6N and BALB/c mice. KEY RESULTS: R-SDS with both protocols similarly induced social avoidance in C57BL/6N mice. In the bone marrow, neutrophils and monocytes were increased, and T cells, B cells, NK cells, and dendritic cells were decreased with both protocols. In the blood, neutrophils and monocytes were increased with both protocols, whereas T cells, B cells, NK cells, and dendritic cells were decreased with one of these. Neutrophils and monocytes were also increased in the spleen. Changes in the bone marrow and increased levels of circulating neutrophils were maintained for 6 days after R-SDS. BALB/c mice showed greater social avoidance and increase in circulating neutrophils than C57BL/6N mice. CONCLUSION AND IMPLICATIONS: In two strains of mice, chronic stress induced neutrophil mobilization and its maintenance. These effects were strain-related and may contribute to the pathology of mental illness.Jul. 2020, British journal of pharmacology, 178(4) (4), 827 - 844, English, International magazineScientific journal
- We investigated the possibility of prostaglandin E2 (PGE2) as one of common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental factors. PGE2 levels in whole brain were significantly increased after exposure to viral infection [injection of polyinosinic-polycytidylic acid (polyI:C)], hypoxia (exposure to CO2), and neglect (separation from the dams) in postnatal day (PD) 2, compared to those after non-exposure. The mice administered polyI:C during PD 2-6 exhibited the impairment of sociality, object recognition memory, and pre-pulse inhibition (PPI) in adult at PD 70, and further, significant decreased spine density of the mPFC in adult mice. Exposure to CO2 at PD 2 and separation from dams during PD 2-21 exhibited the impairment of PPI and decrease of spine density in adult mice. These behavioral impairments induced by administration of polyI:C were recovered by an inhibition of PGE2-EP1 (PGE2 receptor subtype) and of cyclooxygenase (COX). Our findings suggest that PGE2 is one of potential common molecules associated with vulnerability to neurodevelopmental disruptions induced by environmental factors, and PGE2 plays a crucial role in the development of behavioral and neuronal impairments, which are associated with activation of PGE2-EP1.Japanese Pharmacological Society, 2020, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 93, 3-P-282, Japanese
- Severe environmental and social stress induces dysregulation of sleep along with mood and cognitive disturbances. However, the role and mechanism of this sleep dysregulation remain elusive. Here we evaluated sleep-like inactivity measured by voluntary movements and its relationship to social behaviors in mice without or with social defeat stress as well as the stressed mice with subsequent sleep deprivation. Social defeat stress immediately induced sleep-like inactivity with decreased body temperature. In the social interaction test, the control mice showed high social interest and its correlation with social sniffing intensity, the latter of which indicates positive valence of social sniffing. After the stress, these social characteristics were maintained in stress-resilient mice, but disrupted in stress-susceptible mice, leading to social avoidance. Sleep deprivation after the stress decreased social sniffing intensity along with reduced social interest, but enhanced the exploratory activity with the positive valence of social sniffing. We also found by c-Fos immunohistochemistry that the stress activated sleep-related brain regions, the dorsomedial hypothalamus and ventrolateral periaqueductal gray. Collectively, these findings show that stress activates sleep-related brain regions and induces sleep-like inactivity, contributing to multiple roles of stress-induced sleep for social behaviors.2020, Scientific reports, in press(1) (1), 19800 - 19800, English, International magazine[Refereed]Scientific journal
- We recently reported that dopamine D1 receptor in the medial prefrontal cortex (mPFC) is activated by subthreshold social defeat stress and suppresses the induction of depressive-like behavior in mice. However, which mPFC projection(s) mediates this antidepressant-like effect remains poorly understood. Here we show that social defeat stress specifically increased c-Fos expression, a marker for neuronal activity, in distinct brain regions involved in emotional regulation, relative to novelty-induced exploration. Among these brain areas, D1 knockdown in the mPFC decreased social defeat stress-induced c-Fos expression in the interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a subregion of the extended amygdala. Using retrograde adeno-associated virus vectors and transgenic mice expressing Cre recombinase under the D1 promoter, we also found that D1-expressing deep-layer pyramidal neurons in the mPFC send direct projections to the IPAC. These findings indicate that social defeat stress specifically activates neurons in distinct brain areas, among which the IPAC is regulated by dopamine D1 receptor in the mPFC perhaps through direct projections. Thus, this study provides hints toward identifying neural circuits that underlie antidepressant-like effects of stress-induced dopamine D1 receptor signaling in the mPFC.Springer Science and Business Media LLC, Dec. 2019, Scientific Reports, 9(1) (1), 16670 - 16670, English, International magazine, Co-authored internationally[Refereed]Scientific journal
- Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E2, an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE2 synthesis in the brain and whether TLR2/4 are involved in the PGE2 synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE2 synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE2 in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE2 synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE2 synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE2 synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.Springer Science and Business Media LLC, Dec. 2019, Scientific Reports, 9(1) (1), 17548 - 17548, English, International magazine[Refereed]Scientific journal
- We propose a nonscanning three-dimensional (3-D) fluorescence imaging technique using the transport of intensity equation (TIE) and free-space Fresnel propagation. In this imaging technique, a phase distribution corresponding to defocused fluorescence images with a point-light-source-like shape is retrieved by a TIE-based phase retrieval algorithm. From the obtained phase distribution, and its corresponding amplitude distribution, of the defocused fluorescence image, various images at different distances can be reconstructed at the desired plane after Fresnel propagation of the complex wave function. Through the proposed imaging approach, the 3-D fluorescence imaging can be performed in multiple planes. The fluorescence intensity images are captured with the help of an electrically tunable lens; hence, the imaging technique is free from motion artifacts. We present experimental results corresponding to microbeads and a biological sample to demonstrate the proposed 3-D fluorescence imaging technique.SPIE-Intl Soc Optical Eng, Nov. 2019, Journal of Biomedical Optics, 25(03) (03), 1 - 1, English, International magazine[Refereed]Scientific journal
- Stress caused by adverse and demanding conditions, a risk factor for mental illnesses, induces adaptive or maladaptive neural and behavioral consequences, depending on the conditions. Studies using rodent stress models have revealed multiple mechanisms related to dopamine and inflammation for stress-induced neural and behavioral changes. Thus, repeated stress alters activities of ventral tegmental area dopamine neurons projecting to the nucleus accumbens and the medial prefrontal cortex in distinct manners. In the nucleus accumbens, repeated stress decreases activities of D1 receptor-expressing neurons. In the medial prefrontal cortex, single stress increases dopamine D1 receptor signaling, leading to dendritic hypertrophy of excitatory neurons and stress resilience. These changes are attenuated with repetition of stress via prostaglandin E2 , an inflammation-related lipid mediator. Repeated stress activates microglia in the medial prefrontal cortex and the hippocampus. Innate immune receptors, such as the toll-like receptor 2/4 and P2X7, are crucial for repeated stress-induced microglial activation, leading to neural and behavioral changes through proinflammatory cytokines. In addition, repeated stress induces monocyte infiltration to the brain, and impairs the blood-brain barrier in the nucleus accumbens, leading to cytokine leakage to the brain. These monocyte-derived responses are involved in stress-induced behavioral changes. These findings show crucial roles of the accumbal and prefrontal dopamine pathways and inflammatory responses in the brain and body to direct adaptive and maladaptive consequences of stress, and pave the way for identifying a neural origin of stress and understanding the stress-related pathology of mental illnesses.Wiley, Nov. 2019, Psychiatry and Clinical Neurosciences, 73(11) (11), 669 - 675, English, International magazine[Refereed]Scientific journal
- SCOPE: Peptides containing tryptophan-tyrosine sequences, including the lacto-tetrapeptide glycine-threonine-tryptophan-tyrosine (GTWY) and β-lactolin, from β-lactoglobulin in whey enzymatic digestion, enhance hippocampus-dependent memory functions, which are blocked by the systemic administration of dopamine D1-like antagonist. In this study, we investigated the role of the hippocampal dopaminergic system in the memory-enhancing effect of β-lactolin. METHODS AND RESULTS: The results of in vivo microdialysis revealed that oral administration of β-lactolin increased the extracellular concentration of dopamine in the hippocampus and enhanced both spatial working memory, as measured in the Y-maze test, and spatial reference memory, as measured in the novel object location test. These memory-enhancing effects of β-lactolin, but not the baseline memory functions, were impaired by the knockdown of the dopamine D1 receptor subtype in the hippocampus. β-Lactolin also enhanced object memory, as measured by the novel object recognition test. However, D1 knockdown in the hippocampus spared this memory function either with or without the administration of β-lactolin. CONCLUSIONS: The present results indicate that oral administration of β-lactolin increases dopamine release and D1 receptor signaling in the hippocampus, thereby enhancing spatial memory, but it may improve object memory via a separate mechanism.Oct. 2019, Nutrients, 11(10) (10), English, International magazine[Refereed]Scientific journal
- Oxford University Press (OUP), Aug. 2019, International Immunology, 31(9) (9), 579 - 587, English, International magazine
Abstract Prolonged or excessive stress may induce emotional and cognitive disturbances, and is a risk factor for mental illnesses. Using rodent chronic stress models of depression, roles of multiple lipid mediators related to inflammation have been revealed in chronic stress-induced emotional alterations. Prostaglandin (PG) E2, an arachidonic acid (AA)-derived lipid mediator, and its receptor subtype EP1 mediate depression-like behavior induced by repeated social defeat stress through attenuating prefrontal dopaminergic activity. Repeated social defeat stress activates microglia through innate immune receptors, and induces PGE2 synthesis through cyclooxygenase-1, a prostaglandin synthase enriched in microglia. PGD2, another AA-derived lipid mediator, has been implicated in depression induced by chronic stress, although either pro-depressive or anti-depressive actions have been reported. Chronic stress up-regulates hippocampal expression of 5-lipoxygenase, hence synthesis of cysteinyl leukotrienes, thereby inducing depression through their receptors. Consistent with beneficial effects of n-3 fatty acids in the diet of depressive patients, resolvins—a novel class of pro-resolving lipid mediators—in the brain attenuate neuroinflammation-associated depression. These findings in animal models of depression offer lipid mediators and related molecules as novel therapeutic targets for treating depression. To translate these findings into clinics, translational biomarkers to visualize lipid mediator profiles in depressive patients need to be established.[Refereed]Scientific journal - The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we discovered that leucine-histidine (LH) dipeptide suppressed activation of primary microglia. The effects of LH dipeptide orally administered were measured using tail suspension test (TST) in mice injected with lipopolysaccharide and social interaction test in mice received social defeat stress. LH dipeptide reduced pro-inflammatory cytokines upon stimulation in microglia. Orally administered LH dipeptide was delivered to the brain and suppressed the production of pro-inflammatory cytokines in the brain and concomitant depression-like behavior in the TST. Moreover, oral administration of LH dipeptide suppressed the induction of depression- and anxiety-like behaviors induced by repeated social defeat stress. These results indicate that LH dipeptide suppressed the activation of microglia and ameliorated depression-associated emotional disturbances. Further, we found that LH dipeptide was abundant in various fermented products. Together with previous epidemiological reports that daily intake of these fermented foods is negatively associated with the incidence of psychiatric diseases, our findings suggest that food rich in LH dipeptide may improve mental health.Aug. 2019, Nutrients, 11(9) (9), 2161, English, International magazine[Refereed]Scientific journal
- Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Recent studies have shown that the forgetting of contextual fear memory is promoted via increased adult hippocampal neurogenesis induced by neurogenesis enhancers, such as memantine (MEM) and exercise, raising the possibility that neurogenesis enhancers improve PTSD by facilitating the forgetting of traumatic memory. On the other hand, repeated exposure to social defeat (SD) stress by aggressor mice induces social avoidance behavior to the aggressor and chronic anxiety-like behavior. In this study, we assumed this SD stress paradigm as a PTSD-like model and examined the effects of treatment with neurogenesis enhancer MEM on SD stress-induced PTSD-like behavior. Male C57BL/6 mice received SD stress for 10 consecutive days and were assessed for social avoidance memory to the aggressor (memory of aggressor mice) and anxiety-like behavior using social interaction and elevated zero maze tasks. Consistent with previous studies, SD mice formed social avoidance memory and exhibited increased anxiety-like behavior. Importantly, subsequent MEM treatment (once a week for 4 weeks) significantly reduced social avoidance behavior, suggesting that MEM-treated SD mice showed forgetting of social avoidance memory. Interestingly, MEM-treated SD mice showed comparable anxiety-like behavior with control mice that were not exposed to SD stress. Moreover, MEM-treated SD mice showed no reinstatement of social avoidance memory following single re-exposure to the aggressor. Our findings suggest that neurogenesis enhancer not only enhanced the forgetting of traumatic memory but also improved PTSD (anxiety)-like behavior.Aug. 2019, Molecular brain, 12(1) (1), 68 - 68, English, International magazine[Refereed]Scientific journal
- AIMS: Animal studies using various stress models have shown that excessive environmental stress induces depression? and anxiety?like behaviors through inflammatory responses in the brain and periphery. Although the leptomeningeal cells have multiple functions related to inflammatory responses in the brain, whether environmental stress influences the leptomeninges remains unknown. In this study, we aimed to examine phosphorylation of the extracellular signal-regulated kinase (ERK) in the leptomeninges. METHODS: We subjected C57BL/6 male mice to a single episode of social defeat stress and analyzed the expression of phosphorylated ERK in the leptomeninges by immunohistochemistry. RESULTS: Social defeat stress in mice induced phosphorylation of ERK in the leptomeninges, adjacent to vascular endothelial cells and the glia limitans. This ERK phosphorylation was maintained for at least one hour after the stress. CONCLUSIONS: This study shows the effect of environmental stress on the leptomeninges for the first time and paves the way for elucidating its functional role in stress-induced changes in neural functions.Wiley, Jun. 2019, Neuropsychopharmacology Reports, 39(2) (2), 134 - 139, English, International magazine[Refereed]Scientific journal
- Iso-α-acids (IAAs) are hop-derived bitter acids of beer. Epidemiologic studies suggest that moderate alcohol consumption is beneficial for cognitive function, but they do not show the ingredients in alcoholic beverages. Previously, we reported that long-term consumption of IAAs prevents inflammation and Alzheimer pathologies in mice, but their effects on cognitive function have not been evaluated. In the present study, we demonstrated that the consumption of IAAs improves spatial and object recognition memory functions not only in normal Crl:CD1(ICR) male mice but also in mice with pharmacologically induced amnesia. IAA consumption increased the total and extracellular levels of dopamine in the hippocampus of mice and Sprague-Dawley male rats, respectively. Dopamine D1 receptor antagonist treatment and knockdown of dopamine D1 receptor expression in the hippocampus attenuated IAA-induced spatial memory improvement. Furthermore, vagotomy attenuated the effects of IAAs in improving spatial and object recognition memory functions and increasing the total level of dopamine in the hippocampus. These results suggest that the consumption of IAAs activates dopamine D1 receptor-signaling in the hippocampus in a vagus nerve-dependent manner and, consequently, improves spatial and object recognition memory functions. Vagal activation with food components including IAAs may be an easy and safe approach to improve cognitive functions.-Ano, Y., Hoshi, A., Ayabe, T., Ohya, R., Uchida, S., Yamada, K., Kondo, K., Kitaoka, S., Furuyashiki, T. Iso-α-acids, the bitter components of beer, improve hippocampus-dependent memory through vagus nerve activation.Apr. 2019, FASEB J, 33(4) (4), 4987 - 4995, English, International magazine[Refereed]Scientific journal
- Tryptophan-tyrosine (WY)-related peptides including the β-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, β-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.Feb. 2019, Nutrients, 11(2) (2), E348, English, International magazine[Refereed]Scientific journal
- Repeated social defeat stress (R-SDS) induces multiple behavioral changes in mice. However, the relationships between these behavioral changes were not fully understood. In the first experiment, to examine how the social avoidance is related to R-SDS-impaired behavioral flexibility, 10-week-old male C57BL/6N mice received R-SDS followed by the social interaction test and the attentional set shifting task. R-SDS impaired attentional set shifting irrespective of the development of social avoidance. In the second experiment, to examine whether R-SDS affects sexual preference and how this behavioral change is related to the social avoidance and R-SDS-heightened anxiety, another group of 10-week-old male C57BL/6N mice were subjected to R-SDS followed by the social interaction test, the female encounter test and the elevated plus maze test. The anxiety was heightened in the defeated mice without social avoidance, but not in those which showed social avoidance. Furthermore, female preference was increased specifically in the defeated mice which showed heightened anxiety, but was not related to the level of social avoidance. Together, these results showed that attentional set shifting is more sensitive to R-SDS than social interaction, and that female preference is affected by R-SDS in association with heightened anxiety rather than the social avoidance.Springer Science and Business Media LLC, Dec. 2018, Scientific Reports, 8(1) (1), 10454 - 10454, English, International magazine[Refereed]Scientific journal
- Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation of Ulk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whether Ulk2 dysfunction could underlie the pathophysiology of the disease. Here we show that Ulk2 heterozygous (Ulk2+/-) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition. Ulk2+/- neurons showed imbalanced excitatory-inhibitory neurotransmission, due in part to selective down-modulation of gamma-aminobutyric acid (GABA)A receptor surface expression in pyramidal neurons. Genetically reducing p62 gene dosage or suppressing p62 protein levels with an autophagy-inducing agent restored the GABAA receptor surface expression and rescued the behavioral deficits in Ulk2+/- mice. Moreover, expressing a short peptide that specifically interferes with the interaction of p62 and GABAA receptor-associated protein, a protein that regulates endocytic trafficking of GABAA receptors, also restored the GABAA receptor surface expression and rescued the behavioral deficits in Ulk2+/- mice. Thus, the current study reveals a novel mechanism linking deregulated autophagy to functional disturbances of the nervous system relevant to SZ, through regulation of GABAA receptor surface presentation in pyramidal neurons.Sep. 2018, Hum Mol Genet, 27(18) (18), 3165 - 3176, English, International magazine[Refereed]Scientific journal
- Repeated environmental stress has been proposed to induce neural inflammation together with depression and anxiety. Innate immune receptors, such as Toll-like receptors (TLRs), are activated by exogenous or endogenous ligands to evoke inflammation. Here we show that the loss of TLR2 and TLR4 (TLR2/4) abolished repeated social defeat stress (R-SDS)-induced social avoidance and anxiety in mice. TLR2/4 deficiency mitigated R-SDS-induced neuronal response attenuation, dendritic atrophy, and microglial activation in the medial prefrontal cortex (mPFC). Furthermore, mPFC microglia-specific TLR2/4 knockdown blocked social avoidance. Transcriptome analyses revealed that R-SDS induced IL-1α and TNF-α in mPFC microglia in a TLR2/4-dependent manner, and antibody blockade of these cytokines in the mPFC suppressed R-SDS-induced social avoidance. These results identify TLR2/4 as crucial mediators of R-SDS-induced microglial activation in the mPFC, which leads to neuronal and behavioral changes through inflammation-related cytokines, highlighting unexpected pivotal roles of innate immunity in the mPFC in repeated environmental stress-induced behavioral changes. VIDEO ABSTRACT.Aug. 2018, Neuron, 99(3) (3), 464 - 479, English, International magazine[Refereed]Scientific journal
- Springer Science and Business Media LLC, Aug. 2018, Molecular Psychiatry, 23(8) (8), 1717 - 1730, English[Refereed]Scientific journal
- We previously demonstrated that nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) were upregulated after lengthening contractions (LC) in exercised muscle through B2 bradykinin receptor activation and cyclooxygenase (COX)-2 upregulation, respectively, and that these trophic factors sensitized nociceptors resulting in mechanical hyperalgesia (delayed-onset muscle soreness, DOMS). Here, we examined the prostaglandin receptor subtype involved in DOMS. The mechanical withdrawal threshold of the exercised muscle was measured before and after LC in rats administered prostaglandin E2 receptor (EP) antagonists before LC, or in wild-type (WT), EP2 knockout (EP2−/−), and IP knockout (IP−/−) mice. The change in expression of NGF, GDNF, or COX-2 mRNA was examined using real-time RT-PCR in the muscle in EP2−/− and WT mice. None of the antagonists to EP1, EP3, and EP4 receptors (ONO-8713, ONO-AE5-599, and ONO-AE3-208, respectively) induced a significant difference in DOMS compared with controls in rats. WT and IP−/− mice developed mechanical hyperalgesia after LC, but EP2−/− mice did not. Upregulation of NGF, GDNF, and COX-2 mRNA was observed after LC in WT mice but not in EP2−/− mice. Injecting an EP2 agonist (ONO-AE1-259-01) into the mouse muscle increased expression of COX-2 mRNA. These results suggest that EP2 contributes to generating mechanical hyperalgesia through positive feedback upregulation of COX-2 expression in muscle after LC.Blackwell Munksgaard, Mar. 2018, Scandinavian Journal of Medicine and Science in Sports, 28(3) (3), 826 - 833, English[Refereed]Scientific journal
- (公社)日本薬学会, Mar. 2018, 日本薬学会年会要旨集, 138年会(3) (3), 84 - 84, Japanese神経発達脆弱性因子による成体期の精神機能への影響 PGE2の関与
- Involvement of reactive oxygen species (ROS) has been suggested in the development of psychiatric disorders. NOX1 is a nonphagocytic form of NADPH oxidase whose expression in the nervous system is negligible compared with other NOX isoforms. However, NOX1-derived ROS increase inflammatory pain and tolerance to opioid analgesia. To clarify the role of NOX1 in the brain, we examined depressive-like behaviors in mice deficient in Nox1 (Nox1-/Y). Depressive-like behaviors induced by chronic social defeat stress or administration of corticosterone (CORT) were significantly ameliorated in Nox1-/Y Generation of ROS was significantly elevated in the prefrontal cortex (PFC) of mice administrated with CORT, while NOX1 mRNA was upregulated only in the ventral tegmental area (VTA) among brain areas responsible for emotional behaviors. Delivery of miRNA against NOX1 to VTA restored CORT-induced depressive-like behaviors in wild-type (WT) littermates. Administration of CORT to WT, but not to Nox1-/Y, significantly reduced transcript levels of brain-derived neurotrophic factor (bdnf), with a concomitant increase in DNA methylation of the promoter regions in bdnf Delivery of miRNA against NOX1 to VTA restored the level of BDNF mRNA in WT PFC. Redox proteome analyses demonstrated that NMDA receptor 1 (NR1) was among the molecules redox regulated by NOX1. In cultured cortical neurons, hydrogen peroxide significantly suppressed NMDA-induced upregulation of BDNF transcripts in NR1-expressing cells but not in cells harboring mutant NR1 (C744A). Together, these findings suggest a key role of NOX1 in depressive-like behaviors through NR1-mediated epigenetic modification of bdnf in the mesoprefrontal projection.SIGNIFICANCE STATEMENT NADPH oxidase is a source of reactive oxygen species (ROS) that have been implicated in the pathogenesis of various neurological disorders. We presently showed the involvement of a nonphagocytic type of NADPH oxidase, NOX1, in major depressive disorders, including behavioral, biochemical, and anatomical changes in mice. The oxidation of NR1 by NOX1-derived ROS was demonstrated in prefrontal cortex (PFC), which may be causally linked to the downregulation of BDNF, promoting depressive-like behaviors. Given that NOX1 is upregulated only in VTA but not in PFC, mesocortical projections appear to play a crucial role in NOX1-dependent depressive-like behaviors. Our study is the first to present the potential molecular mechanism underlying the development of major depression through the NOX1-induced oxidation of NR1 and epigenetic modification of bdnf.Apr. 2017, The Journal of neuroscience : the official journal of the Society for Neuroscience, 37(15) (15), 4200 - 4212, English, International magazine[Refereed]Scientific journal
- Granulocyte colony-stimulating factor (G-CSF) is widely used for peripheral blood stem/ progenitor mobilization. G-CSF causes low-grade fever that is ameliorated by nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting the activation of arachidonic acid (AA) cascade. How G-CSF regulated this reaction was assessed. G-CSF treatment in mice resulted in fever, which was canceled in prostaglandin E synthase (mPGES-1)-deficient mice. Mobilization efficiency was twice as high in chimeric mice lacking mPGES-1, specifically in hematopoietic cells, suggesting that prostaglandin E-2 (PGE(2)) from hematopoietic cells modulated the bone marrow (BM) microenvironment. Neutrophils from steady-state BM constitutively expressed mPGES-1 and significantly enhanced PGE(2) production in vitro by beta-adrenergic stimulation, but not by G-CSF, which was inhibited by an NSAID. Although neutrophils expressed all beta-adrenergic receptors, only beta-agonist induced this phenomenon. Liquid chromatography-tandem mass spectrometry traced b-agonist-induced PGE(2) synthesis from exogenous deuterium-labeled AA. Spontaneous PGE(2) production was highly efficient in Gr-1(high) neutrophils among BM cells from G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1(high) neutrophils disrupted G-CSF-induced fever. Furthermore, sympathetic denervation eliminated both neutrophil priming for PGE(2) production and fever during G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major PGE(2) producers. PGE(2) upregulated osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable PGE(2) source to modulateBM microenvironment and body temperature. This study provided a novel mechanistic insight into the communication of the nervous system, BMniche components, and hematopoietic cells.AMER SOC HEMATOLOGY, Feb. 2017, BLOOD, 129(5) (5), 587 - 597, English, International magazine[Refereed]Scientific journal
- Japanese Society of Psychosomatic Medicine, 2017, Japanese Journal of Psychosomatic Medicine, 57(9) (9), 922 - 928, Japanese
Social and environmental stress evokes stress responses through endocrine, immune and autonomic nervous systems. However, how these stress responses are integrated to promote emotional changes and mental illnesses remains poorly understood. Recent studies have established critical roles of inflammation-like responses in stress-induced emotional changes, and have been studying about the involvement of endocrine, immune and autonomic nervous systems. In the periphery, stress-induced endocrine responses activate myeloid cells and increase proinflammatory cytokines, whereas stress-induced sympathetic activation increases the numbers of neutrophils and monocytes in the blood. Stress also alters the composition of gut microbiota and activates immune systems. In the brain, stress activates microglial cells and suppresses dopaminergic system in the prefrontal cortex through inflammation-related molecules. These findings suggest that multiple stress responses are converged to inflammation-like responses inside and outside the brain, thereby promoting emotional changes and mental illnesses, and have led us to propose that stress-induced inflammation-like responses are a target for therapeutic development of novel antidepressants.
- Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner. Social isolation induces similar mDia-dependent presynaptic contraction at GABAergic synapses from NAc neurons in the ventral tegmental area (VTA) associated with reduced synaptic efficacy. Optogenetic stimulation of NAc neurons rescues the anxiety phenotype, and injection of a specific ROCK inhibitor, Y-27632, into the VTA reverses both presynaptic contraction and the behavioral phenotype. mDia-ROCK signaling thus mediates actin-dependent presynaptic remodeling in inactivated NAc neurons, which underlies synaptic plasticity in emotional behavioral responses.CELL PRESS, Nov. 2016, CELL REPORTS, 17(9) (9), 2405 - 2417, English, International magazine[Refereed]Scientific journal
- Genetic interactions among AMPK catalytic subunit Ssp2 and glycogen synthase kinases Gsk3 and Gsk31 in Schizosaccharomyces Pombe.In Schizosaccharomyces pombe, Ssp2, an ortholog of AMP-activated protein kinase (AMPK), is critical for cell growth at restrictive temperatures and under glucose depletion as well as sexual differentiation under nitrogen depletion. To identify genes genetically related to Ssp2, we performed a genetic screening to search for the genes whose overexpression rescued the growth defects in Δssp2 cells at restrictive temperatures, and identified 35 cosmids as multicopy suppressor genes. In Southern blot analyses, 22 out of these cosmids were hybridized to an ssp2+ probe. Using nucleotide sequencing, we identified the gsk3+ gene in one of the cosmids, and the remaining 12 cosmids were hybridized to a gsk3+ probe. Overexpression of the gsk3+ gene or the gsk31+ gene, another GSK3 member, rescues defective growth of Δssp2 cells at restrictive temperatures and under glucose depletion as well as sexual differentiation under nitrogen depletion. Δgsk3Δgsk31 double knockout cells, but neither Δgsk3 nor Δgsk31 single knockout cells, phenocopy Δssp2 cells. The deletion of the gsk3+ or gsk31+ gene augments the phenotypes of Δssp2 cells. These findings suggest that Gsk3 and Gsk31 are critical and interact with Ssp2 in multiple cellular functions.Aug. 2016, Kobe J Med Sci, 62(3) (3), E70 - E78, English, Domestic magazine[Refereed]Scientific journal
- In mammalian cells, mTORC1 activity is regulated by Rag GTPases. It is thought that the Ragulator complex and the GATOR (GAP activity towards Rags) complex regulate RagA/B as its GDP/GTP exchange factor (GEF) and GTPase-activating protein (GAP), respectively. However, the functions of components in these complexes remain elusive. Using fission yeast as a model organism, here we found that the loss of Lam2 (SPBC1778.05c), a homo-log of a Ragulator component LAMTOR2, as well as the loss of Gtr1 or Gtr2 phenocopies the loss of Npr2 or Npr3, homologs of GATOR components Nprl2 or Nprl3, respectively. These phenotypes were rescued by TORC1 inhibition using pharmacological or genetic means, and the loss of Lam2, Gtr1, Gtr2, Npr2 or Npr3 disinhibited TORC1 activity under nitrogen depletion, as measured by Rps6 phosphorylation. Consistently, overexpression of GDP-locked Gtr1S20L or GTP-locked Gtr2Q60L, which suppress TORC1 activity in budding yeast, rescued the growth defect of.gtr1 cells or.gtr2 cells, respectively, and the loss of Lam2, Npr2 or Npr3 similarly diminished the vacuolar localization and the protein levels of Gtr1 and Gtr2. Furthermore, Lam2 physically interacted with Npr2 and Gtr1. These findings suggest that Lam2 and Npr2-Npr3 function together as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity for multiple cellular functions.PUBLIC LIBRARY SCIENCE, May 2016, PLOS ONE, 11(5) (5), e0156239, English, International magazine[Refereed]Scientific journal
- In the fission yeast, two Tor isoforms, Tor1 and Tor2, oppositely regulate gene expression of amino acid permeases. To elucidate the transcriptional machinery for these regulations, here we have employed the cap analysis of gene expression (CAGE), a method of analyzing expression profiles and identifying transcriptional start sites (TSSs). The loss of Tor1 decreased, and Tor2 inhibition by its temperature sensitive mutation increased, mRNA expression of isp5(+), per1(+), put4(+) and SPBPB2B2.01. In contrast, the loss of Tor1 increased, and Tor2 inhibition decreased, the expression of cat1(+). These changes were confirmed by semi-quantitative RT-PCR. These opposite effects by the loss of Tor1 and Tor2 inhibition appeared to occur evenly across multiple TSSs for the respective genes. The motif discovery analysis based on the CAGE results identified the GATA motifs as a potential cis-regulatory element for Tor-mediated regulation. In the luciferase reporter assay, the loss of Tor1 reduced, and Tor2 inhibition and nitrogen depletion increased, the activity of isp5(+) promoter as well as that of a GATAAG reporter. One of the GATAAG motifs in isp5(+) promoter was critical for its transcriptional activity, and a GATA transcription factor Gaf1 was critical for the activities of isp5(+) promoter and the GATAAG reporter. Furthermore, Tor2 inhibition and nitrogen depletion induced nuclear localization of Gaf1 from the cytosol and its dephosphorylation. These results suggest that Tor2 inhibition, which is known to be induced by nitrogen depletion, promotes nuclear localization of Gaf1, thereby inducing isp5(+) transcription through Gaf1 binding to the GATAAG motif in its promoter. Since Gaf1 was also critical for transcription of per1(+) and put4(+), Tor-Gaf1 signaling may coordinate transcription of multiple amino acid permeases according to nutrient availability.PUBLIC LIBRARY SCIENCE, Dec. 2015, PLOS ONE, 10(12) (12), e0144677, English, International magazine[Refereed]Scientific journal
- Neonicotinoids, some of the most widely used pesticides in the world, act as agonists to the nicotinic acetylcholine receptors (nAChRs) of insects, resulting in death from abnormal excitability. Neonicotinoids unexpectedly became a major topic as a compelling cause of honeybee colony collapse disorder, which is damaging crop production that requires pollination worldwide. Mammal nAChRs appear to have a certain affinity for neonicotinoids with lower levels than those of insects; there is thus rising concern about unpredictable adverse effects of neonicotinoids on vertebrates. We hypothesized that the effects of neonicotinoids would be enhanced under a chronic stressed condition, which is known to alter the expression of targets of neonicotinoids, i.e., neuronal nAChRs. We performed immunohistochemical and behavioral analyses in male mice actively administered a neonicotinoid, clothianidin (CTD; 0, 10, 50 and 250 mg/kg/day), for 4 weeks under an unpredictable chronic stress procedure. Vacuolated seminiferous epithelia and a decrease in the immunoreactivity of the antioxidant enzyme glutathione peroxidase 4 were observed in the testes of the CTD+stress mice. In an open field test, although the locomotor activities were not affected, the anxiety-like behaviors of the mice were elevated by both CTD and stress. The present study demonstrates that the behavioral and reproductive effects of CTD become more serious in combination with environmental stress, which may reflect our actual situation of multiple exposure.JAPAN SOC VET SCI, Oct. 2015, JOURNAL OF VETERINARY MEDICAL SCIENCE, 77(10) (10), 1207 - 1215, English, Domestic magazine[Refereed]Scientific journal
- Characterization of tamoxifen as an antifungal agent using the yeast Schizosaccharomyces pombe model organism.Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases.Oct. 2015, Kobe J Med Sci, 61(2) (2), E54 - E63, English, Domestic magazine[Refereed]Scientific journal
- Amino acid transporters are located at specific subcellular compartments, and their localizations are regulated by the extracellular availability of amino acids. In yeast, target of rapamycin (TOR) activation induces the internalization of amino acid transporters located at the plasma membrane. However, whether and how TOR signaling regulates other amino acid transporters located at intracellular compartments remains unknown. Here, we demonstrate that in the fission yeast, the TOR inhibitor Torin-1 induces the transfer of several yellow fluorescent protein (YFP)-fused intracellular amino acid transporters, including Agp3, Isp5, Aat1, and Put4, from trans-Golgi/endosomes into the vacuoles. By contrast, the localizations of YFP-fused Can1, Fnx1, and Fnx2 transporter proteins were unaffected upon Torin-1 treatment. There are two TOR isoforms in fission yeast, Tor1 and Tor2. Whereas tor1 deletion did not affect the Torin-1-induced transfer of Agp3-YFP, Tor2 inhibition using a temperature-sensitive mutant induced the transfer of Agp3-YFP to the vacuolar lumen, similar to the effects of Torin-1 treatment. Tor2 inhibition also induced the transfer of the YFP-fused Isp5, Aat1, and Put4 transporter proteins to the vacuoles, although only partial transfer of the latter two transporters was observed. Under nitrogen depletion accompanied by reduced Tor2 activity, Agp3-YFP was transferred from the trans-Golgi/endosomes to the plasma membrane and then to the vacuoles, where it was degraded by the vacuolar proteases Isp6 and Psp3. Mutants with constitutively active Tor2 showed delayed transfer of Agp3-YFP to the plasma membrane upon nitrogen depletion. Cells lacking Tsc2, a negative regulator of Tor2, also showed a delay in this process in a Tor2-dependent manner. Taken together, these findings suggest that constitutive Tor2 activity is critical for the retention of amino acid transporters at trans-Golgi/endosomes. Moreover, nitrogen depletion suppresses Tor2 activity through Tsc2, thereby promoting the surface expression of these transporters.PUBLIC LIBRARY SCIENCE, Oct. 2015, PLOS ONE, 10(10) (10), e0139045, English, International magazine[Refereed]Scientific journal
- Azole antifungals directly inhibit enzymes for ergosterol biosynthesis, and this direct action is thought to underlie antifungal actions of these drugs. Recent studies showed that azoles alter expression of genes for various cellular functions. However, transcription factors regulated by azoles and their roles in antifungal actions remain poorly characterized. Using luciferase assay, we found that miconazole increased luciferase activity under the promoter containing the cAMP response element (CRE) motif. This azole-induced activation of CRE reporter was abolished in Atf1-deficient cells, suggesting that azoles induce Atf1 activation. As Atf1 is activated by stress-activated MAP kinase Sty1 upon various stressors, we examined its involvement. Azoles increased phosphorylation of Sty1 for its activation, and Sty1 deletion impaired azole-induced CRE reporter activation. In contrast, deletion of Pyp1, a tyrosine phosphatase which negatively regulates Sty1, increased CRE reporter activation. In addition, cells deficient in Atf1 and stress-activated MAP kinase pathway showed resistance to azoles, whereas cells lacking Pyp1 increased azole susceptibility, suggesting a critical role for azole-induced activation of MAP kinase-Atf1 pathway in antifungal actions of azoles. Collectively, these results suggest that azoles activate stress-activated MAP kinase pathway, thereby facilitating Atf1-mediated transcription for antifungal effects.WILEY-BLACKWELL, Sep. 2015, GENES TO CELLS, 20(9) (9), 695 - 705, English, International magazine[Refereed]Scientific journal
- In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd(-/-) mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3'-untranslated region (3'UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube-like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD. (C) 2015 Elsevier Inc. All rights reserved.ELSEVIER SCIENCE INC, Mar. 2015, NEUROBIOLOGY OF AGING, 36(3) (3), 1356 - 1368, English, International magazine[Refereed]Scientific journal
- Feb. 2015, Seikagaku. The Journal of Japanese Biochemical Society, 87(1) (1), 122 - 4, Japanese, Domestic magazine[A role of prostaglandin E2-mediated regulation of prefrontal dopaminergic activity under repeated social defeat stress].Scientific journal
- Excessive or prolonged stress causes cognitive and emotional changes and is thought to be a risk factor for psychiatric disorders. Recent studies in rodents showed roles and actions of arachidonic acid (AA)-derived bioactive lipids, namely, prostaglandin (PG) E 2 and endocannabinoids (eCB), and their receptors in emotional regulation under psychological stress induced by social and environmental stimuli. Stress exposure increases synthesis of PGE 2 in the brain, which suppresses emotional impulsivity under acute stress and facilitates depression and anxiety-like behaviors under repeated stress. This PGE 2 action is mediated, at least in part, through dopaminergic regulation by EP1, a PGE receptor subtype. Stress exposure also increases synthesis of 2-arachidonoylglycerol (2-AG), one eCB species, which suppresses depression and anxiety-like behaviors through multiple brain structuresthrough its receptor CB1. Thus, stress activates both the PGE 2 -EP1 pathway and the 2-AG-CB1 pathway, which have distinct, mostly opposing, roles in emotional regulation under stress. COX-1, a PGsynthase enriched in microglia, is critical for stress-induced behavioral changes as well as PGE 2 synthesis in the brain. Given a recent report that PGE 2 synthesis in the brain mostly depends on 2-AG metabolism to AA, stress-induced 2-AG synthesis may underlie concomitant PGE 2 synthesis. Collectively, the PGE 2 -EP1 and 2-AG-CB1 pathways as well as their crosstalk may be targets for pharmaceutical development for stress-related pathophysiology in psychiatric disorders.Springer Japan, Jan. 2015, Bioactive Lipid Mediators: Current Reviews and Protocols, 315 - 328, English[Refereed]In book
- DNA replication stress induces the transcriptional activation of rhp51(+), a fission yeast recA homolog required for repair of DNA double strand breaks. However, the mechanism by which DNA replication stress activates rhp51(+) transcription is not understood. The promoter region of rhp51(+) contains two damage-responsive elements (DREs) and two MluI cell cycle box (MCB) motifs. Using luciferase reporter assays, we examined the role of these elements in rhp51(+) transcription. The fulllength rhp51(+) promoter and a promoter fragment containing MCB motifs only, but not a fragment containing DREs, mediated transcriptional activation upon DNA replication stress. Removal of the MCB motifs from the rhp51(+) promoter abolished the induction of rhp51(+) transcription by DNA replication stress. Consistent with a role for MCB motifs in rhp51(+) transcription activation, deletion of the MBF (MCB-binding factor) co-repressors Nrm1 and Yox1 precluded rhp51(+) transcriptional induction in response to DNA replication stress. Using cells deficient in checkpoint signaling molecules, we found that the Rad3-Cds1/Chk1 pathway partially mediated rhp51(+) transcription in response to DNA replication stress, suggesting the involvement of unidentified checkpoint signaling pathways. Because MBF is critical for G1/S transcription, we examined how the cell cycle affected rhp51(+) transcription. The transcription of rhp51(+) and cdc18(+), an MBF-dependent G1/S gene, peaked simultaneously in synchronized cdc25-22 cells. Furthermore, DNA replication stress maintained transcription of rhp51(+) similarly to cdc18(+). Collectively, these results suggest that MBF and its regulators mediate rhp51(+) transcription in response to DNA replication stress, and underlie rhp51(+) transcription at the G1/S transition.PUBLIC LIBRARY SCIENCE, Nov. 2014, PLOS ONE, 9(11) (11), e111936, English, International magazine[Refereed]Scientific journal
- JAPANESE PHARMACOLOGICAL SOC, 2014, JOURNAL OF PHARMACOLOGICAL SCIENCES, 124, 75P - 75P, EnglishThe possibility of prostaglandin E-2 (PGE(2)) as a common molecule associated with vulnerability to neurodevelopmental disruptions[Refereed]
- mDia is an actin nucleator and polymerization factor regulated by the small GTPase Rho and consists of three isoforms. Here, we found that mice lacking mDia1 and mDia3, two isoforms expressed in the brain, in combination (mDia-DKO mice) show impaired left-right limb coordination during locomotion and aberrant midline crossing of axons of corticospinal neurons and spinal cord interneurons. Given that mice lacking Ephrin-B3-EphA4 signaling show a similar impairment in locomotion, we examined whether mDia is involved in Ephrin-B3-EphA4 signaling for axon repulsion. In primary cultured neurons, mDia deficiency impairs growth cone collapse and axon retraction induced by chemo-repellants including EphA ligands. In mDia-DKO mice, the Ephrin-B3-expressing midline structure in the spinal cord is disrupted, and axons aberrantly cross the spinal cord midline preferentially through the region devoid of Ephrin-B3. Therefore, mDia plays multiple roles in the proper formation of the neural network in vivo.WILEY-BLACKWELL, Oct. 2013, GENES TO CELLS, 18(10) (10), 873 - 885, English, International magazine[Refereed]Scientific journal
- The mechanism underlying the crosstalk between multiple G protein-coupled receptors remains poorly understood. We previously reported that prostaglandin E receptor EP1 facilitates dopamine D1 receptor signaling in striatal slices and promotes behavioral responses induced by D1 receptor agonists. Here, using human embryonic kidney (HEK)-293T cells expressing D1 and EP1, we have analyzed the mechanism underlying EP1-mediated facilitation of D1 receptor signaling. Fluorescent immunostaining showed that EP1 and D1 receptors are partly colocalized in the cells, and coprecipitation experiments revealed a molecular complex of EP1 and D1 receptors. Treatment of the cells with 17S,17,20-dimethyl-2,5-ethano-6-oxo-PGE1 (ONO-DI-004), an EP1-selective agonist, enhanced cAMP production induced by D1 agonists (+/-)-6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide (SKF-81297) and 6-chloro-2,3,4,5-tetrahydro-1-(3-methylphenyl)-3-(2-propenyl)-1H-3-benzazepine-7,8-diol hydrobromide (SKF-83822). Although this facilitative effect of EP1 stimulation was not affected by pharmacologic blockade of EP1-induced Ca2+ increase, it was blocked by overexpression of Gt(alpha) as a G(beta gamma) scavenger. Consistently, depletion of adenylyl cyclase (AC) 7, a G(beta gamma)-sensitive AC isoform, abolished the facilitative action of EP1 on D1-induced cAMP production. Notably, neither G(t alpha) overexpression nor AC7 depletion affected cAMP production induced by D1 stimulation alone. In contrast, depletion of AC6, another AC isoform, reduced cAMP production induced by D1 stimulation alone, but spared its facilitation by EP1 stimulation. Collectively, these data suggest that, through complex formation with D1, EP1 signaling directs the D1 receptor through G(beta gamma) to be coupled to AC7, an AC isoform distinct from those used by the D1 receptor alone, in HEK-293T cells.AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, Sep. 2013, MOLECULAR PHARMACOLOGY, 84(3) (3), 476 - 486, English, International magazine[Refereed]Scientific journal
- Prostaglandin E2 (PGE2) regulates hematopoietic stem/progenitor cell (HSPC) activity. However, the receptor(s) responsible for PGE2 signaling remains unclear. Here, we identified EP4 as a receptor activated by PGE2 to regulate HSPCs. Knockdown of Ep4 in HSPCs reduced long-term reconstitution capacity, whereas an EP4-selective agonist induced phosphorylation of GSK3β and β-catenin and enhanced long-term reconstitution capacity. Next, we analyzed the niche-mediated effect of PGE2 in HSPC regulation. Bone marrow mesenchymal progenitor cells (MPCs) expressed EP receptors, and stimulation ofMPCs with PGE2 significantly increased their ability to support HSPC colony formation. Among the EP receptor agonists, only an EP4 agonist facilitated the formation of HSPC colonies after the coculture with MPCs. PGE2 up-regulated the expression of cytokine-, cell adhesion-, extracellular matrix-, and protease-related genes in MPCs. We also examined the function of PGE2/EP4 signaling in the recovery of the HSPCs after myelosuppression. The administration of PGE2 or an EP4 agonist facilitated the recovery of HSPCs from 5-fluorouracil (5-FU)-induced myelosuppression, indicating a role for PGE2/EP4 signaling in this process. Altogether, these data suggest that EP4 is a key receptor for PGE2-mediated direct and indirect regulation of HSPCs.American Society of Hematology, 2013, Blood, 121(11) (11), 1995 - 2007, English, International magazine[Refereed]Scientific journal
- JAPANESE PHARMACOLOGICAL SOC, 2013, JOURNAL OF PHARMACOLOGICAL SCIENCES, 121, 123P - 123P, EnglishInvolvement of prostaglandin E2 in behavioral abnormalities induced by neonatal immune activation[Refereed]
- Prolonged or intensive stress results in emotional and cognitive deficits and is a major risk factor for psychiatric disorders such as depression. Since the molecular mechanisms of how biological adaptations to stress go awry remains elusive, pharmaceutical development targeting stress has not been established. In rodents, repeated stress alters functions of multiple brain areas including the medial prefrontal cortex (mPFC) that confers stress resilience, thereby causing depression, anxiety, and working memory deficit. The mesocortical dopaminergic pathway that regulates such stress-coping functions is attenuated with repetition of stress via prostaglandin (PG) E-2, a bioactive lipid derived from arachidonic acid, and its receptor EP1. Several findings suggest that microglia activated by repeated stress are involved in emotional and cognitive changes as a source of inflammation-related molecules such as PGE(2) and IL-1 beta. IL-1 signaling is critical not only for emotional changes but also for microglial activation induced by repeated stress. Furthermore, purinergic signaling via the P2X7 receptor that can trigger PGE(2) and IL-1 beta production in microglia has been implicated in the pro-depressive effect of repeated stress as well as depressive disorders. Collectively, inflammation-related molecules that link repeated stress to mPFC dysfunction are potential targets of pharmaceutical development for psychiatric disorders.JAPANESE PHARMACOLOGICAL SOC, Oct. 2012, JOURNAL OF PHARMACOLOGICAL SCIENCES, 120(2) (2), 63 - 69, English, Domestic magazine[Refereed][Invited]Scientific journal
- ScopeWe found that rubiscolin-6, a d opioid agonist peptide derived from d-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), a major protein of green leaves, stimulates food intake after oral administration in mice. We therefore investigated its mechanism. Methods and resultsOrexigenic activity after oral administration of rubiscolin-6 was blocked by central administration of naltrindole, an antagonist for d opioid receptor, suggesting that orally administered rubiscolin-6 stimulates food intake via central d opioid receptor activation. The orexigenic activity of rubiscolin-6 was inhibited by celecoxib, a cyclooxygenase (COX)-2 inhibitor. The hypothalamic mRNA expression of COX-2 and lipocallin-type (L) prostaglandin D synthase (PGDS) was elevated in response to rubiscolin-6 administration. Rubiscolin-6 stimulated food intake in wild-type and hematopoietic (H)-PGDS knockout (KO), but not L-PGDS KO mice. Interestingly, rubiscolin-6 stimulated food intake in L-PGDSflox/Nescre mice, which were deficient in L-PGDS in the brain parenchyma, but not leptomeninges. The orexigenic effect of rubiscolin-6 was abolished by genetic deletion of DP1 receptor for PGD2, and by MK0524 or BIBO3304, an antagonist of DP1 receptor or of Y1 receptor for neuropeptide Y, respectively. ConclusionOrally administered rubiscolin-6 may stimulate food intake through COX-2 and leptomeningeal L-PGDS, followed by DP1 and Y1 receptors, downstream of the central d opioid receptor.WILEY-BLACKWELL, Aug. 2012, MOLECULAR NUTRITION & FOOD RESEARCH, 56(8) (8), 1315 - 1323, English, International magazine[Refereed]Scientific journal
- Roles of altered striatal function in major depressionMajor depression, a psychiatric disorder characterized by depressive mood and loss of interest and pleasure, is a leading cause of disability and suicide in developed countries. However, the mechanisms that underlie major depression remain to be elucidated. Clinical studies on patients with major depression have shown abnormalities in multiple brain areas, each of which can account for a distinct symptom or endophenotype. Notably, the striatum in healthy control subjects responds to positive emotional stimuli and to positive feedback signals during cognitive tasks, but these striatal responses are greatly reduced in depressive patients. Given the role of the striatum in behavioral learning with positive reinforcers, abnormalities as such suggest that impairment in reward processing and/or reinforcement learning in major depression is the basis of anhedonia and reduced psychomotor activity. In animal studies, stress - a risk factor for major depression- is frequently used to induce behavioral depression. Repeated social defeat stress increases the excitability of dopamine neurons and subsequent CREB-mediated transcription in the nucleus accumbens shell, leading to behavioral depression. Surprisingly, this pathway seems not to be involved in behavioral depression caused by prolonged social isolation, suggesting distinct mechanisms underlying the two stressful contexts. In contrast, ΔFosB-mediated gene expression in the nucleus accumbens shell confers resilience to stress. Repeated social defeat stress induces accumbal ΔFosB expression in a stress-resilient subset of individuals, whereas prolonged social isolation decreases this expression, leading to stress susceptibility. In addition to emotional changes, chronic stress also alters the mode of instrumental behavior from goal-directed to habitual responding, with consistent morphological changes in striatal subregions responsible for the corresponding behavioral modes. Therefore, these clinical and preclinical findings suggest that striatal abnormalities play a role in emotional and cognitive changes associated with major depression.Aug. 2012, Brain and Nerve, 64(8) (8), 919 - 926, Japanese, Domestic magazine[Refereed]Scientific journal
- Apr. 2012, Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 139(4) (4), 152 - 6, Japanese, Domestic magazine[Role of prostaglandin signaling in stress and its implication in pharmaceutical development of antidepressants].Scientific journal
- Apr. 2012, Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 139(4) (4), 141 - 141, Japanese, Domestic magazine[Environmental factors that influence the pathophysiology of mental disorders in various life stages and the design of molecular- targeting drugs for these disorders].Scientific journal
- This study explored the physiological roles of PGE-type receptor 4 (EP4) in auditory function. EP4-deficient mice exhibited slight hearing loss and a reduction of distortion-product otoacoustic emissions (DPOAEs) with loss of outer hair cells (OHCs) in cochleae. After exposure to intense noise, these mice showed significantly larger threshold shifts of auditory brain stem responses (ABRs) and greater reductions of DPOAEs than wild-type mice. A significant increase of OHC loss was confirmed morphologically in the cochleae of EP4-deficient mice. Pharmacological inhibition of EP4 had a similar effect to genetic deletion, causing loss of both hearing and OHCs in C57BL/6 mice, indicating a critical role for EP4 signaling in the maintenance of auditory function. Pharmacological activation of EP4 significantly protected OHCs against noise trauma, and attenuated noise-induced hearing loss in C57BL/6 mice. These findings suggest that EP4 signaling is necessary for the maintenance of cochlear physiological function and for cochlear protection against noise-induced damage, in particular OHCs. EP4 might therefore be an effective target for cochlear disease therapeutics. (c) 2011 Elsevier Ltd. All rights reserved.PERGAMON-ELSEVIER SCIENCE LTD, Mar. 2012, NEUROPHARMACOLOGY, 62(4) (4), 1841 - 1847, English, International magazine[Refereed]Scientific journal
- Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E-2 (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.SOC NEUROSCIENCE, Mar. 2012, JOURNAL OF NEUROSCIENCE, 32(12) (12), 4319 - 4329, English, International magazine[Refereed]Scientific journal
- In brain development, distinct types of migration, radial migration and tangential migration, are shown by excitatory and inhibitory neurons, respectively. Whether these two types of migration operate by similar cellular mechanisms remains unclear. We examined neuronal migration in mice deficient in mDia1 (also known as Diap1) and mDia3 (also known as Diap2), which encode the Rho-regulated actin nucleators mammalian diaphanous homolog 1 (mDia1) and mDia3. mDia deficiency impaired tangential migration of cortical and olfactory inhibitory interneurons, whereas radial migration and consequent layer formation of cortical excitatory neurons were unaffected. mDia-deficient neuroblasts exhibited reduced separation of the centrosome from the nucleus and retarded nuclear translocation. Concomitantly, anterograde F-actin movement and F-actin condensation at the rear, which occur during centrosomal and nuclear movement of wild-type cells, respectively, were impaired in mDia-deficient neuroblasts. Blockade of Rho-associated protein kinase (ROCK), which regulates myosin II, also impaired nuclear translocation. These results suggest that Rho signaling via mDia and ROCK critically regulates nuclear translocation through F-actin dynamics in tangential migration, whereas this mechanism is dispensable in radial migration.NATURE PUBLISHING GROUP, Mar. 2012, NATURE NEUROSCIENCE, 15(3) (3), 373 - U193, English, International magazine[Refereed]Scientific journal
- During development of the central nervous system, the apical-basal polarity of neuroepithelial cells is critical for homeostasis of proliferation and differentiation of neural stem cells. While adherens junctions at the apical surface of neuroepithelial cells are important for maintaining the polarity, the molecular mechanism regulating integrity of these adherens junctions remains largely unknown. Given the importance of actin cytoskeleton in adherens junctions, we have analyzed the role of mDia, an actin nucleator and a Rho effector, in the integrity of the apical adherens junction. Here we show that mDia1 and mDia3 are expressed in the developing brain, and that mDia3 is concentrated in the apical surface of neuroepithelium. Mice deficient in both mDia1 and mDia3 develop periventricular dysplastic mass widespread throughout the developing brain, where neuroepithelial cell polarity is impaired with attenuated apical actin belts and loss of apical adherens junctions. In addition, electron microscopic analysis revealed abnormal shrinkage and apical membrane bulging of neuroepithelial cells in the remaining areas. Furthermore, perturbation of Rho, but not that of ROCK, causes loss of the apical actin belt and adherens junctions similarly to mDia-deficient mice. These results suggest that actin cytoskeleton regulated by Rho-mDia pathway is critical for the integrity of the adherens junctions and the polarity of neuroepithelial cells, and that loss of this signaling induces aberrant, ectopic proliferation and differentiation of neural stem cells.PUBLIC LIBRARY SCIENCE, Sep. 2011, PLOS ONE, 6(9) (9), e25465, English, International magazine[Refereed]Scientific journal
- (公社)日本生化学会, Sep. 2011, 日本生化学会大会プログラム・講演要旨集, 84回, 3T8p - 7, JapanesePGE2はEP1/EP4受容体を介して抗不安作用を示す
- (公社)日本生化学会, Sep. 2011, 日本生化学会大会プログラム・講演要旨集, 84回, 3P - 0588, JapaneseRho依存的アクチン重合因子mDiaはephrinによる軸索成長円錐の退縮に重要である(mDia, a Rho effector and actin nucleator, is critical for growth cone retraction in ephrin-induced axonal repulsion)
- The extracellular dopamine level is regulated not only by synaptic inputs to dopamine neurons but also by local mechanisms surrounding dopaminergic terminals. However, much remains to be investigated for the latter mechanism. Thromboxane A(2) is one of the cyclooxygenase products derived from arachidonic acid, and acts on its cognate G protein-coupled receptor [thromboxane receptor (TP)]. We show here that TP in the striatum locally facilitates dopamine overflow. Intrastriatal injection of a TP agonist increased extracellular dopamine levels in the striatum as measured by in vivo microdialysis. TP stimulation also augmented electrically evoked dopamine overflow from striatal slices. Conversely, TP deficiency reduced dopamine overflow evoked by N-methyl-D-aspartic acid (NMDA) and acetylcholine in striatal slices. TP immunostaining showed that TP is enriched in vascular endothelial cells. Pharmacological blockade of nitric oxide (NO) synthesis and genetic deletion of endothelial NO synthase (eNOS) suppressed NMDA/acetylcholine-induced dopamine overflow. This involvement of NO was abolished in TP-deficient slices, suggesting a role for eNOS-derived NO synthesis in TP-mediated dopamine overflow. As a functional consequence of TP-mediated dopamine increase, a TP agonist suppressed GABAergic inhibitory postsynaptic currents in medium spiny neurons through a D2-like receptor-dependent mechanism. Finally, TP is involved in sucrose intake, a dopamine-dependent motivational behavior. These data suggest that TP stimulation in the striatum locally facilitates dopamine overflow evoked by synaptic inputs via NO synthesis in endothelial cells.WILEY-BLACKWELL, Aug. 2011, EUROPEAN JOURNAL OF NEUROSCIENCE, 34(4) (4), 594 - 604, English, International magazine[Refereed]Scientific journal
- BACKGROUND AND PURPOSE Cerebral aneurysm is a frequent cerebrovascular event and a major cause of fatal subarachnoid haemorrhage, but there is no medical treatment for this condition. Haemodynamic stress and, recently, chronic inflammation have been proposed as major causes of cerebral aneurysm. Nevertheless, links between haemodynamic stress and chronic inflammation remain ill-defined, and to clarify such links, we evaluated the effects of prostaglandin E-2 (PGE(2)), a mediator of inflammation, on the formation of cerebral aneurysms. EXPERIMENTAL APPROACH Expression of COX and prostaglandin E synthase (PGES) and PGE receptors were examined in human and rodent cerebral aneurysm. The incidence, size and inflammation of cerebral aneurysms were evaluated in rats treated with COX-2 inhibitors and mice lacking each prostaglandin receptor. Effects of shear stress and PGE receptor signalling on expression of pro-inflammatory molecules were studied in primary cultures of human endothelial cells (ECs). KEY RESULTS COX-2, microsomal PGES-1 and prostaglandin E receptor 2 (EP2) were induced in ECs in the walls of cerebral aneurysms. Shear stress applied to primary ECs induced COX-2 and EP2. Inhibition or loss of COX-2 or EP2 in vivo attenuated each other's expression, suppressed nuclear factor kappa B (NF-kappa B)-mediated chronic inflammation and reduced incidence of cerebral aneurysm. EP2 stimulation in primary ECs induced NF-kappa B activation and expression of the chemokine (C-C motif) ligand 2, essential for cerebral aneurysm. CONCLUSIONS AND IMPLICATIONS These results suggest that shear stress activated PGE(2)-EP2 pathway in ECs and amplified chronic inflammation via NF-kappa B. We propose EP2 as a therapeutic target in cerebral aneurysm.WILEY-BLACKWELL, Jul. 2011, BRITISH JOURNAL OF PHARMACOLOGY, 163(6) (6), 1237 - 1249, English[Refereed]Scientific journal
- We found that centrally administered prostaglandin (PG) E-2 exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP1 and EP4 receptors, among four receptor subtypes for PGE(2), mimicked the anxiolytic-like activity of PGE(2). The anxiolytic-like activity of PGE(2) was blocked by an EP1 or EP4 antagonist, as well as in EP4 but not EP1 knockout mice. Central activation of either EP1 or EP4 receptors resulted in anxiolytic-like activity. The PGE(2)-induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT1A, dopamine D-1 and GABA(A) receptors. Taken together, PGE(2) exhibits anxiolytic-like activity via EP1 and EP4 receptors, with downstream involvement of 5-HT1A, D-1 and GABA(A) receptor systems. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.ELSEVIER SCIENCE BV, Jul. 2011, FEBS LETTERS, 585(14) (14), 2357 - 2362, English, International magazine[Refereed]Scientific journal
- FEDERATION AMER SOC EXP BIOL, Mar. 2011, FASEB JOURNAL, 25(3) (3), 813 - 818, English, International magazine[Refereed][Invited]Scientific journal
- Stress is a state of physiological or psychological strain caused by adverse stimuli; responses to stress include activation of the sympathetic nervous system, glucocorticoid secretion and emotional behaviors. Prostaglandin E-2 (PGE(2)), acting through its four receptor subtypes (EP1, EP2, EP3 and EP4), is involved in these stress responses. Studies of EP-selective drugs and mice lacking specific EPs have identified the neuronal pathways regulated by PGE(2). In animals with febrile illnesses, PGE(2) acts on neurons expressing EP3 in the preoptic hypothalamus. In illness-induced activation of the hypothalamic-pituitary-adrenal axis, EP1 and EP3 regulate distinct neuronal pathways that converge at the paraventricular hypothalamus. During psychological stress, EP1 suppresses impulsive behaviors via the midbrain dopaminergic systems. PGE(2) promotes illness-induced memory impairment, yet also supports hippocampus-dependent memory formation and synaptic plasticity via EP2 in physiological conditions. In response to illness, PGE(2) is synthesized by enzymes induced in various cell types inside and outside the brain, whereas constitutively expressed enzymes in neurons and/or microglia synthesize PGE(2) in response to psychological stress. Dependent on the type of stress stimuli, PGE(2) released from different cell types activates distinct EP receptors, which mobilize multiple neuronal pathways, resulting in stress responses.NATURE PUBLISHING GROUP, Mar. 2011, NATURE REVIEWS ENDOCRINOLOGY, 7(3) (3), 163 - 175, English, International magazine[Refereed][Invited]Scientific journal
- Dopamine (DA) is a neuromodulator that is critical for sensory-motor, cognitive and emotional functions. We previously found that mice lacking prostaglandin E receptor EP1 showed impulsive emotional behaviors accompanied by enhanced DA turnover in the frontal cortex and striatum. Given that these behavioral phenotypes were corrected by DA receptor antagonists, we hypothesized that EP1 deficiency causes a hyperdopaminergic state for its behavioral phenotype. Here we tested this hypothesis by examining the EP1 action in the nigrostriatal dopaminergic system. We first used microdialysis and found an elevated extracellular DA level in the dorsal striatum of EP1-deficient mice compared with wild-type mice. Despite the EP1 expression in the striatum, neither deficiency nor activation of EP1 altered the intrastriatal control for DA release, uptake or degradation. Immunohistochemistry revealed punctate EP1 signals apposed with dopaminergic neurons in the substantia nigra pars compacta (SNc). Many EP1 signals were colocalized with a marker for GABAergic synapses. Further, an EP1 agonist enhanced GABA(A)-mediated inhibitory inputs to SNc dopaminergic neurons in midbrain slices. Therefore, the prostaglandin E-2-EP1 signaling directly enhances GABAergic inputs to SNc dopaminergic neurons. The lack of this EP1 action may lead to a hyperdopaminergic state of EP1-deficient mice.WILEY-BLACKWELL, Dec. 2009, EUROPEAN JOURNAL OF NEUROSCIENCE, 30(12) (12), 2338 - 2346, English, International magazine[Refereed]Scientific journal
- Receptor-activator of NF-kappa B ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland(1-4). RANKL and RANK are also expressed in the central nervous system(5,6). However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1 beta and TNF alpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.NATURE PUBLISHING GROUP, Nov. 2009, NATURE, 462(7272) (7272), 505 - 509, English, International magazine[Refereed]Scientific journal
- Stress is a condition in which the body homeostasis is perturbed by various stimuli such as sickness and psychological stimuli. Stress evokes adaptive responses including febrile, neuroendocrine, and behavioral responses. Prostaglandin (PG) E(2) is a metabolite from arachidonic acid, and exerts its functions through G-protein-coupled receptors called EP1, EP2, EP3, and EP4. Recent studies using knockout mice and selective drugs revealed the roles of these receptors in stress responses. Upon sickness, PGE(2) mediates fever through EP3, while both EP1 and EP3 are involved in ACTH release. In addition, EP1 controls impulsive behaviors under psychological stress through the dopaminergic system. PGE(2) produced by various cell types may integrate multiple stress stimuli through PGE receptor subtypes for adaptive responses.ELSEVIER SCI LTD, Feb. 2009, CURRENT OPINION IN PHARMACOLOGY, 9(1) (1), 31 - 38, English, International magazine[Refereed]Scientific journal
- Orbitofrontal cortex (OFC) neurons encode rewards and the cues that predict them, providing a neural substrate for outcome expectancy, an important component of goal-directed behavior in animals and humans. Here, we recorded and analyzed single units from rat lateral OFC during performance of a task in which the encoding of an expected rewarding outcome could be isolated from the response made in obtaining it. We found concurrent encoding of the expected outcome and the behavioral response in mostly separate populations of OFC units, in each phase of task performance: odor sampling, behavioral response, and waiting during the delay before reward delivery. Population analyses showed that outcome encoding broadly spanned across each behavioral phase, whereas response-selective firings were time-locked to the behavioral events, especially the completion of the behavioral response. A significant subset of outcome-selective units maintained selective firings from either odor sampling or response initiation until reward delivery. In contrast, response-selective units typically showed transient activation time locked to the behavioral events and were less likely to maintain selective firings across behavioral phases than outcome-selective units. These data demonstrate a broader role of OFC information processing in goal-directed behavior, beyond its widely recognized role in outcome expectancy.SOC NEUROSCIENCE, May 2008, JOURNAL OF NEUROSCIENCE, 28(19) (19), 5127 - 5138, English, International magazine[Refereed]Scientific journal
- Prostaglandin E 2 (PGE 2) exerts its actions via four subtypes of the PGE receptor, EP1-4. We show that mice deficient in EP1 exhibited significantly attenuated Th1 response in contact hypersensitivity induced by dinitrofluorobenzene ( DNFB). This phenotype was recapitulated in wild-type mice by administration of an EP1-selective antagonist during the sensitization phase, and by adoptive transfer of T cells from sensitized EP1(-/-) mice. Conversely, an EP1-selective agonist facilitated Th1 differentiation of naive T cells in vitro. Finally, CD11c(+) cells containing the inducible form of PGE synthase increased in number in the draining lymph nodes after DNFB application. These results suggest that PGE 2 produced by dendritic cells in the lymph nodes acts on EP1 in naive T cells to promote Th1 differentiation.ROCKEFELLER UNIV PRESS, Nov. 2007, JOURNAL OF EXPERIMENTAL MEDICINE, 204(12) (12), 2865 - 2874, English, International magazine[Refereed]Scientific journal
- Dopamine is involved in multiple neural functions including motor control, reward and motivational processing, learning and reinforcement, and cognitive attention. Dopamine binds to two distinct classes of receptors, namely D-1 and D-2, to exert these functions. Various endogenous substances regulate dopamine signaling, although their physiological functions are not fully understood. Here, we examined the role of prostaglandin E-2 (PGE(2)) and one of its receptors, EP1, in dopaminergic function in the striatum. EP1 was expressed in both preprodynorphin-containing D-1 and preproenkephalin-containing D-2 neurons, and PGE(2) was produced in striatal slices in response to both D-1 and D-2 dopamine receptor stimulation. EP1- deficient mice exhibited significant suppression of hyperlocomotion induced by cocaine or SKF81297 (6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine hydrobromide), a D-1 agonist, and significant attenuation of catalepsy induced by raclopride, aD(2) antagonist. Despite these behavioral defects, the extracellular concentration of dopamine was not suppressed in the striatum of EP1- deficient mice, and the densities of D-1 and D-2 receptors in the striatum were not different between the two genotypes. Stimulation of the D-1 receptor induced phosphorylation of dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 in striatal slices, and the addition of indomethacin, a PG synthesis inhibitor, attenuated the D-1 agonist- induced increase in DARPP-32 -Thr34 phosphorylation. The further addition of an EP1 agonist restored the indomethacin-attenuated phosphorylation. Furthermore, both D-1- and D-2-mediated changes in the DARPP-32 -Thr34 phosphorylation were attenuated in EP1 (-/-) slices. These results suggest that PGE(2) is formed in response to dopamine receptor stimulation in the striatum and amplifies both D-1 and D-2 receptor signaling via EP1.SOC NEUROSCIENCE, Nov. 2007, JOURNAL OF NEUROSCIENCE, 27(47) (47), 12900 - 12907, English, International magazine[Refereed]Scientific journal
- Research using laboratory animals, alongside clinical studies of human patients, support a role for the orbitofrontal cortex (OFC) in adaptive decision-making and goal-directed behavior. The functions of OFC neurons within this domain have been studied extensively in both rats and primates. Electrophysiological recordings during performance of relevant behavioral tasks provide a coherent portrait of OFC encoding that is reward related. OFC neurons represent associative relationships between events, encoding information that is predictive of outcome value. That encoding can be understood as a neural basis for deficits seen after OFC damage in the use of outcome expectancy to guide performance. There is less agreement, however, on whether OFC itself plays a role in translating information on outcome expectancy into the actual guidance of overt behavioral responding. New findings indicate that rat OFC neurons prominently encode additional task-related information and events related to goal-directed action. This encoding can occur in populations of OFC neurons that are independent of the OFC neurons representing reward value. The significance of this emerging evidence may require studies that address the larger scale network through which OFC integrates expected outcome information with behavioral control.BLACKWELL PUBLISHING, 2007, LINKING AFFECT TO ACTION: CRITICAL CONTRIBUTIONS OF THE ORBITOFRONTAL CORTEX, 1121, 193 - 215, English, International magazine[Refereed]Scientific journal
- Despite the critical importance of Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) II signaling in neuroplasticity, only a limited amount of work has so far been available regarding the presence and significance of another predominant CaMK subfamily, the CaMKI/CaMKIV family, in the central nervous system. We here searched for kinases with a core catalytic structure similar to CaMKI and CaMKIV. We isolated full-length cDNAs encoding three mouse CaMKI/CaMKIV-related kinases, CLICK-I (CL1)/doublecortin and CaM kinase-Like (DCAMKL)1, CLICK-II (CL2)/DCAMKL2, and CLICK-I, II-related (CLr)/DCAMKL3, the kinase domains of which had an intermediate homology not only to CaMKI/CaMKIV but also to CaMKII. Furthermore, CL1, CL2, and CLr were highly ;expressed in the central nervous system, in a neuron-specific fashion. CL1 alpha and CL1 beta were shorter isoforms of DCAMKL1, which lacked the doublecortin-like domain (Dx). In contrast, CL2 alpha and CL2 beta contained a full N-terminal Dx, whereas CLr only possessed a partial and dysfunctional Dx. Interestingly, despite a large similarity in the kinase domain, CL1/CL2/CLr had an impact on CRE-dependent gene expression distinct from that of the related CaMKI/CaMKIV and CaMKII. Although these were previously shown to activate Ca2+/cAMP-response element-binding protein (CREB)-dependent transcription, we here show that CL1 and CL2 were unable to significantly phosphorylate CREB Ser-133 and rather inhibited CRE-dependent gene expression by a dominant mechanism that bypassed CREB and was mediated by phosphorylated TORC2.AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Jul. 2006, JOURNAL OF BIOLOGICAL CHEMISTRY, 281(29) (29), 20427 - 20439, English, International magazine[Refereed]Scientific journal
- Animals under stress take adaptive actions that may lead to various types of behavioral disinhibition. Such behavioral disinhibition, when expressed excessively and impulsively, can result in harm in individuals and cause a problem in our society. We now show that, under social or environmental stress, mice deficient in prostaglandin E receptor subtype EP1 (Ptger1(-/-)) manifest behavioral disinhibition, including impulsive aggression with defective social interaction, impaired cliff avoidance, and an exaggerated acoustic startle response. This phenotype was reproduced in wild-type mice by administration of an EP1-selective antagonist, whereas administration of an EP1-selective agonist suppressed electric-shock-induced impulsive aggression. Dopamine turnover in the frontal cortex and striatum was increased in Ptger1(-/-) mice, and administration of dopaminergic antagonists corrected their behavioral phenotype. These results suggest that prostaglandin E-2 acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans.NATL ACAD SCIENCES, Nov. 2005, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 102(44) (44), 16066 - 16071, English, International magazine[Refereed]Scientific journal
- Extensive pharmacological studies have recently emerged indicating that group 2 metabotropic glutamate receptors (mGluRs) comprising mGluR2 and mGluR3 subtypes are associated with several neurological and psychiatric disorders. mGluR2 is widely distributed both presynaptically and postsynaptically in a variety of neuronal cells, but the physiological role of mGluR2 in brain function is poorly understood. This investigation involves a comprehensive behavioral analysis of mGluR2(-/-) knockout (KO) mice to explore the physiological role of mGluR2 in brain function. Although, under general observation, mGluR2(-/-) KO mice appeared to have no behavioral abnormalities, they exhibited several lines of behavioral alterations in the enforcing and defined behavioral tests. They showed a significant increase in locomotor sensitization and conditioned place preference in association with repeated cocaine administration, indicating that mGluR2 contributes to behavioral responses implicated in reinforcement and addiction of cocaine. Upon in vivo microdialysis analysis after cocaine administration, not only did extracellular levels of dopamine increase but also the response pattern of glutamate release markedly changed in the nucleus accumbens of mGluR2(-/-) KO mice. The mGluR2(-/-) KO mice also showed significant impairment in motor coordination in the accelerating rota-rod test and exhibited hyperlocomotion in novel environmental and stressful conditions, when assessed by the open-field and forced-swim tests. These results indicate that the inhibitory mGluR2 plays a pivotal role in synaptic regulation of glutamatergic transmission in the neural network.NATL ACAD SCIENCES, Mar. 2005, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 102(11) (11), 4170 - 4175, English, International magazine[Refereed]Scientific journal
- During a screen for novel putative Ca2+/calmodulin-dependent protein kinase (CaMK)-like CREB kinases (CLICKs), we have cloned a full-length cDNA for CLICK-III/CaMKIgamma, an isoform of the CaMKI family with an extended C-terminal domain ending with CAAX motif (where AA is aliphatic acid). As expected from the similarity of its kinase domain with the other CaMKI isoforms, full activation of CLICK-III/CaMKIgamma required both Ca2+/CaM and phosphorylation by CaMKK. We also found that Ca2+/cAMP-response element-binding protein (CREB) was a good substrate for CLICK-III/CaMKIgamma, at least in vitro. Interestingly enough, CLICKIII/CaMKIgamma transcripts were most abundant in neurons, with the highest levels in limited nuclei such as the central nucleus of the amygdala (CeA) and the ventromedial hypothalamus. Consistent with the presence of the CAAX motif, CLICK-III/CaMKIgamma was found to be anchored to various membrane compartments, especially to Golgi and plasma membranes. Both point mutation in the CAAX motif and treatment with compactin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, disrupted such membrane localization, suggesting that membrane localization of CLICK-III/CaMKIgamma occurred in a prenylation-dependent way. These findings provide a novel mechanism by which neuronal CaMK activity could be targeted to specific membrane compartments.AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, May 2003, JOURNAL OF BIOLOGICAL CHEMISTRY, 278(20) (20), 18597 - 18605, English, International magazine[Refereed]Scientific journal
- Rho-GTPase has been implicated in axon outgrowth. However, not all of the critical steps controlled by Rho have been well characterized. Using cultured cerebellar granule neurons, we show here that stromal cell-derived factor (SDF)-1alpha, a neural chemokine, is a physiological ligand that can turn on two distinct Rho-dependent pathways with opposite consequences. A low concentration of the ligand stimulated a Rho-dependent pathway that mediated facilitation of axon elongation. In contrast, Rho/ROCK activation achieved by a higher concentration of SDF-1alpha caused repression of axon formation and induced no more increase in axon length. However, even at this higher concentration a Rho-dependent axon elongating activity could be recovered upon removal of ROCK activity using Y-27632. SDF-1alpha-induced axon elongating activity under ROCK inhibition was replicated by the dominant-active form of the mammalian homologue of the Drosophila gene Diaphanous (mDia)1 and counteracted by its dominant-negative form. Furthermore, RNAi knockdown of mDia1 abolished SDF-1alpha-induced axon elongation. Together, our results support a critical role for an SDF-1alpha/Rho/mDia1 pathway in mediating axon elongation.ROCKEFELLER UNIV PRESS, Apr. 2003, JOURNAL OF CELL BIOLOGY, 161(2) (2), 381 - 391, English, International magazine[Refereed]Scientific journal
- Sickness evokes various neural responses, one of which is activation of the hypothalamo-pituitary-adrenal (HPA) axis. This response can be induced experimentally by injection of bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1. Although prostaglandins (PGs) long have been implicated in LPS-induced HPA axis activation, the mechanism downstream of PGs remained unsettled. By using mice lacking each of the four PGE receptors (EP1-EP4) and an EP1-selective antagonist, ONO-8713, we showed that both EP1 and EP3 are required for adrenocorticotropic hormone release in response to LPS. Analysis of c-Fos expression as a marker for neuronal activity indicated that both EP1 and EN contribute to activation of neurons in the paraventricular nucleus of the hypothalamus (PVN). This analysis also revealed that EP1, but not EP3, is involved in LPS-induced activation of the central nucleus of the amygdala. EP1 immunostaining in the PVN revealed its localization at synapses on corticotropin-releasing hormone-containing neurons. These findings suggest that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness.NATL ACAD SCIENCES, Apr. 2003, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 100(7) (7), 4132 - 4137, English, International magazine[Refereed]Scientific journal
- Cytoskeleton is believed to contribute to activity-dependent processes underlying neuronal plasticity, such as regulations of cellular morphology and localization of signaling proteins. However, how neuronal activity controls actin cytoskeleton remains obscure. Taking advantage of confocal imaging of enhanced GFP-actin in the primary culture of hippocampal neurons, we show that synaptic activity induces multiple types of actin reorganization, both at the spines and at the somatic periphery. Activation of N-methyl-D-aspartate receptors, accompanied with a local rise in [Ca2+](i), was sufficient to trigger a slow and sustained recruitment of actin into dendritic spines. In contrast, opening of voltage-gated Ca2+ channels rapidly and reversibly enhanced cortical actin at the somatic periphery but not in the spines, in keeping with a high transient rise in somatic [Ca2+](i). These data suggest that spatiotemporal dynamics of [Ca2+](i), triggered by activation of N-methyl-D-aspartate receptors and voltage-gated Ca2+ channels, provides the molecular basis for activity-de pendent actin remodeling.NATL ACAD SCIENCES, Oct. 2002, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 99(22) (22), 14458 - 14463, English, International magazine[Refereed]Scientific journal
- The small GTPase Rho acts on two effectors, ROCK and mDia1, and induces stress fibers and focal adhesions. However, how ROCK and mDia1 individually regulate signals and dynamics of these structures remains unknown. We stimulated serum-starved Swiss 3T3 fibroblasts with LPA and compared the effects of C3 exoenzyme, a Rho inhibitor, with those of Y-27632, a ROCK inhibitor. Y-27632 treatment suppressed LPA-induced formation of stress fibers and focal adhesions as did C3 exoenzyme but induced membrane ruffles and focal complexes, which were absent in the C3 exoenzyme-treated cells. This phenotype was suppressed by expression of N17Rac. Consistently, the amount of GTP-Rac increased significantly by Y-27632 in LPA-stimulated cells. Biochemically, Y-27632 suppressed tyrosine phosphorylation of paxillin and focal adhesion kinase and not that of Cas. Inhibition of Cas phosphorylation with PP1 or expression of a dominant negative Cas mutant inhibited Y-27632-induced membrane ruffle formation. Moreover, Crk-II mutants lacking in binding to either phosphorylated Cas or DOCK180 suppressed the Y-27632-induced membrane ruffle formation. Finally, expression of a dominant negative mDia1 mutant also inhibited the membrane ruffle formation by Y-27632. Thus, these results have revealed the Rho-dependent Rac activation signaling that is mediated by mDia1 through Cas phosphorylation and antagonized by the action of ROCK.ROCKEFELLER UNIV PRESS, May 2002, JOURNAL OF CELL BIOLOGY, 157(5) (5), 819 - 830, English, International magazine[Refereed]Scientific journal
- Coordination of microtubules and the actin cytoskeleton is important in several types of cell movement. mDia1 is a member of the formin-homology family of proteins and an effector of the small GTPase Rho. It contains the Rho-binding domain in its amino terminus and two distinct regions of formin homology, FH1 in the middle and FH2 in the carboxy terminus. Here we show that expression of mDia1(Delta N3), an active mDia1 mutant containing the FH1 and FH2 regions without the Rho-binding domain, induces bipolar elongation of HeLa cells and aligns microtubules in parallel to F-actin bundles along the long axis of the cell. The cell elongation and microtubule alignment caused by this mutant is abolished by co-expression of an FH2-region fragment, and expression of mDia1(Delta N3) containing point mutations in the FH2 region causes an increase in the amount of disorganized F-actin without cell elongation and microtubule alignment. These results indicate that mDia1 may coordinate microtubules and F-actin through its FH2 and FH1 regions, respectively.NATURE PUBLISHING GROUP, Jan. 2001, NATURE CELL BIOLOGY, 3(1) (1), 8 - 14, English[Refereed]Scientific journal
- A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neuronsWe tested the contribution of the small GTPase Rho and its downstream target p160ROCK during the early stages of axon formation in cultured cerebellar granule neurons, p160ROCK inhibition, presumably by reducing the stability of the cortical actin network, triggered immediate outgrowth of membrane ruffles and filopodia, followed by the generation of initial growth cone-like membrane domains from which axonal processes arose. Furthermore, a potentiation in both the size and the motility of growth cones was evident, though the overall axon elongation rate remained stable. Conversely, overexpression of dominant active forms of Rho or ROCK was suggested to prevent initiation of axon outgrowth. Taken together, our data indicate a novel role for the Rho/ROCK pathway as a gate critical for the initiation of axon outgrowth and the control of growth cone dynamics.CELL PRESS, May 2000, NEURON, 26(2) (2), 431 - 441, English[Refereed]Scientific journal
- The small GTPase Rho, which regulates cell shape, is thought to contribute to cytokinesis. Recently, Citron was characterized as a Rho target. This large protein contains a Ser/Thr kinase domain related to that of ROCK, another Rho effector. Both endogenous Citron and recombinant Citron localize to the cleavage furrow in dividing cells and to the midbody in postmitotic cells. Moreover, overexpression of Citron deleted from its C-terminal sequence caused abnormal contractions specifically during cytokinesis, resulting in the formation of multinucleated cells. Cell shape, F-actin, intermediate filaments, and microtubules appeared essentially normal in these cells during interphase. Thus, Citron is a Rho effector that appears to function during cytokinesis, modulating its contractile process. In brain, however, Citron is highly expressed in a subset of neurons as a brain-specific isoform that lacks a kinase domain, Citron-N. This protein accumulates in synapses and associates to the NMDA receptor via interaction with the adaptor protein PSD95, suggesting that the function of Citron is specialized in the neurons. Microsc. Res. Tech. 49:123-126, 2000. (C) 2000 Wiley-Liss, Inc.WILEY-LISS, Apr. 2000, MICROSCOPY RESEARCH AND TECHNIQUE, 49(2) (2), 123 - 126, English[Refereed]Scientific journal
- Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamusProteins of the membrane-associated guanylate kinase family play an important role in the anchoring and clustering of neurotransmitter receptors in the postsynaptic density (PSD) at many central synapses. However, relatively little is known about how these multifunctional scaffold proteins might provide a privileged site for activity- and cell type-dependent specification of the postsynaptic signaling machinery. Rho signaling pathway has classically been implicated in mechanisms of axonal outgrowth, dendrogenesis, and cell migration during neural development, but its contribution remains unclear at the synapses in the mature CNS. Here, we present evidence that Citron, a Rho-effector in the brain, is enriched in the PSD fraction and interacts with PSD-95/synapse-associated protein (SAP)-90 both in vivo and in vitro. Citron colocalization with PSD-95 occurred, not exclusively but certainly, at glutamatergic synapses in a limited set of neurons, such as the thalamic excitatory neurons; Citron expression, however, could not be detected in the principal neurons of the hippocampus and the cerebellum in the adult mouse brain. In a heterologous system, Citron was shown to form a heteromeric complex not only with PSD-95 but also with NMDA receptors. Thus, Citron-PSD-95/SAP-90 interaction may provide a region- and cell type-specific link between the Rho signaling cascade and the synaptic NMDA receptor complex.SOC NEUROSCIENCE, Jan. 1999, JOURNAL OF NEUROSCIENCE, 19(1) (1), 109 - 118, English[Refereed]Scientific journal
- 日本神経化学会, Sep. 1998, 神経化学, 37(3) (3), 410 - 410, JapaneseRho標的分子,Citronは視床のグルタミン酸性シナプスでPSD-95と結合する
- Using a mouse embryo cDNA library, we conducted a two-hybrid screening to identify new partners for the small GTPase Rho. One clone obtained by this procedure contained a novel cDNA of 291 base pairs and interacted strongly with RhoA and RhoC, weakly with RhoB, are not at all with Rac1 and Cdc42Hs. Full-length cDNAs were then isolated from a mouse brain library. While multiple splicing variants were common, we identified three cDNAs with an identical open reading frame encoding a 61-kDa protein that we named rhotekin (from the Japanese ''teki'', meaning target). The N-terminal part of rhotekin, encoded by the initial cDNA and produced in bacteria as a glutathione S-transferase fusion protein, exhibited in vitro binding to S-35-labeled guanosine 5'-3'O-(thio)triphosphate-bound Rho, but not to Rac1 of Cdc42Hs in ligand overlay assays. In addition, this peptide inhibited both endogenous and GTPase-activating proteins-stimulated Rho GTPase activity. The amino acid sequence of this region shares similar to 30% identity with the Rho-binding domains of rhophilin and a serine/threonine kinase, PKN, two other Rho target proteins that we recently identified (Watanabe, G., Saito, Y., Madaula, P., Ishizuki, T., Fujisawa, K., Morii, N., Mukai, H., Ono, Y., Kakizuka, A., and Narumiya, S. (1996) Science 271, 645-648). Thus, not only is rhotekin a novel partner for Rho, but it also belongs to a wide family of proteins that bear a consensus Rho-binding sequence at the N terminus. To our knowledge, this is the first conserved sequence for Rho effectors, and we have termed this region Rho effector motif class 1.AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Jun. 1996, JOURNAL OF BIOLOGICAL CHEMISTRY, 271(23) (23), 13556 - 13560, English[Refereed]Scientific journal
- Using the yeast two hybrid system and overlay assays me identified a putative rholrac effector, citron, which interacts with the GTP-bound forms of rho and rac1, but not with cdc42. Extensive homologies to known proteins were not observed. This 183 kDa protein contains a C6H2 zinc finger, a PH domain, and a long coiled-coil forming region including 4 leucine zippers and the rholrac binding site, We recently identified three others putative rho effecters characterized by a common rho binding motif. Citron does not share this motif and displays a distinctive protein organization, thus defining a separate class of rho partners.ELSEVIER SCIENCE BV, Dec. 1995, FEBS LETTERS, 377(2) (2), 243 - 248, English[Refereed]Scientific journal
- 日本臨床分子医学会, Apr. 2023, 日本臨床分子医学会学術総会プログラム・抄録集, 58回, 56 - 56, Japanese脳内炎症は骨格筋のC/EBP経路を介してストレス性筋萎縮を促進する
- (一社)日本糖尿病学会, Apr. 2023, 糖尿病, 66(Suppl.1) (Suppl.1), S - 189, Japanese脳内炎症は骨格筋のC/EBP経路を介してストレス性筋萎縮を促進する
- 2023, 日本薬理学会年会要旨集(Web), 97thSocial stress induces microglial contact with synapses, contributing to the release of heparan sulfate from synaptic proteoglycans in mice
- (一社)日本肥満学会, Nov. 2022, 肥満研究, 28(Suppl.) (Suppl.), 322 - 322, Japanese脳内炎症は骨格筋のC/EBP経路を介してストレス性筋萎縮を促進する
- 2022, 日本神経化学会大会抄録集(Web), 65thマウスの社会ストレスは前頭前皮質錐体神経細胞の樹状突起消失に先行して細胞内変性を誘導する
- Excessive or chronic social stress induces emotional and cognitive disturbances and precipitates mental illness. Altered neuronal morphology and functions in the medial prefrontal cortex (mPFC) underlie these behavioral abnormalities. However, its subcellular mechanisms remain elusive. Here we examined ultrastructural and multi-omics changes in the mPFC after social stress in mice. Social stress caused the loss of dendritic branches with morphological alterations of subcellular mitochondria and induced synaptic shrinkage selectively at the synapses with mitochondria. Multi-omics and functional analyses revealed that social stress deteriorated mitochondrial functions with altered mitochondrial proteome at synapses and dysregulated central metabolic pathways in the mPFC. Molecular biological and pharmacological manipulation targeting central metabolism and mitochondria attenuated the synaptic shrinkage and depression-related behaviors. These findings demonstrate that chronic social stress alters the central metabolism at mPFC synapses, leading to neuronal pathology and depression-related behaviors.Japanese Pharmacological Society, 2022, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 96, 3-B-O06-4, Japanese
- Aging causes cognitive and motivational declines, but the biological basis remains elusive. Here we analyzed distinct behavioral effects of aging in C57BL6N (B6N) and C57BL/6J (B6J) strains. In this study, mice first learned a visual discrimination task to obtain food rewards by responding to the correct one of two visual stimuli. Then, they learned a response direction task of responding to either left or right for food rewards. Attentional set-shifting, behavioral flexibility between the tasks, is known to depend on working memory. Aged B6N mice showed motivational declines in both tasks. By contrast, task motivation was intact in aged B6J mice, but some of them showed a deficit in attentional set-shifting. We also analyzed synaptic proteomes in the medial prefrontal cortex, a brain region crucial for attentional set-shifting. Young and aged B6J mice showed differential expression of many synaptic proteins, some of which increased only in a subset of the aged mice with attentional set-shifting intact. These findings suggest that different biological mechanisms related to genetic and synaptic factors underlie motivation and cognitive declines with aging.Japanese Pharmacological Society, 2022, Proceedings for Annual Meeting of The Japanese Pharmacological Society, 95, 1-SS-43, Japanese
- (公社)日本生物工学会, 2021, 日本生物工学会大会講演要旨集, 73rd, 148 - 148, JapaneseStress history monitoring based on mass spectrometry imaging in hair strand
- SPRINGERNATURE, Dec. 2020, NEUROPSYCHOPHARMACOLOGY, 45(SUPPL 1) (SUPPL 1), 107 - 108, EnglishChronic Stress-Induced Epigenetic Changes of MicrogliaSummary international conference
- NATURE PUBLISHING GROUP, Dec. 2019, NEUROPSYCHOPHARMACOLOGY, 44(SUPPL 1) (SUPPL 1), 120 - 121, EnglishRoles and Mechanisms of Neuroinflammation in Stress and DepressionSummary international conference
- 2018, 日本薬学会年会要旨集(CD-ROM), 138th神経発達脆弱性因子による成体期の精神機能への影響:PGE2の関与
- JAPANESE PHARMACOLOGICAL SOC, Mar. 2017, JOURNAL OF PHARMACOLOGICAL SCIENCES, 133(3) (3), S221 - S221, EnglishElevated p62 and attenuated autophagy cause GABA receptor downregulation and underlie the pathophysiology of neuropsychiatric manifestationSummary international conference
- OXFORD UNIV PRESS, Jun. 2016, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19, 122 - 122, EnglishInnate immune molecules activate microglia in mPFC to induce neuronal and emotional changes in mice.Summary international conference
- OXFORD UNIV PRESS, Jun. 2016, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19, 96 - 96, EnglishDopamine D1 receptor in the medial prefrontal cortex mediates behavioral resilience under stress in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, Mar. 2016, JOURNAL OF PHARMACOLOGICAL SCIENCES, 130(3) (3), S122 - S122, EnglishRepeated stress activates mPFC microglia through innate immune molecules for neuronal and emotional changes in miceSummary international conference
- 名城大学総合研究所, 2016, 名城大学総合研究所紀要, (21) (21), 93 - 96, Japanese周産期における免疫応答異常による精神機能への影響 : Prostaglandin E₂ (PGE₂)-EP1受容体シグナル伝達系の関与
- Roles of dopaminergic systems and inflammation-related molecules derived from microglia in stress-induced behavioral changesRepeated stress induces emotional changes and cognitive impairments, and is a risk factor for psychiatric disorders. Rodent studies have revealed critical roles of dopaminergic systems and inflammation-related molecules derived from microglia in repeated stress-induced behavioral changes. Acute stress preferentially activates the dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) through glucocorticoid receptor. This dopaminergic activation impairs working memory functions, but suppresses stress-induced social avoidance. Repeated stress attenuates this dopaminergic pathway, and consequently impairs working memory function and promotes stress-induced social avoidance. In contrast, repeated stress increases the excitability of the dopaminergic pathway projecting to the nucleus accumbens (NAc), from which BDNF is released in NAc and promotes stress-induced social avoidance and anhedonia. In addition, repeated stress induces expression of inflammation-related molecules in microglia through beta-adrenergic receptors. Under repeated stress, IL-1 beta induces behavioral depression and anxiety, perhaps partly through suppressing proliferation of neural stem cells in the hippocampus. IL-1 receptor signaling in endothelial cells augments expression of inflammation-related cytokines in microglia, thereby promoting stress-induced behavioral changes. TNF alpha and IL-6 are also critical for stress-induced depression-like behaviors. Repeated stress increases synthesis of prostaglandin (PG) E2 in microglia through PG synthase COX1. PGE2 in turn attenuates the dopaminergic pathway to mPFC through EP1 receptor, thereby promoting social avoidance by repeated stress. These findings show that repeated stress induces behavioral changes through neurotransmitters and inflammation-related molecules as well as the crosstalk between neurons and microglia.JAPANESE ASSOC STUDY PAIN, 2016, PAIN RESEARCH, 31(1) (1), 1 - 8, JapaneseBook review
- JAPANESE PHARMACOLOGICAL SOC, Jul. 2015, JOURNAL OF PHARMACOLOGICAL SCIENCES, 128(3) (3), S92 - S92, EnglishA role for mDia, a Rho-regulated actin nucleator, in regulating morphology of presynaptic terminals and increased anxiety-like behavior induced by social isolation stress in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, Jul. 2015, JOURNAL OF PHARMACOLOGICAL SCIENCES, 128(3) (3), S91 - S91, EnglishThe prostaglandin E-2 induces neuronal and behavioral impairments like psychiatric disordersSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, Jul. 2015, JOURNAL OF PHARMACOLOGICAL SCIENCES, 128(3) (3), S43 - S43, EnglishThe role of innate immune molecules in behavioral changes induced by repeated social defeat stress in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, Jul. 2015, JOURNAL OF PHARMACOLOGICAL SCIENCES, 128(3) (3), S140 - S140, EnglishTOR signaling pathway regulates transcription of Isp5, an amino acid permease, through GATA transcription factor Gaf1 in fission yeastSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, Jul. 2015, JOURNAL OF PHARMACOLOGICAL SCIENCES, 128(3) (3), S227 - S227, EnglishA role for dopamine D1 receptor in the medial prefrontal cortex in stress-induced emotional changesSummary international conference
- 日本臨床精神神経薬理学会・日本神経精神薬理学会, Nov. 2014, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 24回・44回, 206 - 206, Japanese新生仔期マウスへのプロスタグランジンE2暴露が若年期や成体期における精神行動に及ぼす影響
- Roles of inflammation-related molecules in emotional changes induced by repeated stressStress is a risk factor for psychiatric disorders. Studies using rodent stress models have shown critical roles for inflammation-related molecules in stress-induced behavioral changes. Under chronic mild stress, IL-1 beta through IL-1 receptor type 1 (IL-1RI) in the brain activates the hypothalamic-pituitary-adrenal axis, thereby stimulating glucocorticoid release, which in turn decreases motivation to obtain reward. IL-1 beta can also suppress proliferation of neural progenitor cells directly through IL-1RI and/or indirectly through glucocorticoid. In repeated social defeat stress, endothelial IL-1RI is involved in stress-induced upregulation of inflammation-related molecules and elevated anxiety. Prostaglandin (PG) E-2 and its receptor EP1 mediate elevated anxiety and social avoidance induced by repeated social defeat through attenuating a stress-coping action of the meso-prefrontal dopaminergic pathway. IL-10 and PGE(2) are thought to be released from microglia activated by repeated stress. Whereas the mechanism for stress-induced microglial activation remains elusive, it has been reported that repeated stress induces migration of peripheral macrophages into the brain in a manner dependent on IL-1RI and multiple chemokines, which are also critical for stress-induced elevated anxiety. These findings reveal multiple actions of inflammation-related molecules in the brain and the crosstalk between neurons and microglia as well as that between the brain and the periphery in rodent stress models.JAPANESE SOC NEUROPSYCHOPHARMACOLOGY-JSNP, Aug. 2014, JAPANESE JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 34(4) (4), 109 - 115, Japanese, Domestic magazine
- JAPANESE PHARMACOLOGICAL SOC, 2014, JOURNAL OF PHARMACOLOGICAL SCIENCES, 124, 98P - 98P, EnglishA role for mDia, a Rho-regulated actin nucleator, in elevated anxiety induced by social isolation stress in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2014, JOURNAL OF PHARMACOLOGICAL SCIENCES, 124, 215P - 215P, EnglishThe innate immune signaling plays an essential role in stress-induced emotional changesSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2014, JOURNAL OF PHARMACOLOGICAL SCIENCES, 124, 217P - 217P, EnglishFunctional changes of the medial prefrontal cortex induced by repeated social defeat stress in miceSummary international conference
- NATURE PUBLISHING GROUP, Dec. 2013, NEUROPSYCHOPHARMACOLOGY, 38, S548 - S549, EnglishA Role for Innate Immune Signaling in Microglia in Behavioral Changes Induced by Repeated Social Defeat Stress in MiceSummary international conference
- SPRINGER, Feb. 2013, NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 386, S57 - S57, EnglishMetabolomic investigation in TP receptor deficient miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2013, JOURNAL OF PHARMACOLOGICAL SCIENCES, 121, 80P - 80P, EnglishA role for inflammation-related molecules in behavioral depression induced by repeated stress in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2013, JOURNAL OF PHARMACOLOGICAL SCIENCES, 121, 64P - 64P, EnglishProstaglandin E receptor EP1 forms a complex with dopamine D1 receptor, regulates ligand binding of D1 receptors, and stimulates D1-induced cAMP production through G beta(Y) in HEK293T cellsSummary international conference
- 01 Dec. 2012, 日本薬理學雜誌 = Folia pharmacologica Japonica, 140(6) (6), 307 - 307, Japaneseストレスとミクログリア
- 日本臨床精神神経薬理学会・日本神経精神薬理学会, Oct. 2012, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 22回・42回, 167 - 167, Japanese新生仔期の免疫異常により惹起される行動障害におけるプロスタグランジンE2の関与
- 01 Oct. 2012, 日本薬理學雜誌 = Folia pharmacologica Japonica, 140(4) (4), 185 - 185, Japaneseストレスにおける中脳ドパミン系の役割
- 先端医学社, Jul. 2012, 分子精神医学, 12(3) (3), 215 - 217, Japanese注目の遺伝子(第18回)ストレス関連分子プロスタグランジンE₂
- JAPANESE PHARMACOLOGICAL SOC, 2012, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118, 29P - 29P, EnglishAttenuation of the mesocortical dopaminergic pathway and concomitant microglial activation in repeated social defeat stress in mice: Possible link via prostaglandin signalingSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2012, JOURNAL OF PHARMACOLOGICAL SCIENCES, 118, 8P - 8P, EnglishRoles of prostaglandin E-2-mediated dopaminergic regulation for emotional behavior under stressSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2011, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 256P - 256P, EnglishProstaglandin E receptor EP1 exerts a Ca2+-independent action in augmenting dopamine D1 receptor signaling via the C terminal domain of EP1Summary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2011, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 175P - 175P, EnglishProstaglandin E-2-EP2 signaling mediates chronic inflammation in cerebral aneurysm formation via NF-kappa BSummary international conference
- ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E167 - E167, EnglishSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2011, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 252P - 252P, EnglishProstaglandin E receptor EP1 is critical for social withdrawal and the plasticity of dopaminergic neurons after repeated social defeat in miceSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2011, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 133P - 133P, EnglishRoles of mDia isoforms, a Rho effector, in neuroblast migrationSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2011, JOURNAL OF PHARMACOLOGICAL SCIENCES, 115, 47P - 47P, EnglishRoles of prostaglandin E-2 in emotional behavior under acute and chronic stressSummary international conference
- ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E130 - E130, EnglishSummary international conference
- ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E52 - E52, EnglishSummary international conference
- 金原一郎記念医学医療振興財団, Sep. 2010, 生体の科学, 61(5) (5), 474 - 477, Japaneseドパミン系と興奮性シナプス可塑性におけるプロスタグランジンE2とその受容体の役割 (シナプスをめぐるシグナリンク)
- JAPAN ENDOCRINE SOC, Mar. 2010, ENDOCRINE JOURNAL, 57, S538 - S539, EnglishCentral control of body temperature by the osteoclast differentiation factors RANK/RANKSummary international conference
- 医歯薬出版, 02 Jan. 2010, 医学のあゆみ, 232(1) (1), 68 - 73, JapaneseRoles of prostanoid in stress responses
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E47 - E47, EnglishSummary international conference
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E121 - E121, EnglishSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2010, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 190P - 190P, EnglishRoles of thromboxane receptor in dopamine signaling in the striatumSummary international conference
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E355 - E355, EnglishSummary international conference
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E138 - E138, EnglishSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2010, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 123P - 123P, EnglishRoles of prostaglandin E2 and its receptor EP1 in adaptive selection of emotional behaviorsSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2010, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 190P - 190P, EnglishRoles of prostaglandin E2 and its receptor EP1 in social withdrawal due to repeated social defeat in miceSummary international conference
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E171 - E171, EnglishSummary international conference
- ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E235 - E235, EnglishSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2010, JOURNAL OF PHARMACOLOGICAL SCIENCES, 112, 190P - 190P, EnglishTwo opposite actions of prostaglandin E receptor EP1 on dopamine D1 receptor signalingSummary international conference
- ELSEVIER IRELAND LTD, 2009, NEUROSCIENCE RESEARCH, 65, S95 - S95, EnglishSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2008, JOURNAL OF PHARMACOLOGICAL SCIENCES, 106, 67P - 67P, EnglishProstaglandin E-2 acts on EP1 receptor and amplifies both dopamine D1 and D2 receptor signaling in the striatumSummary international conference
- ELSEVIER IRELAND LTD, 2008, NEUROSCIENCE RESEARCH, 61, S261 - S261, EnglishRodent orbitofrontal cortex separately encodes response and outcome information during performance of goal-directed behaviorSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2008, JOURNAL OF PHARMACOLOGICAL SCIENCES, 106, 231P - 231P, EnglishProstaglandin E receptor EP1 enhances GABA-mediated inhibition of dopaminergic neurons in the substantia nigra and suppresses dopamine level in dorsal striatumSummary international conference
- ELSEVIER IRELAND LTD, 2008, NEUROSCIENCE RESEARCH, 61, S221 - S221, EnglishProstaglandin E receptor EP1 enhances GABA-mediated inhibition of dopaminergic neurons in the substantia nigra and suppresses dopamine level in dorsal striatumSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2008, JOURNAL OF PHARMACOLOGICAL SCIENCES, 106, 94P - 94P, EnglishFacilitation of Th1-mediated immune response by prostaglandin E receptor EP1Summary international conference
- ELSEVIER IRELAND LTD, 2008, NEUROSCIENCE RESEARCH, 61, S81 - S81, EnglishProstaglandin E receptor EP1 amplifies dopaminergic signaling in the striatumSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2007, JOURNAL OF PHARMACOLOGICAL SCIENCES, 103, 55P - 55P, EnglishPGE(2)-EP1 signaling facilitate Th1 immune responseSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2007, JOURNAL OF PHARMACOLOGICAL SCIENCES, 103, 135P - 135P, EnglishProstaglandin e receptor subtype EP1 regulates dopamine receptor signaling in the striatum.Summary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2006, JOURNAL OF PHARMACOLOGICAL SCIENCES, 100, 93P - 93P, EnglishPGE2 receptor EP1 enhance Th1 differentiationSummary international conference
- ELSEVIER IRELAND LTD, 2006, NEUROSCIENCE RESEARCH, 55, S170 - S170, EnglishProstaglandin E2 potentiates dopamine D1 receptor signaling via EP1Summary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2006, JOURNAL OF PHARMACOLOGICAL SCIENCES, 100, 193P - 193P, EnglishProstaglandin E-2 potentiates D1R signaling via EP1Summary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2005, JOURNAL OF PHARMACOLOGICAL SCIENCES, 97, 273P - 273P, EnglishProstaglandin E-2 modulates midbrain dopaminergic system via its receptor EP1Summary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2004, JOURNAL OF PHARMACOLOGICAL SCIENCES, 94, 228P - 228P, EnglishProstaglandin E receptor EP1 regulates dopamine release in vivoSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2004, JOURNAL OF PHARMACOLOGICAL SCIENCES, 94, 56P - 56P, EnglishProstanoid receptor-dependent mechanism regulating stress-related behaviorsSummary international conference
- JAPANESE PHARMACOLOGICAL SOC, 2004, JOURNAL OF PHARMACOLOGICAL SCIENCES, 94, 18P - 18P, EnglishBehavioral approaches for emotion in the prostaglandin E receptor mutant miceSummary international conference
- 2003, 日本脳神経外科学会総会抄録集, 62nd(CD-ROM Abstracts) (CD-ROM Abstracts)「神経再生移植(2)」低分子量G蛋白Rho情報伝達系操作による機能的神経再生の可能性の探索:軸索伸展制御機構の解析
- JAPANESE PHARMACOLOGICAL SOC, 2003, JOURNAL OF PHARMACOLOGICAL SCIENCES, 91, 21P - 21P, EnglishDynamic and activity-dependent control of neuronal actin cytoskeleton.Summary international conference
- 2002, 生化学, 74(8) (8)新規CREB kinase CLICK-I&IIによるCREB抑制の可能性
- 2002, 日本神経科学大会プログラム・抄録集, 25thRhoGTPase effector mDia1の軸索伸展過程における役割の解析
- 2002, 日本神経科学大会プログラム・抄録集, 25th海馬神経細胞におけるCa2+とアクチン細胞骨格の時間的・空間的制御
- 2002, 日本脳神経外科学会総会抄録集, 61st(CD-ROM Abstracts) (CD-ROM Abstracts)Rho 情報伝達系操作により機能的神経再生ができるか?:Rho 情報伝達系による軸索伸展制御機構の解析
- 2002, 日本神経科学大会プログラム・抄録集, 25th新規CaM kinase CLICK-IIIのクローニング及び解析
- 2002, 生化学, 74(8) (8)新規CREBキナーゼCLICK-IIIによるCREB活性化機構
- 01 Dec. 1998, 日本分子生物学会年会プログラム・講演要旨集, 21, 643 - 643, JapaneseCitron, a Rho target, interacts with PSD-95 at glutamatergic synapses in the thalamus
- 01 Dec. 1998, 日本分子生物学会年会プログラム・講演要旨集, 21, 199 - 199, JapaneseNeuronal CREB signaling and synaptic Ca^<2+> influx
- Joint work, Part III Lipid Mediators and Diseases, 22. Roles and actions of arachidonic acid-derived bioactive lipids in stress-related behaviors., Springer, Nov. 2015, 315-328Bioactive Lipid Mediators Current Reviews and Protocols
- INTERNATIONAL COLLEGE OF NEUROPSYCHOPHARMACOLOGY
- SOCIETY FOR NEUROSCIENCE
- JAPANESE ASSOCIATION FOR THE STUDY OF PAIN
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- THE JAPANESE SOCIETY OF NEUROPSYCHOPHARMACOLOGY
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- JAPANESE SOCIETY OF BIOLOGICAL PSYCHIATRY