論文 - 溝口　博之

Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic Reln deletion (vol 1010, pg 178407, 2026) Open Access

Zhu, YY; Kitagawa, K; Mori, D; Matsuzaki, T; Nagai, T; Nabeshima, T; Takemoto-Kimura, S; Ikesue, H; Ozaki, N; Mizoguchi, H; Yamada, K

EUROPEAN JOURNAL OF PHARMACOLOGY   1012 巻   頁： 178469   2026年1月

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記述言語：英語   出版者・発行元：European Journal of Pharmacology  

The authors regret that the online Supplementary figures published in the article appeared blurry, affecting the clarity of data visualization. The authors have prepared revised high-resolution versions of all supplementary figures to ensure accurate presentation. Supplementary Figure 1.(Figure presented) Supplementary Figure 2.(Figure presented) Supplementary Figure 3.(Figure presented) Supplementary Figure 4.(Figure presented) In addition, several minor factual errors were identified in Supplementary Figure 2, and the corrected information is provided below: Supplementary Figure 2B legend. Current: Reln^del/del: n = 4. Correct: Reln^del/del: n = 5. Correct Supplementary Figure 2B. An unintended duplicate plotted data point was included in the WT group and has now been removed. Supplementary Figure 2D legend. Current: Reln^del/del: n = 3. Correct: Reln^del/del: n = 4. 3. Statistics table. Current:Figure S2BWT = 10Treatment (between columns): F (2, 22) = 14.32, P = 0.0001Body weight: WT vs. Reln^del/+:P = 0.9446Reln^del/+ = 10Body weight: WT vs. Reln^del/del:P = 0.0001Reln^del/del = 5 Correct:(Figure presented)Figure S2BWT = 9Gene: F (2, 21) = 13.79, P = 0.0001Body weight: WT vs. Reln^del/+:P = 0.9174Reln^del/+ = 10Body weight: WT vs. Reln^del/del:P = 0.0002Reln^del/del = 5 Current:Figure S2DWT = 3Treatment (between columns): F (2, 7) = 5.742, P = 0.0334Reln^del/+ = 3Reln^del/del = 4 Correct:Figure S2DWT = 3Gene: F (2, 7) = 5.742, P = 0.0334Reln^del/+ = 3Reln^del/del = 4 These corrections are purely factual and do not affect the raw data, statistical analyses, or the scientific conclusions of the study. All original raw data remain accurate and consistent with the revised supplementary figures. The authors would like to apologize for any inconvenience caused.

DOI： 10.1016/j.ejphar.2025.178469

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Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic<i> Reln</i> deletion Open Access

Zhu, YY; Kitagawa, K; Mori, D; Matsuzaki, T; Nagai, T; Nabeshima, T; Takemoto-Kimura, S; Ikesue, H; Ozaki, N; Mizoguchi, H; Yamada, K

EUROPEAN JOURNAL OF PHARMACOLOGY   1010 巻   頁： 178407   2026年1月

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記述言語：英語   出版者・発行元：European Journal of Pharmacology  

Reelin is an essential extracellular matrix glycoprotein that regulates cortical layers formation and has been implicated in several neuropsychiatric conditions, including schizophrenia (SCZ). To explore its role in brain function and its potential involvement in SCZ, we developed a Reln heterozygous deletion ( Reln ^del/+) mouse model that replicates a genetic deletion identified in a Japanese patient with SCZ. In previous studies, we demonstrated that Reln ^del/+ mice exhibit cognitive impairments in a visual discrimination test. In the present study, we found that Reln ^del/+ mice displayed impairments in social novelty recognition and social odor responses, whereas social preference and non-social odor responses remained intact. Immunohistochemical analyses revealed a significant decrease in the numbers of calcium/calmodulin-dependent protein kinase II-positive glutamatergic pyramidal neurons, gamma-aminobutyric acid-ergic interneurons, parvalbumin-positive interneurons and somatostatin-positive interneurons in the medial prefrontal cortex (mPFC) of Reln ^del/+ mice. Furthermore, Reln ^del/+ mice exhibited significant deficits in excitatory spine density and morphology, along with a reduced number of PV boutons in the mPFC compared to wild-type (WT) controls. Finally, we demonstrated that injection of adeno-associated virus (AAV)-R36-Myc into the mPFC improved social novelty impairments in Reln ^del/+ mice, with no observable effects in WT controls. These findings indicate that Reln ^del/+ mice provide a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Furthermore, the efficacy of AAV-R36-Myc highlights the therapeutic potential of Reelin replacement, warranting further investigation as a targeted treatment strategy for SCZ.

DOI： 10.1016/j.ejphar.2025.178407

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Acute systemic immune challenge induces cognitive impairments and anhedonia through interferon-induced transmembrane protein 3 in adult male mice Open Access

Zhu, WJ; Sobue, A; Tanaka, R; Hada, K; Ibi, D; Liu, Y; Matsuzaki, T; Nagai, T; Nabeshima, T; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Ikesue, H; Yamada, K

BEHAVIOURAL BRAIN RESEARCH   496 巻   頁： 115832   2026年1月

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記述言語：英語   出版者・発行元：Behavioural Brain Research  

Systemic immune challenge can also cause neuropsychiatric abnormalities. Interferon-induced transmembrane protein 3 (IFITM3) plays a crucial role in cellular immune defense. Previously, we have demonstrated that IFITM3 affects neurodevelopment during the early developmental stage in mice, acting through innate immune activation. However, the pathophysiological significance of IFITM3 in immune system activation in adulthood remains unclear. To address this issue, we aimed to analyze the expression level of IFITM3 in the brain and the behavioral abnormalities in polyriboinosinic-polyribocytidylic acid (polyI:C)-treated adult male C57/BL6J wild-type (WT) and Ifitm3^-/- mice. The expression levels of Ifitm3 mRNA and protein were significantly upregulated in the medial prefrontal cortex (mPFC), striatum, and hippocampus 24 h after polyI:C treatment in WT mice compared to saline-treated control mice. Furthermore, behavioral experiments revealed that polyI:C treatment induced cognitive dysfunction and anhedonia in WT mice, whereas Ifitm3^-/- mice were resistant to these disorders. In conclusion, our results demonstrated that in adult mice, immune activation following polyI:C treatment may induce cognitive dysfunction and anhedonia through IFITM3 upregulation in the brain. These results suggest that IFITM3 is an attractive therapeutic target for neuropsychiatric dysfunction following immune activation in adulthood.

DOI： 10.1016/j.bbr.2025.115832

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Abnormal behaviors and glial responses in an animal model of tau pathology Open Access

Liu, Y; Sobue, A; Sahara, N; Isobe, M; Tanaka, R; Zhu, YY; Zhu, WJ; Matsuzaki, T; Yamanaka, K; Yamada, K; Mizoguchi, H

MOLECULAR BRAIN   18 巻 ( 1 ) 頁： 83   2025年11月

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記述言語：英語   出版者・発行元：Molecular Brain  

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

DOI： 10.1186/s13041-025-01252-4

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Activation of orexin neurons changes reward-based decision-making strategies Open Access

Mizoguchi, H; Katahira, K; Inutsuka, A; Kaneko, R; Ono, D; Hada, K; Murata, Y; Yasuike, S; Isobe, M; Kusaba, M; Dong, YT; Iida, H; Fukumoto, K; Yanagawa, Y; Yamanaka, A; Yamada, K

PNAS NEXUS   4 巻 ( 11 ) 頁： pgaf322   2025年11月

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記述言語：英語   出版者・発行元：Pnas Nexus  

Orexin neurons regulate physiological functions, including not only energy homeostasis and wakefulness but also motivated behaviors. These neurons play important roles in linking metabolic requirements to such behaviors. However, it is unknown whether these neurons are involved in reward-based choice behavior. We recently developed a transgenic rat line that expresses Cre recombinase exclusively in orexin neurons. Here, we examined the roles of orexin neurons in reward choice behavior under conditions of uncertainty in a gambling test in rats and analyzed the changes in choice behavior when orexin neurons were manipulated using chemogenetic approaches. In the gambling test, chemogenetic activation of orexin neurons resulted in risky arm choice. Positive, but not negative, reward-prediction error contributed to reward-based risky choice when orexin neurons were activated. These risky choice behaviors were canceled by suvorexant, an orexin receptor antagonist. In addition, suvorexant administered alone led to conservative choice behavior. The computational approach revealed that orexin/orexin neurons modulate the learning process and motivational value of rewards. Thus, our data suggest that orexin/orexin neurons affect the processing of reward-prediction error and alter strategy in reward-based decision-making.

DOI： 10.1093/pnasnexus/pgaf322

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Twinfilin-1 phosphorylation in reelin signaling regulates actin dynamics and spine development Open Access

Dong, GY; Mori, D; Matsuzaki, T; Tanaka, R; Itoh, N; Matsui, T; Sato, A; Arioka, Y; Okumura, H; Fukaya, R; Kuba, H; Nagai, T; Nabeshima, T; Ikesue, H; Kohno, T; Hattori, M; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Yamada, K

PHARMACOLOGICAL RESEARCH   221 巻   頁： 107986   2025年11月

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

Reelin is an extracellular glycoprotein essential for neuronal migration, spine development, and synaptic plasticity. Impaired reelin signaling is linked to neurological disorders, including schizophrenia and autism. While reelin mutant (reeler) mice exhibit behavioral deficits associated with impaired spine formation, the underlying molecular mechanisms remain unclear. We identified Twinfilin-1 (Twf1) as a downstream effector of reelin signaling via phosphoproteomic analysis, based on its reduced tyrosine phosphorylation in reeler mice. We found that Src regulated Twf1 phosphorylation at tyrosine 309, and reelin stimulation increased Twf1 phosphorylation in neurons, an effect blocked by the Src inhibitor PP2. A phospho-resistant Twf1 mutant (Twf1 Y309F) showed reduced capping protein binding and a lower F/G-actin ratio. Twf1^Y309F mice exhibited cognitive deficits, reduced spine density, smaller spine head size, and a decreased F/G-actin ratio in synaptosomes. These findings highlight Twf1 phosphorylation as a key component of reelin signaling involved in actin remodeling and spine development.

DOI： 10.1016/j.phrs.2025.107986

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Augmented orexin/hypocretin signaling underlies negative affect during acute oxycodone abstinence in rats.

Newman KA, Stiritz VA, Cheng J, Yamanaka A, Mizoguchi H, James MH, Aston-Jones G

Research square     2025年10月

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記述言語：英語  

DOI： 10.21203/rs.3.rs-7652324/v1

PubMed

Exploring dosing of anti-MRSA antibiotics for patients undergoing prolonged hemodiafiltration: a single-center retrospective study Open Access

Fukuzawa, S; Miyagawa, Y; Kawarada, Y; Saeki, Y; Nishijima, Y; Washino, Y; Mizoguchi, H; Yamada, K; Ikesue, H

RENAL REPLACEMENT THERAPY   11 巻 ( 1 )   2025年9月

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出版者・発行元：Renal Replacement Therapy  

Background: Prolonged hemodiafiltration (HDF) is a blood purification therapy used for fulminant hepatitis to improve impaired consciousness, hemodynamics, hyperammonemia, and renal function. Methicillin-resistant Staphylococcus aureus (MRSA) infections, including sepsis and fulminant hepatitis, are routinely treated with antibiotics. However, no studies have investigated the effects of prolonged HDF on the pharmacokinetics of the anti-MRSA antibiotics teicoplanin and vancomycin. We performed an exploratory assessment of optimal dosing of these drugs in critically ill patients undergoing prolonged HDF. Methods: In this single-center retrospective study, we enrolled patients who underwent therapeutic drug monitoring after the administration of a maintenance dose of teicoplanin or vancomycin during prolonged HDF. Patients treated with teicoplanin were categorized into albumin (ALB) administration, plasma exchange (PE), and normal administration groups. The pharmacokinetics of vancomycin were relatively unaffected by serum ALB levels; therefore, patients treated with vancomycin were categorized into PE and normal administration groups. Dialysis prescription parameters were recorded for each patient. These parameters are summarized alongside the maintenance doses and trough concentrations of anti-MRSA antibiotics in a table 7. Results: During prolonged HDF, the dialysis flow rate was 30,000 mL/h (interquartile range [IQR], 30,000–30,000), and the hemofiltration ratio was 2000 mL/h (IQR 2000–2500). In the normal administration group, the median maintenance dose of teicoplanin was 10.4 mg/kg/day (IQR 6.5–13.3), and the trough concentration was 17.4 μg/mL (IQR 15.9–17.8). In the ALB and PE groups, the median maintenance of teicoplanin dose was 9.4 mg/kg/day (IQR 7.8–9.9), and the trough concentration was 9.2 μg/mL (IQR 8.1–10.9). The median maintenance dose of vancomycin in the normal administration group was 40.7 mg/kg/day (IQR 25.4–45.7), and the trough concentration was 10.2 μg/mL (IQR 9.5–10.4). In the PE group, the maintenance dose of vancomycin was 23.0 mg/kg/day, and the trough concentration was 4.43 μg/mL. Conclusions: The findings of this study suggest that when administering teicoplanin and vancomycin to patients undergoing prolonged HDF, their maintenance dosages may need to be adjusted not only according to dialysis prescription parameters, but also in consideration of the patient’s general condition and concomitant therapies such as plasma exchange or albumin administration.

DOI： 10.1186/s41100-025-00666-z

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Orexinergic neurons contribute to autonomic cardiovascular regulation for locomotor exercise Open Access

Narai, E; Yoshimura, Y; Honaga, T; Mizoguchi, H; Yamanaka, A; Hiyama, TY; Watanabe, T; Koba, S

JOURNAL OF PHYSIOLOGY-LONDON   603 巻 ( 18 ) 頁： 4973 - 4989   2025年9月

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記述言語：英語   出版者・発行元：Journal of Physiology  

Abstract: While the hypothalamic orexinergic nervous system is established as having a pivotal role in the long-term regulation of various organismic functions, including wakefulness, metabolism and hypertensive states, whether this system contributes to the rapid autonomic cardiovascular regulation during physical activity remains elusive. This study aimed to elucidate the role of the orexinergic nervous system in transmitting volitional motor signals, i.e. central command, to drive somatomotor and sympathetic cardiovascular responses. We first found that this system is activated by voluntary locomotor exercise as evidenced by an increased expression of Fos, a marker of neural activation, in the orexinergic neurons of Sprague–Dawley rats engaged in spontaneous wheel running. Next, using transgenic Orexin-Cre rats for optogenetic manipulation of orexinergic neurons, we found that optogenetic excitation of orexinergic neurons caused sympathoexcitation on a subsecond timescale under anaesthesia. In freely moving conscious rats, this excitatory stimulation rapidly elicited exploration-like behaviours, predominantly locomotor activity, along with pressor and tachycardiac responses. Meanwhile, optogenetic inhibition of orexinergic neurons during spontaneous wheel running immediately suppressed locomotor activities and blood pressure elevation without affecting basal cardiovascular homeostasis. Taken together, these findings demonstrate the essential role of the orexinergic nervous system in the central circuitry that transmits central command signals for locomotor exercise. This study not only offers insights into the brain circuit mechanisms precisely regulating autonomic cardiovascular systems during voluntary exercise but also likely contributes to our understanding of brain mechanisms underlying abnormal cardiovascular adjustments to exercise in pathological conditions, such as hypertension. (Figure presented.). Key points: The hypothalamic orexinergic nervous system plays various roles in the long-term regulation of autonomic and endocrine functions, as well as motivated behaviours. We present a novel, rapid role of the orexinergic nervous system, revealing its significance as a crucial substrate in the brain circuit mechanisms that coordinate somatomotor and autonomic cardiovascular controls for locomotor exercise. Our data demonstrate that orexinergic neurons relay volitional motor signals, playing a necessary and sufficient role in the autonomic cardiovascular regulation required for locomotor exercise in rats. The findings contribute to our understanding of how the brain precisely regulates autonomic cardiovascular systems during voluntary exercise, providing insights into the central neural mechanisms that enhance physical performance moment-by-moment during exercise.

DOI： 10.1113/JP285791

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レンボレキサント導入後早期の安全性に関する年齢層別比較 Open Access

中村 美菜, 堀田 彰悟, 小木曽 若苗, 溝口 博之, 山田 清文

医療薬学   51 巻 ( 6 ) 頁： 392 - 400   2025年6月

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記述言語：日本語   出版者・発行元：一般社団法人日本医療薬学会  

DOI： 10.5649/jjphcs.51.392

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CiNii Research

A hyper-activatable <i>CAMK2A</i> variant associated with intellectual disability causes exaggerated long-term potentiation and learning impairments Open Access

Pan, M; Liu, PW; Ozawa, Y; Arima-Yoshida, F; Dong, GY; Sawahata, M; Mori, D; Nagase, M; Fujii, H; Ueda, S; Yabuuchi, Y; Liu, XZ; Narita, H; Konno, A; Hirai, H; Ozaki, N; Yamada, K; Kidokoro, H; Bito, H; Mizoguchi, H; Watabe, AM; Horigane, SI; Takemoto-Kimura, S

TRANSLATIONAL PSYCHIATRY   15 巻 ( 1 ) 頁： 95   2025年3月

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記述言語：英語   出版者・発行元：Translational Psychiatry  

Intellectual disability (ID) is a neurodevelopmental disorder (NDD) characterized by impairments in intellectual and adaptive functioning, and is highly co-morbid with other NDDs. Recently, de novo missense variants in the gene, CAMK2A, which encodes calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), an abundant neuronal protein crucial for synaptic plasticity, learning and memory, have been implicated in ID. However, the causative impact of these mutations remains underexplored. In this study, we developed a heterozygous knock-in mouse model carrying the most prevalent ID-associated CAMK2A de novo missense variant, P212L, as a gain-of-function allele. The knock-in mice exhibited increased autophosphorylation of CaMKIIα, indicative of exuberant kinase activity, and consistently showed dendritic spine abnormalities and exaggerated hippocampal long-term potentiation induced by a subthreshold low-frequency stimulation. Furthermore, a comprehensive behavioral evaluation, including learning and memory tasks, revealed prominent phenotypes recapitulating the complex clinical phenotypes of humans with ID/NDDs harboring the same variant. Taken together, we propose that aberrant enhancement of CaMKIIα signaling by the heterozygous P212L mutation underlies a subset of ID/NDD features. These findings provide new insights into the pathogenesis of ID/NDDs, specifically through the genetic up-shifting of the critical memory regulator, CaMKII. Additionally, the established mouse model, with both construct and face validity, is expected to significantly contribute to the understanding and future therapeutic development of ID/NDDs.

DOI： 10.1038/s41398-025-03316-4

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Population pharmacokinetic model of tranexamic acid in patients who undergo cardiac surgery with cardiopulmonary bypass Open Access

Nakai, T; Tamura, T; Miyagawa, Y; Inagaki, T; Mutsuga, M; Yamada, S; Yamada, K; Nishiwaki, K; Mizoguchi, H

EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY   81 巻 ( 3 ) 頁： 441 - 449   2025年3月

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記述言語：英語   出版者・発行元：European Journal of Clinical Pharmacology  

Purpose: Tranexamic acid (TXA) is widely used as an antifibrinolytic drug. However, studies to determine the optimal blood concentration of TXA have produced inconsistent results. During cardiac surgery, cardiopulmonary bypass (CPB) has serious effects on drug distribution, elimination, and plasma concentration. Therefore, we aimed to establish a population pharmacokinetics model of TXA in patients undergoing cardiac surgery with CPB that considers renal function as a covariate, thereby facilitating personalized treatment. Methods: In total, 453 TXA plasma samples were prospectively collected from 77 patients who underwent cardiac surgery with CPB. Plasma concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model of TXA was analyzed using nonlinear mixed-effects modeling. Results: The two-compartment–based model with combined errors was determined as the best. The final model included the effect of bodyweight and CL<inf>cr</inf> may be summarized as V<inf>1</inf> (L) = 12.77 × (bodyweight / 61.4)^0.911, V<inf>2</inf> (L) = 6.857, CL<inf>1</inf> (L/h) = 3.263 × [CL<inf>cr</inf> (L/h) / 61.0]^0.752, CL<inf>2</inf> (L/h) = 2.859. Conclusion: Patients who undergo cardiac surgery with CPB may require an adjusted dose of TXA tailored to CPB due to lower CL<inf>1</inf> and increased V<inf>1</inf>. Our TXA population pharmacokinetic model may be useful for developing individualized dosing designs for TXA in patients who undergo cardiac surgery with CPB.

DOI： 10.1007/s00228-025-03802-0

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GLIA RESPONSES ARE ASSOCIATED WITH ABNORMAL BEHAVIORS IN AN ANIMAL MODEL OF TAU PATHOLOGIES

Liu, Y; Mizoguchi, H; Sobue, A; Sahara, N; Yamanaka, K; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   28 巻   2025年2月

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DOI： 10.1093/ijnp/pyae059.497

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A RHO-KINASE 2 SELECTIVE INHIBITOR KD025 AMELIORATES SCHIZOPHRENIA-LIKE BEHAVIORS IN MK-801-TREATED MICE

Tanaka, R; Liu, Y; Liao, JZ; Mouri, A; Nagai, T; Nabeshima, T; Kaibuchi, K; Tachibana, D; Kobayashi, Y; Ozaki, N; Mizoguchi, H; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   28 巻   頁： i51 - i52   2025年2月

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DOI： 10.1093/ijnp/pyae059.090

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ACTIVITIES OF OREXIN NEURONS IN MOTIVATIVE BEHAVIOR

Mizoguchi, H; Dong, YT; Yamanaka, A; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   28 巻   頁： I24 - I25   2025年2月

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DOI： 10.1093/ijnp/pyae059.043

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MATERIAL STRENGTH OF GLULAM COLUMN WITH RECTANGULAR NOTCHED HOLE IN TENSILE-BOLTED COLUMN BASE JOINT: Strength reduction of glued laminated timber subjected to repeated compression and tension stress Open Access

Yamazaki Y., Mizoguchi H., Matsuda K., Akiyama N.

Journal of Structural and Construction Engineering   89 巻 ( 826 ) 頁： 1397 - 1406   2024年12月

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出版者・発行元：Journal of Structural and Construction Engineering  

Column base joints of mid-to high-rise wooden buildings are subjected to large bending moment and axial force, and they should be designed to prevent brittle failure mode. In this research, tensile-bolted glulam column base joints are tested, and the strength of the cross-section with rectangular notched holes for anchorage is evaluated. The effect of repeated compression and tension stress history is particularly focused on. It is found that the tension strength might be decreased if 80-90% of compression strength was applied to the material.

DOI： 10.3130/aijs.89.1397

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COVID-19軽症・中等症患者における薬剤関連問題に対する病棟薬剤師介入効果の評価 Open Access

福澤 翔太, 宮川 泰宏, 川原田 祐貴, 松永 安未, 當麻 丹香, 佐伯 友里, 溝口 博之, 山田 清文

医療薬学   50 巻 ( 11 ) 頁： 614 - 621   2024年11月

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記述言語：日本語   出版者・発行元：一般社団法人日本医療薬学会  

DOI： 10.5649/jjphcs.50.614

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CiNii Research

The Use of Text Mining to Obtain a Historical Overview of Research on Therapeutic Drug Monitoring Open Access

Matsuzaki, T; Mizoguchi, H; Yamada, K

BIOLOGICAL & PHARMACEUTICAL BULLETIN   47 巻 ( 11 ) 頁： 1883 - 1892   2024年11月

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記述言語：英語   出版者・発行元：公益社団法人 日本薬学会  

Therapeutic drug monitoring (TDM) is a routine clinical practice used to individualize drug dosing to maintain drug efficacy and minimize the consequences of overexposure. TDM is applied to many drug classes, including immunosuppressants, antineoplastic agents, and antibiotics. Considerable effort has been made to establish routine TDM practices for each drug. However, because TDM has been developed within the context of specific drugs, there is insufficient understanding of historical trends within the field of TDM research as a whole. In this study, we employed text-mining approaches to explore trends in the TDM research field. We first performed a PubMed search to determine which drugs and drug classes have been extensively studied in the context of TDM. This investigation revealed that the most commonly studied drugs are tacrolimus, followed by cyclosporine and vancomycin. With regard to drug classes, most studies focused on immunosuppressants, antibiotics, and antineoplastic agents. We also subjected PubMed records of TDM-related studies to a series of text-mining pipelines. Our analyses revealed how TDM research has evolved over the years, thereby serving as a cornerstone for forecasting future research trends.

DOI： 10.1248/bpb.b24-00319

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Mice with deficiency in <i>Pcdh15</i>, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature Open Access

Mori, D; Inami, C; Ikeda, R; Sawahata, M; Urata, S; Yamaguchi, ST; Kobayashi, Y; Fujita, K; Arioka, Y; Okumura, H; Kushima, I; Kodama, A; Suzuki, T; Hirao, T; Yoshimi, A; Sobue, A; Ito, T; Noda, Y; Mizoguchi, H; Nagai, T; Kaibuchi, K; Okabe, S; Nishiguchi, K; Kume, K; Yamada, K; Ozaki, N

TRANSLATIONAL PSYCHIATRY   14 巻 ( 1 ) 頁： 216   2024年5月

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記述言語：英語   出版者・発行元：Translational Psychiatry  

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

DOI： 10.1038/s41398-024-02952-6

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Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice Open Access

Mori, D; Ikeda, R; Sawahata, M; Yamaguchi, S; Kodama, A; Hirao, T; Arioka, Y; Okumura, H; Inami, C; Suzuki, T; Hayashi, Y; Kato, H; Nawa, Y; Miyata, S; Kimura, H; Kushima, I; Aleksic, B; Mizoguchi, H; Nagai, T; Nakazawa, T; Hashimoto, R; Kaibuchi, K; Kume, K; Yamada, K; Ozaki, N

TRANSLATIONAL PSYCHIATRY   14 巻 ( 1 ) 頁： 138   2024年3月

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記述言語：英語   出版者・発行元：Translational Psychiatry  

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

DOI： 10.1038/s41398-023-02679-w

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人工心肺装置を用いた心臓手術患者におけるトラネキサム酸の母集団薬物動態モデルの構築

中井 剛, 田村 高廣, 宮川 泰宏, 稲垣 孝行, 六鹿 雅登, 山田 成樹, 山田 清文, 西脇 公俊, 溝口 博之

日本臨床薬理学会学術総会抄録集   45 巻 ( 0 ) 頁： 118   2024年

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記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

<p>【目的】心臓手術において、人工心肺装置（CPB）の使用は血液の希釈や装置との接触などの影響により、血小板機能異常や凝固・線溶反応の亢進を伴いやすく、しばしば大量出血を引き起こす。このような手術において、抗線溶薬であるトラネキサム酸（TXA）は患者の出血、輸血および再手術を減らすために使用されている。一方、TXAの大量投与は痙攣発作や血栓症を誘発することが指摘されているが、その投与方法は一定ではなく、母集団薬物動態（PPK）解析の報告も乏しい。また、TXA は主に尿中に排泄されるため、腎機能を考慮したPPKモデルを確立する必要がある。本研究ではCPBを用いた心臓手術患者において、腎機能を考慮したTXAのPPKモデルを構築することを目的とした。 【方法】名古屋大学医学部附属病院にて2021年8月から2022年8月の間でCPBを用いた心臓手術においてTXAを使用した患者77名を対象に前向き観察研究を実施した。手術開始時TXA 1,000mg投与開始後約0.5、1、2、5時間後およびCPB離脱後TXA 1,000mg再投与開始後1、6、16時間後にて採血を行い、遠心分離後血漿を回収し、血中濃度測定を行った。また、電子カルテよりレトロスペクティブに収集した患者背景から有意な共変量を選定した。上記の解析にはPhoenix NLME 8.4.0ソフトウェアを用いた。本研究は名古屋大学観察研究専門審査委員会の承認（2021-0250）を得て実施した。 【結果・考察】術中およびCPB離脱後のTXA濃度範囲はそれぞれ3.488-118.3 μg/mLおよび1.463-138.8 μg/mLであった。モデル解析の結果、2-コンパートメントモデルが適切であった。対象患者の体重中央値61.4 kgおよびクレアチニンクリアランス（CL_cr）の中央値61.0 mL/minにおいて、PPKパラメータである薬物クリアランス、中心コンパートメントおよび末梢コンパートメントの分布容積、コンパートメントクリアランスはそれぞれ3.26 L/h、12.77 L、2.859 L、6.857 L/hであった。共変量探索の結果、TXAの薬物クリアランスおよび中心コンパートメントに影響する因子として、それぞれ体重およびCL_crの影響が組み込まれた。ブートストラップ法とGoodness-of-fit plotによりモデルの適格性が確認された。 【結論】本研究では、CPBを用いた心臓手術患者において、腎機能を考慮したTXAのPPKモデルを構築した。本研究で構築したモデルおよび得られた知見は、CPBを用いた心臓手術患者におけるTXAの適正使用に寄与するものと考えられる。</p>

DOI： 10.50993/jsptsuppl.45.0_118

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Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia Open Access

Liao, JZ; Dong, GY; Zhu, WJ; Wulaer, B; Mizoguchi, H; Sawahata, M; Liu, Y; Kaibuchi, K; Ozaki, N; Nabeshima, T; Nagai, T; Yamada, K

PHARMACOLOGICAL RESEARCH   194 巻   頁： 106838   2023年8月

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

Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic treatment in SCZ improves positive symptoms but has major side effects and little impact on negative symptoms and cognitive impairment. The pathoetiology of SCZ remains unclear, but is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)–treated male mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced VD impairment. Fasudil also significantly suppressed the increase in the number of c-Fos–positive cells in the infralimbic medial prefrontal cortex (infralimbic mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, another Rho kinase inhibitor, into the infralimbic mPFC or DMS significantly ameliorated METH-induced VD impairment. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Oral administration of haloperidol and fasudil ameliorated METH-induced VD impairment, while clozapine had little effect. Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit.

DOI： 10.1016/j.phrs.2023.106838

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Fasudil ameliorates methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated gene mutations in the Arhgap10 gene

Tanaka, R; Liao, JZ; Mori, D; Nagai, T; Matsuzaki, T; Nabeshima, T; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Yamada, K

BRITISH JOURNAL OF PHARMACOLOGY   180 巻   頁： 1004 - 1004   2023年7月

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Retrospective Analysis of Neutrophil-to-Lymphocyte Ratio in Patients with Melanoma Who Received Ipilimumab Monotherapy or Ipilimumab in Combination with Nivolumab in Japan Open Access

Matsumura, Y; Kawarada, Y; Matsuo, M; Yokota, K; Mizoguchi, H; Akiyama, M; Yamada, K

BIOLOGICAL & PHARMACEUTICAL BULLETIN   46 巻 ( 3 ) 頁： 427 - 431   2023年3月

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記述言語：英語   出版者・発行元：公益社団法人 日本薬学会  

Studies have reported an association between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis in patients with melanoma treated with ipilimumab. However, it remains unclear whether NLR is useful in Japanese patients with melanoma, and if so, what is the optimal cut-off value. We retrospectively examined 38 patients who received ipilimumab from August 2015 to November 2021 at Nagoya University Hospital. We divided patients into two groups: 1–2 versus 3–4 cycles of ipilimumab. In univariate analysis, baseline neutrophil count and NLR were significantly higher in patients who discontinued ipilimumab within 2 cycles. With receiver operating characteristic analysis, the optimal NLR cut-off value was found to be 3.4 (area under the curve, 0.75; 95% confidence interval, 0.58–0.92). In multivariate logistic regression analysis, baseline NLR >3.4 was an independent risk factor for ipilimumab discontinuation (odds ratio, 15.6; 95% confidence interval, 3.0–82) that was significantly associated with shorter progression-free survival (PFS) (p=0.003, log-rank test). In conclusion, NLR >3.4 is useful for selecting Japanese patients with melanoma who might have better PFS with ipilimumab-containing treatment. Because the optimal NLR cut-off value in this study was lower than values in American and European studies, it possibly differs by race. Hence, it should be extrapolated to Japanese patients with caution.

DOI： 10.1248/bpb.b22-00750

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Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the <i>Arhgap10</i> gene 査読有り Open Access

Tanaka, R; Liao, JZ; Hada, K; Mori, D; Nagai, T; Matsuzaki, T; Nabeshima, T; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Yamada, K

PHARMACOLOGICAL RESEARCH   187 巻   頁： 106589   2023年1月

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

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

DOI： 10.1016/j.phrs.2022.106589

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タウ病態モデルマウスにみられる行動異常とグリア細胞応答

LIU YUE, 溝口 博之, 祖父江 顕, 佐原 成彦, 山中 宏二, 山田 清文

日本薬理学会年会要旨集   97 巻 ( 0 ) 頁： 2-B-P-037   2023年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

DOI： 10.1254/jpssuppl.97.0_2-b-p-037

CiNii Research

Nanobody-based RFP-dependent Cre recombinase for selective anterograde tracing in RFP-expressing transgenic animals 査読有り Open Access

Inutsuka, A; Maejima, S; Mizoguchi, H; Kaneko, R; Nomura, R; Takanami, K; Sakamoto, H; Onaka, T

COMMUNICATIONS BIOLOGY   5 巻 ( 1 ) 頁： 979   2022年9月

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記述言語：英語   出版者・発行元：Communications Biology  

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

DOI： 10.1038/s42003-022-03944-2

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Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia 査読有り Open Access

Takase, S; Liao, JZ; Liu, Y; Tanaka, R; Miyagawa, Y; Sawahata, M; Sobue, A; Mizoguchi, H; Nagai, T; Kaibuchi, K; Ozaki, N; Yamada, K

EUROPEAN JOURNAL OF PHARMACOLOGY   931 巻   頁： 175207   2022年9月

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記述言語：英語   出版者・発行元：European Journal of Pharmacology  

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

DOI： 10.1016/j.ejphar.2022.175207

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A machine learning model that emulates experts' decision making in vancomycin initial dose planning 査読有り Open Access

Matsuzaki, T; Kato, Y; Mizoguchi, H; Yamada, K

JOURNAL OF PHARMACOLOGICAL SCIENCES   148 巻 ( 4 ) 頁： 358 - 363   2022年4月

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

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

DOI： 10.1016/j.jphs.2022.02.005

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New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction 査読有り Open Access

Tsuneura, Y; Nakai, T; Mizoguchi, H; Yamada, K

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   23 巻 ( 3 )   2022年2月

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

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

DOI： 10.3390/ijms23031829

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Mice with exonic <i>RELN</i> deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks 査読有り Open Access

Liao, JZ; Dong, GY; Wulaer, B; Sawahata, M; Mizoguchi, H; Mori, D; Ozaki, N; Nabeshima, T; Nagai, T; Yamada, K

BEHAVIOURAL BRAIN RESEARCH   416 巻   頁： 113569   2022年1月

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

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

DOI： 10.1016/j.bbr.2021.113569

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Dynamic changes in orexin activities associated with reward-based motivative behavior

董 彧弢, 溝口 博之, 山中 章弘, 山田 清文

日本薬理学会年会要旨集   95 巻 ( 0 ) 頁： 1-SS-08   2022年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

DOI： 10.1254/jpssuppl.95.0_1-ss-08

CiNii Research

アルツハイマー病モデルマウスにおける脳内IFITM3の発現変化

LIU YUE, 溝口 博之, 祖父江 顕, 山中 宏二, 山田 清文

日本薬理学会年会要旨集   96 巻 ( 0 ) 頁： 1-B-P-333   2022年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

DOI： 10.1254/jpssuppl.96.0_1-b-p-333

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Alzheimer's Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment 査読有り Open Access

Nakai, T; Yamada, K; Mizoguchi, H

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   22 巻 ( 11 )   2021年6月

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

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

DOI： 10.3390/ijms22115549

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Analysis of Reelin signaling and neurodevelopmental trajectory in primary cultured cortical neurons with RELN deletion identified in schizophrenia 査読有り Open Access

Tsuneura, Y; Sawahata, M; Itoh, N; Miyajima, R; Mori, D; Kohno, T; Hattori, M; Sobue, A; Nagai, T; Mizoguchi, H; Nabeshima, T; Ozaki, N; Yamada, K

NEUROCHEMISTRY INTERNATIONAL   144 巻   頁： 104954   2021年3月

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

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

DOI： 10.1016/j.neuint.2020.104954

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REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories 査読有り Open Access

Izawa, S; Chowdhury, S; Miyazaki, T; Mukai, Y; Ono, D; Inoue, R; Ohmura, Y; Mizoguchi, H; Kimura, K; Yoshioka, M; Terao, A; Kilduff, TS; Yamanaka, A

SCIENCE   365 巻 ( 6459 ) 頁： 1308 - +   2019年9月

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

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

DOI： 10.1126/science.aax9238

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Preproenkephalin-expressing ventral pallidal neurons control inhibitory avoidance learning 査読有り Open Access

Macpherson, T; Mizoguchi, H; Yamanaka, A; Hikida, T

NEUROCHEMISTRY INTERNATIONAL   126 巻   頁： 11 - 18   2019年6月

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

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

DOI： 10.1016/j.neuint.2019.02.011

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Maternal separation as a risk factor for aggravation of neuropathic pain in later life in mice.

Mizoguchi H, Fukumoto K, Sakamoto G, Jin S, Toyama A, Wang T, Suzumura A, Sato J

Behavioural brain research   359 巻   頁： 942 - 949   2019年2月

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

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

DOI： 10.1016/j.bbr.2018.06.015

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Nicotine and varenicline ameliorate changes in reward-based choice strategy and altered decision-making in methamphetamine-treated rats.

Mizoguchi H, Wang T, Kusaba M, Fukumoto K, Yamada K

Behavioural brain research   359 巻   頁： 935 - 941   2019年2月

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

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

DOI： 10.1016/j.bbr.2018.06.016

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[Physiological centers of decision-making: manipulation of neural activity in insular cortex by AAV]. Open Access

Mizoguchi H, Yamada K

Nihon yakurigaku zasshi. Folia pharmacologica Japonica   153 巻 ( 5 ) 頁： 224 - 230   2019年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

<p>依存症は世界銀行・WHO（世界保健機関）が報告するDALY（障害調整生命年）によると，世界トップ10に入る健康を脅かす疾患である．中でも，アルコール乱用を初めとする物質依存・薬物使用障害のDALYは若年層において非常に高い数値を示している．国内に目を向けても，薬物逮捕ラッシュの芸能界が表すように薬物汚染は止まっていない．また統合型リゾート推進法の成立により日本でもカジノが解禁されることから，ギャンブル依存者の急増という社会的且つ医薬学的問題も懸念される．さらにWHOはゲーム障害を精神疾患と認定したことからも，新たな依存症の包括的理解に向けた機序解明と医学的に適切な予防対策や治療戦略の発信が期待されている．ではなぜ，私たちはゲーム，ギャンブル，薬物に〝はまる〟のか？　なぜ，一度手を染めた人はリスクを負っても危険ドラッグや覚せい剤の売買をするのか？　なぜ治療したはずなのに依存症は再発するのか？　どうして自分をコントロールできなくなるのか？　そして，こうした症状は脳のどこから生まれるのか？　私たちはちょっと変わった視点（意思決定）から，依存者の脳と心の問題に迫ってきた．一方，近年の目まぐるしい実験技術の進歩により，遺伝子発現を制御するための多種多様なウイルスベクターが開発された．細胞特異的に遺伝子を発現させ，その細胞・神経の活動をコントロールすることも可能となった．今ではウイルスベクターを用いた行動薬理実験が当然のように行われ，顕著で分かりやすい研究成果が発表されている．著者らもこの手法を用いて特定の脳領域の活動や細胞活性を操作した時の意思決定について検討してきた．本稿では，意思決定について概説するとともに，当研究室で行ったウイルスベクターを用いた意思決定・行動選択研究への応用について述べる．</p>

DOI： 10.1254/fpj.153.224

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マウスのリスク意思決定を評価する試験法の開発

溝口 博之, 王 天, Saifullah Md. Ali Bin, 福本 和哉, 山田 清文

日本薬理学会年会要旨集   92 巻 ( 0 ) 頁： 1-P-023 - P-023   2019年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

DOI： 10.1254/jpssuppl.92.0_1-p-023

CiNii Research

Behavioral characterization of APP knock-in mice model in touchscreen-based tests aiming early detection of Alzheimer's disease.

Saifullah MD. Ali Bin, 小峯 起, 祖父江 顕, 山中 宏二, 溝口 博之

日本薬理学会年会要旨集   92 巻 ( 0 ) 頁： 1-P-041 - P-041   2019年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬理学会  

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

DOI： 10.1254/jpssuppl.92.0_1-p-041

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認知症との共生社会を支える基礎研究 Open Access

柳井 修一, 髙瀨 堅吉, 山口 哲生, 内田 さえ, 泉尾 直孝, 溝口 博之, 稲垣 宏樹, 日下 菜穂子

日本心理学会大会発表論文集   82 巻 ( 0 ) 頁： SS-029 - SS-029   2018年9月

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記述言語：日本語   出版者・発行元：公益社団法人 日本心理学会  

DOI： 10.4992/pacjpa.82.0_ss-029

Open Access

CiNii Research

AN OPERANT TASK FOR TESTING RISKY DECISION-MAKING IN MICE

Wang, T; Fukumoto, K; Mizoguchi, H; Yamada, K

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   42 巻   頁： 48A - 48A   2018年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Web of Science

ギャンブル障害の現状と薬剤師の役割 査読有り

溝口 博之

医薬ジャーナル   54(4) 巻   頁： 1037 - 1040   2018年

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DOI： 10.20837/12018041037

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創薬標的としてのnAChR：精神疾患患者で喫煙率が高い理由！？

溝口 博之

ファルマシア   53 巻 ( 9 ) 頁： 923 - 923   2017年

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記述言語：日本語   出版者・発行元：公益社団法人 日本薬学会  

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

DOI： 10.14894/faruawpsj.53.9_923

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Hypothalamic peptidergic neurons regulates sleep/wakefulness and memory

Izawa, S; Inoue, R; Mukai, Y; Terao, A; Chowdhury, S; Mizoguchi, H; Yamanaka, A

JOURNAL OF SLEEP RESEARCH   25 巻   頁： 115 - 116   2016年9月

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Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged <i>Caspr</i> mutant mouse shambling

Takagishi, Y; Katanosaka, K; Mizoguchi, H; Murata, Y

NEUROBIOLOGY OF AGING   43 巻   頁： 34 - 46   2016年7月

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記述言語：英語   出版者・発行元：Neurobiology of Aging  

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

DOI： 10.1016/j.neurobiolaging.2016.03.020

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Chronic Hyponatremia Causes Neurologic and Psychologic Impairments. 査読有り Open Access

Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, Nakashima K, Ochiai H, Takeuchi S, Kiyota A, Fukumoto K, Iwama S, Takagishi Y, Hayashi Y, Arima H, Komatsu Y, Murata Y, Oiso Y

Journal of the American Society of Nephrology : JASN   27 巻 ( 3 ) 頁： 766 - 80   2016年3月

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

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancermay also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.

DOI： 10.1681/ASN.2014121196

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Usefulness of DREADD technology combined with adeno-associated virus vector in behavioral pharmacology

Mizoguchi, H; Yamanaka, A; Yamada, K

JOURNAL OF PHARMACOLOGICAL SCIENCES   130 巻 ( 3 ) 頁： S73 - S73   2016年3月

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Insular neural system controls decision-making in healthy and methamphetamine-treated rats. 査読有り Open Access

Mizoguchi H, Katahira K, Inutsuka A, Fukumoto K, Nakamura A, Wang T, Nagai T, Sato J, Sawada M, Ohira H, Yamanaka A, Yamada K

Proceedings of the National Academy of Sciences of the United States of America   112 巻 ( 29 ) 頁： E3930 - 9   2015年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

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

DOI： 10.1073/pnas.1418014112

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The insular neural system controls decision-making in healthy and drug-dependent rats

Mizoguchi, H; Yamada, K

JOURNAL OF PHARMACOLOGICAL SCIENCES   128 巻 ( 3 ) 頁： S61 - S61   2015年7月

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Web of Science

Mice carrying a schizophrenia-associated mutation of the <i>Arhgap10</i> gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons 査読有り 国際誌 Open Access

Hada, K; Wulaer, B; Nagai, T; Itoh, N; Sawahata, M; Sobue, A; Mizoguchi, H; Mori, D; Kushima, I; Nabeshima, T; Ozaki, N; Yamada, K

MOLECULAR BRAIN   14 巻 ( 1 ) 頁： 21 - 21   2021年1月

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

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

DOI： 10.1186/s13041-021-00735-4

Open Access

Web of Science

Scopus

PubMed

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease 査読有り 国際誌 Open Access

Sobue, A; Komine, O; Hara, Y; Endo, F; Mizoguchi, H; Watanabe, S; Murayama, S; Saito, T; Saido, TC; Sahara, N; Higuchi, M; Ogi, T; Yamanaka, K

ACTA NEUROPATHOLOGICA COMMUNICATIONS   9 巻 ( 1 ) 頁： 1 - 1   2021年1月

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

Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App^{NL-G-F/NL-G-F} with amyloid pathology, rTg4510 with tauopathy, and SOD1^G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1^G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

DOI： 10.1186/s40478-020-01099-x

Open Access

Web of Science

Scopus

PubMed

Analysis of Reelin signaling and neurodevelopmental trajectory in primary cultured cortical neurons with RELN deletion identified in schizophrenia. 招待有り 査読有り

Tsuneura Y, Sawahata M, Itoh N, Miyajima R, Mori D, Kohno T, Hattori M, Sobue A, Nagai T, Mizoguchi H, Nabeshima T, Ozaki N, Yamada K

Neurochemistry International.   144 巻   頁： 104954   2021年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuint.2020.104954

Touchscreen-based location discrimination and paired associate learning tasks detect cognitive impairment at an early stage in an <i>App</i> knock-in mouse model of Alzheimer's disease 査読有り Open Access

Saifullah, MAB; Komine, O; Dong, YT; Fukumoto, K; Sobue, A; Endo, F; Saito, T; Saido, TC; Yamanaka, K; Mizoguchi, H

MOLECULAR BRAIN   13 巻 ( 1 ) 頁： 147   2020年11月

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

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

DOI： 10.1186/s13041-020-00690-6

Open Access

Web of Science

Scopus

PubMed

Methamphetamine use causes cognitive impairment and altered decision-making 査読有り

Mizoguchi, H; Yamada, K

NEUROCHEMISTRY INTERNATIONAL   124 巻   頁： 106 - 113   2019年3月

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

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

DOI： 10.1016/j.neuint.2018.12.019

Web of Science

Scopus

PubMed

AN OPERANT TASK FOR TESTING RISKY DECISION-MAKING IN MICE

Wang T, Fukumoto K, Mizoguchi H, Yamada K

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH   42 巻   頁： 48A-48A   2018年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

GAP junction/hemichannel blockers ameliorate the disease progression of FTLD/ALS mice

Takeuchi H, Mizoguchi H, Tanaka F, Suzumura A

JOURNAL OF THE NEUROLOGICAL SCIENCES   381 巻   頁： 714-715 - 715   2017年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jns.2017.08.2013

Web of Science

Disrupted axon-glia interactions at the paranode in myelinated nerves cause axonal degeneration and neuronal cell death in the aged Caspr mutant mouse shambling. 査読有り

Takagishi Y, Katanosaka K, Mizoguchi H, Murata Y

Neurobiology of Aging   43 巻   頁： 34-46   2016年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neurobiolaging.2016.03.020.

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments Open Access

Fujisawa Haruki, Sugimura Yoshihisa, Takagi Hiroshi, Mizoguchi Hiroyuki, Takeuchi Hideyuki, Izumida Hisakazu, Nakashima Kohtaro, Ochiai Hiroshi, Takeuchi Seiji, Kiyota Atsushi, Fukumoto Kazuya, Iwama Shintaro, Takagishi Yoshiko, Hayashi Yoshitaka, Arima Hiroshi, Komatsu Yukio, Murata Yoshiharu, Oiso Yutaka

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   27 巻 ( 3 ) 頁： 766 - 780   2016年3月

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DOI： 10.1681/ASN.2014121196

Web of Science

Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction. 査読有り

Mouri A, Hoshino Y, Narusawa S, Ikegami K, Mizoguchi H, Murata Y, Yoshimura T, Nabeshima T

Psychoneuroendocrinology   48 巻   頁： 147-161   2014年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.psyneuen.2014.05.021

Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin 査読有り Open Access

Doi Y, Takeuchi H, Mizoguchi H, Fukumoto K, Horiuchi H, Jin S, Kawanokuchi J, Parajuli B, Sonobe Y, Mizuno T, Suzumura A

PLoS One   9 巻 ( 7 ) 頁： e103458   2014年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1371/journal.pone.0103458

Open Access

Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment. 査読有り

Fukumoto K, Mizoguchi H, Takeuchi H, Horiuchi H, Kawanokuchi J, Jin S, Mizuno T, Suzumura A.

Behav. Brain Res.   268 巻   頁： 88-93   2014年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.bbr.2014.03.046

Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice 査読有り Open Access

Ibi D, Nagai T, Nakajima A, Mizoguchi H, Kawase T, Tsuboi D, Kano S, Sato Y, Hayakawa M, Lange UC, Adams DJ, Surani MA, Satoh T, Sawa A, Kaibuchi K, Nabeshima T, Yamada K.

Glia   61 巻 ( 5 ) 頁： 679-693   2013年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1002/glia.22461

Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures. 査読有り Open Access

Mizoguchi H, Yamada K.

Clinical Psychopharmacology and Neuroscience   11 巻 ( 2 ) 頁： 45-52   2013年

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.9758/cpn.2013.11.2.45

Open Access

Involvement of matrix metalloproteinase-9 in the development of morphine tolerance. 査読有り

Nakamoto K, Kawasaki S, Kobori T, Fujita-Hamabe W, Mizoguchi H, Yamada K, Nabeshima T and Tokuyama S.

Eur J Pharmacol.   683 巻   頁： 86-92   2012年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejphar.2012.03.006

Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice.

Takuma K, Mizoguchi H, Funatsu Y, Hoshina Y, Himeno Y, Fukuzaki E, Kitahara Y, Arai S, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T and Yamada K.

Neuroscience.   207 巻   頁： 261-273   2012年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Placental extract improves hippocampal neuronal loss and fear memory impairment resulting from chronic restraint stress in ovariectomized mice. 査読有り

Takuma K, Mizoguchi H, Funatsu Y, Kitahara Y, Ibi D, Kamei H, Matsuda T, Koike K, Inoue M, Nagai T and Yamada K.

J Pharmacol Sci.   120 巻 ( 2 ) 頁： 89-97   2012年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice. 査読有り Open Access

Furukawa-Hibi Y, Alkam T, Nitta A, Matsuyama A, Mizoguchi H, Suzuki K, Moussaoui S, Yu QS, Greig NH, Nagai T, Yamada K.

Behav. Brain Res.   225 巻 ( 1 ) 頁： 222-229   2011年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.bbr.2011.07.035

Low barometric pressure aggravates neuropathic pain in guinea pigs. 査読有り

Sato J, Itano Y, Funakubo M, Mizoguchi H, Itoh M, Mori R.

Neurosci. Lett.   503 巻 ( 2 ) 頁： 152-156   2011年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.neulet.2011.08.030

Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity. 査読有り

Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A.

Am J Pathol.   179 巻 ( 4 ) 頁： 2016-2027   2011年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus. 査読有り

Mizoguchi H, Nakade J, Tachibana M, Ibi D, Someya E, Koike H, Kamei H, Nabeshima T, Itohara S, Takuma K, Sawada M, Sato J, Yamada K.

J Neurosci.   31 巻 ( 36 ) 頁： 12963-12971   2011年9月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nicotine ameliorates impairment of working memory in methamphetamine-treated rats. 査読有り

Mizoguchi H, Ibi D, Takase F, Nagai T, Kamei H, Toth E, Sato J, Takuma K, Yamada K.

Behav Brain Res.   220 巻 ( 1 ) 頁： 159-163   2011年6月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2011.01.036

Lowering barometric pressure aggravates depression-like behavior in rats. 査読有り

Mizoguchi H, Fukaya K, Mori R, Itoh M, Funakubo M, Sato J.

Behav Brain Res.   218 巻   頁： 190-193   2011年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2010.11.057

Pharmacologic treatment with GABAB receptor agonist of methamphetamine-induced cognitive impairment in mice._BBB 査読有り

Mizoguchi H, Yamada K.

Current Neuropharmacol.   9 巻 ( 1 ) 頁： 109-112   2011年3月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage. 査読有り

Shichi K, Fujita-Hamabe W, Harada S, Mizoguchi H, Yamada K, Nabeshima T, Tokuyama S.

J Pharmacol Exp Ther.     頁： in press   2011年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. 査読有り Open Access

Takeuchi H, Mizoguchi H, Doi Y, Jin S, Noda M, Liang J, Li H, Zhou Y, Mori R, Yasuoka S, Li E, Parajuli B, Kawanokuchi J, Sonobe Y, Sato J, Yamanaka K, Sobue G, Mizuno T, Suzumura A.

PLoS One.   6 巻 ( 6 ) 頁： e21108   2011年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0021108

Open Access

Matrix metalloproteinases contribute to neuronal dysfunction in animal models of drug dependence, Alzheimer's disease, and epilepsy. 招待有り

Mizoguchi H, Yamada K, Nabeshima T.

Biochem Res Internat.     頁： 681385   2011年

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. 査読有り Open Access

Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A, Yoneyama M, Ogita K, Yoneda Y, Nabeshima T, Nagai T, Yamada K.

J Neurochem.   114 巻 ( 6 ) 頁： 1840-1851   2010年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1471-4159.2010.06893.x

Oral supplementation with Leu-Ile, a hydrophobic dipeptide, prevents the impairment of memory induced by amyloid beta in mice via restraining the hyperphosphorylation of extracellular signal-regulated kinase. 査読有り

Alkam T, Nitta A, Furukawa-Hibi Y, Niwa M, Mizoguchi H, Yamada K, Nabeshima T.

Behav Brain Res.   210 巻 ( 2 ) 頁： 184-190   2010年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2010.02.028

Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. 査読有り

Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G.

J Neurosci.   30 巻 ( 16 ) 頁： 5702-5712   2010年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alterations of emotional and cognitive behaviors in matrix metalloproteinase-2 and -9-deficient mice. 査読有り

Mizoguchi H., Ibi D., Takuma K., Toth E., Sato J., Itohara S, Nabeshima T, Yamada K.

The Open Behav Sci J.   4 巻   頁： 19-25   2010年4月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. 査読有り

Ibi D, Nagai T, Koike H, Kitahara Y, Mizoguchi H, Niwa M, Jaaro-Peled H, Nitta A, Yoneda Y, Nabeshima T, Sawa A, Yamada K.

  206 巻 ( 1 ) 頁： 32-37   2010年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2009.08.027

Therapeutic potential of nicotine for methamphetamine-induced impairment of sensorimotor gating: Involvement of pallidotegmental neurons. 査読有り

Mizoguchi H, Arai S, Koike H, Ibi D, Kamei H, Nabeshima T, Kim HC, Takuma K, and Yamada K.

Psychopharmacology(Berl)   207 巻 ( 2 ) 頁： 235-243   2009年12月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mice Deficient for Glucagon Gene-Derived Peptides Display Normoglycemia and Hyperplasia of Islet {alpha}-Cells But Not of Intestinal L-Cells. 査読有り

Hayashi Y, Yamamoto M, Mizoguchi H, Watanabe C, Ito R, Yamamoto S, Sun XY, and Murata Y.

Mol Endocrinol.   23 巻 ( 12 ) 頁： 1990-1999   2009年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Microglia activated with toll-like receptor 9 ligand CpG attenuate oligomeric amyloid β neurotoxicity in vitro and in vivo models of Alzheimer's disease. 査読有り

Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M, Doi M, Michikawa M, Takeuchi H, and Suzumura A.

Am J Pathol.   175 巻 ( 5 ) 頁： 2121-2132   2009年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. 査読有り

Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS.

Proc Natl Acad Sci U S A.   106 巻 ( 47 ) 頁： 20021-20026   2009年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

*Matrix metalloprotease-9 inhibition improves amyloid β-mediated cognitive impairment and neurotoxicity in mice. 査読有り

Mizoguchi H, Takuma K, Fukuzaki E, Ibi D, Someya E, Akazawa K, Alkam T, Tsunekawa H, Mouri A, Noda Y, Nabeshima T, and Yamada K.

J Pharmacol Exp Ther.   331 巻 ( 1 ) 頁： 14-22   2009年10月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neonatal phencyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood. 査読有り

Nakatani-Pawlak A, Yamaguchi K, Tatsumi Y, Mizoguchi H and Yoneda Y.

Biol Pharm Bull.   32 巻 ( 9 ) 頁： 1576-1583   2009年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Behavioral abnormality and pharmacologic response in social isolation-reared mice. 査読有り

Behav Brain Res.   202 巻 ( 1 ) 頁： 114-121   2009年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2009.03.028

Neonatal polyI:C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. 査読有り

Ibi D, Nagai T, Kitahara Y, Mizoguchi H, Koike H, Shiraki A, Takuma K, Kamei H, Noda Y, Nitta A, Nabeshima T, Yoneda Y, and Yamada K.

Neurosci Res.   64 巻 ( 3 ) 頁： 297-305   2009年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neures.2009.03.015

GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. 査読有り

Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Kamei H, Kim HC, and Yamada K.

Eur J Pharmacol.   602 巻 ( 1 ) 頁： 101-104   2009年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ejphar.2008.10.065

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABA(B) Receptor Agonist Baclofen. 査読有り

Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Takahashi K, Kamei H, Nabeshima T, and Yamada K.

Neuropsychopharmacology   33 巻 ( 13 ) 頁： 3164-3175   2008年12月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The extensive nitration of neurofilament light chain in the hippocampus is associated with the cognitive impairment induced by amyloid beta in mice. 査読有り

Alkam T, Nitta A, Mizoguchi H, Itoh A, Murai R, Nagai T, Yamada K, and Nabeshima T.

The Journal of Pharmacology and Experimental Therapeutics   327 巻 ( 1 ) 頁： 137-147   2008年10月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ovariectomy increases neuronal amyloid-beta binding alcohol dehydrogenase level in the mouse hippocampus. 査読有り

Fukuzaki E, Takuma K, Funatsu Y, Himeno Y, Kitahara Y, Gu B, Mizoguchi H, Ibi D, Koike K, Inoue M, Yan SD, and Yamada K.

Neurochem Int.   52 巻 ( 7 ) 頁： 1358-1364   2008年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. 査読有り

Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y, Kamei H, Nagai T, Yoneda Y, Nabeshima T, and Yamada K.

Journal of Nuerochemistry   105 巻 ( 3 ) 頁： 921-932   2008年5月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1471-4159.2007.05207.x

Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice. 査読有り

Alkam T, Nitta A, Mizoguchi H, Saito K, Seshima M, Itoh A, Yamada K, and Nabeshima T.

Behavioural Brain Research   189 巻 ( 1 ) 頁： 100-106   2008年5月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Role of tissue plasminogen activator in the sensitization of methamphetamine-induced dopamine release in the nucleus accumbens. 査読有り

Fukakusa A, Nagai T, Mizoguchi H, Otsuka N, Kimura H, Kamei H, Kim HC, Nabeshima T, Takuma K, and Yamada K.

Journal of Nuerochemistry   105 巻 ( 2 ) 頁： 436-444   2008年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1471-4159.2007.05142.x

Enhanced activity of hippocampal BACE1 in a mouse model of postmenopausal memory deficits. 査読有り

Fukuzaki E, Takuma K, Himeno Y, Yoshida S, Funatsu Y, Kitahara Y, Mizoguchi H, Ibi D, Koike K, Inoue M, and Yamada K.

Neuroscience Letter   433 巻 ( 2 ) 頁： 141-145   2008年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neulet.2007.12.060

Improvement by minocycline of methamphetamine-induced impairment of recognition memory in mice. 査読有り

Mizoguchi H, Takuma T, Fukakusa A, Ito Y, Nakatani A, Ibi D, Kim H-C and Yamada K.

Psychopharmacology (Berl)   196 巻 ( 2 ) 頁： 233-241   2008年2月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00213-007-0955-0

Tissue plasminogen activator is not involved in methamphetamine-induced neurotoxicity. 査読有り Open Access

Fukakusa A, Mizoguchi H, Koike H, Nabeshima T, Takuma K, Yamada K.

Journal of Pharmacological Sciences   106 巻 ( 2 ) 頁： 321-324   2008年2月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1254/jphs.SC0070328

Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats. 査読有り

Takuma K, Hoshina Y, Arai S, Himeno Y, Matsuo A, Funatsu Y, Kitahara Y, Ibi D, Hayase M, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M, and Yamada K.

Neuroscience   149 巻 ( 1 ) 頁： 256-262   2008年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuroscience.2007.07.042

*Neuropsychotoxicity of abused drugs: involvement of matrix metalloproteinase-2 and -9 and tissue inhibitor of matrix metalloproteinase-2 in methamphetamine-induced behavioral sensitization and reward in rodents. 査読有り

Mizoguchi H, Yamada K, and Nabeshima T.

Journal of Pharmacological Sciences   106 巻 ( 1 ) 頁： 9-14   2008年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of post-synaptic dopamine D(1) receptors promotes the release of tissue plasminogen activator in the nucleus accumbens via PKA signaling. 査読有り

Ito M, Nagai T, Mizoguchi H, Sato K, Hayase M, Otsuka N, Fukakusa A, Kumagai N, Kim HC, Nabeshima T, Takuma K, and Yamada K.

Journal of Neurochemistry   17 巻   2007年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol. 査読有り

Nagai T, Takuma K, Dohniwa M, Ibi D, Mizoguchi H, Kamei H, Nabeshima T, Yamada K.

Psychopharmacology (Berl)   194 巻 ( 1 ) 頁： 21-32   2007年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00213-007-0820-1

*Role of matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in methamphetamine-induced behavioral sensitization and reward: Implications for dopamine receptor downregulation and dopamine release 査読有り

Mizoguchi H, Yamada K, Mouri A, Niwa M, Mizuno T, Noda Y, Nitta A, Itohara S, Banno Y, and Nabeshima T.

Journal of Neurochemistry   102 巻 ( 5 ) 頁： 1548-1560   2007年9月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A novel molecule "shati" is involved in methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. 査読有り

Niwa M, Nitta A, Mizoguchi H, Ito Y, Noda Y, Nagai T, and Nabeshima T.

Journal of Neuroscience   27 巻 ( 28 ) 頁： 7604-7615   2007年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice 査読有り

Takahashi K, Nagai T, Kamei H, Maeda K, Matsuya T, Arai S, Mizoguchi H, Yoneda Y, Nabeshima T, Takuma K, and Yamada K.

Biological Psychiatry   62 巻 ( 2 ) 頁： 148-157   2007年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.biopsych.2006.06.035

Oral vaccination with a viral vector containing A{beta} cDNA attenuates age-related A{beta} accumulation and memory deficits without causing inflammation in a mouse Alzheimer model 査読有り

Mouri A, Noda Y, Hara H, Mizoguchi H, Tabira T, and Nabeshima T.

Journal of Federation of American Societies for Experimental Biology   21 巻 ( 9 ) 頁： 2135-2148   2007年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35). 査読有り

Alkam T, Nitta A, Mizoguchi H, Itoh A, and Nabeshima T.

Behavioural Brain Research   180 巻 ( 2 ) 頁： 139-145   2007年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid (25-35) i.c.v.-injected mice: involvement of dopaminergic systems 査読有り

Wang D, Noda Y, Zhou Y, Mouri A, Mizoguchi H, Nitta A, Chen W, and Nabeshima T.

Neuropsychopharmacology   32 巻 ( 6 ) 頁： 1261-1271   2007年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Possible involvement of protease-activated receptor-1 in the regulation of morphine-induced dopamine release and hyperlocomotion by the tissue plasminogen activator-plasmin system 査読有り

Ito M, Nagai T, Mizoguchi H, Fukakusa A, Nakanishi Y, Kamei H, Nabeshima T, Takuma K, and Yamada K.

Journal of Nuerochemistry   101 巻 ( 5 ) 頁： 1392-1399   2007年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1471-4159.2006.04423.x

17beta-Estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats 査読有り

Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, Arai S, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M, and Yamada K.

Neuroscience   146 巻 ( 1 ) 頁： 60-68   2007年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reinforcing effects of morphine are reduced in tissue plasminogen activator-knockout mice 査読有り

Yan Y, Yamada K, Mizoguchi H, Noda Y, Nagai T, Nitta A, and Nabeshima T.

Neuroscience   146 巻 ( 1 ) 頁： 50-59   2007年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.neuroscience.2007.01.011

*Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9-deficient mice 査読有り

Mizoguchi H, Yamada K, Niwa M, Mouri A, Mizuno T, Noda Y, Nitta A, Itohara S, Banno Y, and Nabeshima T.

Journal of Neurochemistry   100 巻 ( 6 ) 頁： 1579-1588   2007年3月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex 査読有り Open Access

Nagai T, Takuma K, Kamei H, Ito Y, Nakamichi N, Ibi D, Nakanishi Y, Murai M, Mizoguchi H, Nabeshima T, and Yamada K.

Learning & Memory   14 巻 ( 3 ) 頁： 117-125   2007年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/lm.461407

Open Access

Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine 査読有り Open Access

Maeda K, Sugino H, Hirose T, Kitagawa H, Nagai T, Mizoguchi H, Takuma K, and Yamada K

Journal of Pharmacological Sceiences   103 巻 ( 3 ) 頁： 299-308   2007年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1254/jphs.FP0061424

Synergistic effects of adenosine A (2A) antagonist and L-DOPA on rotational behaviors in 6-hydrocydopamine-induced hemi-parkinsonian mouse model 査読有り

4. Matsuya T, Takuma K, Sato K, Asai M, Murakami Y, Miyoshi S, Noda A, Nagai T, Mizoguchi H, Nabeshima S, and Yamada K.

Journal of Pharmacological Sciences   103 巻 ( 3 ) 頁： 329-332   2007年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A novel azaindolizinone derivative ASET1446 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) improves methamphetamine-induced impairment of recognition memory in mice by activating extracellular signal-regulated kinase 1/2 査読有り

Ito Y, Takuma K, Mizoguchi H, Nagai T, and Yamada K.

The Journal of Pharmacology and Experimental Therapeutics   320 巻 ( 2 ) 頁： 819-827   2007年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1 査読有り

Nagai T, Ito M, Nakamichi N, Mizoguchi H, Kamei H, Fukakusa A, Nabeshima T, Takuma K, and Yamada K.

Journal of Neuroscience   26 巻 ( 47 ) 頁： 12374-12383   2006年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effects of single and repeated administration of methamphetamine or morphine on neuroglycan C gene expression in the rat brain 査読有り Open Access

Ishikawa K, Nitta A, Mizoguchi H, Mouri A, Murai R, Miyamoto Y, Noda Y, Kitaichi K, Yamada K, and Nabeshima T

The International Journal of Neuropsychopharmacology   9 巻 ( 4 ) 頁： 407-415   2006年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/S1461145705005870

Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid Beta and impairment of learning and memory 査読有り

Zou LB, Mouri A, Iwata N, Saido TC, Wang D, Wang MW, Mizoguchi H, Noda Y, and Nabeshima T.

The Journal of Pharmacology and Experimental Therapeutics   317 巻 ( 1 ) 頁： 334-340   2006年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Relapse of methamphetamine-seeking behavior in C57BL/6J mice demonstrated by a reinstatement procedure involving intravenous self-administration 査読有り

Yan Y, Nitta A, Mizoguchi H, Yamada K, and Nabeshima T.

Behavioural Brain Research   168 巻 ( 1 ) 頁： 137-143   2006年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbr.2005.11.030

グルタミン酸作動性神経系と統合失調症モデル動物 査読有り Open Access

毛利彰宏, 野田幸裕, 溝口博之, 鍋島俊隆

日本薬理学雑誌   127 巻 ( 1 ) 頁： 4-8   2006年1月

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記述言語：日本語  

DOI： 10.1254/fpj.127.4

Open Access

薬物弁別試験-依存性薬物の自覚効果と依存形成機構の解明 招待有り Open Access

溝口博之, 野田幸裕, 鍋島俊隆

日本薬理学雑誌   126 巻 ( 1 ) 頁： 17-23   2005年7月

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担当区分：筆頭著者   記述言語：日本語  

DOI： 10.1254/fpj.126.17

Open Access

*Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors 査読有り

Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, and Nabeshima T.

Molecular Pharmacology   65 巻 ( 5 ) 頁： 1293-1301   2004年5月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1124/mol.65.5.1293

Protection by constitutively formed nitric oxide of intestinal damage induced by indomethacin in rats 査読有り

Tanaka A, Mizoguchi H, Kunikata T, Miyazawa T, and Takeuchi K.

Journal of Physiology-Paris   95 巻 ( 1-6 ) 頁： 35-41   2001年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Protection by aspirin of indomethacin-induced small intestinal damage in rats: Mediation by salicylic acid 査読有り

Takeuchi K, Hase S, Mizoguchi H, Komoike Y, and Tanaka A.

Journal of Physiology-Paris   95 巻 ( 1-6 ) 頁： 51-57   2001年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Protective effect of rebamipide on indomethacine-induced intestinal damage in rats 査読有り

Mizoguchi H, Ogawa Y, Kanatsu K, Tanaka A, Kato S, and Takeuchi K

Journal of Gastroenterology and Hepatology   16 巻 ( 10 ) 頁： 1112-1119   2001年10月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats-role of endogenous nitric oxide 査読有り

Tanaka A, Mizoguchi H, Hase S, Miyazawa T, and Takeuchi K

Medical Sceience Monitor   7 巻 ( 5 ) 頁： 869-877   2001年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lack of Gastric Toxicity of Nitric Oxide-Releasing Indomethacin, NCX-530, in Experimental Animals 査読有り

Takeuchi K, Mizoguchi H, Araki H, Komoike Y, and Suzuki K

Digest Disease Science   46 巻 ( 8 ) 頁： 1805-1818   2001年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons 査読有り

Takeuchi K, Suzuki K, Mizoguchi H, Araki H, and Nishiwaki H

Journal of Gastroenterology and Hepatology   16 巻 ( 3 ) 頁： 282-289   2001年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lack of small intestinal toxicity of nitric oxide-releasing indomethacin, NCX-530, in rats 査読有り

Mizoguchi H, Hase S, Tanaka A, and Takeuchi K

Alimentary Pharmacology & Therapeutics   15 巻 ( 2 ) 頁： 257-267   2001年2月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastrointestinal sparing anti-inflammatory drugs-effects on ulcerogenic and healing responses 査読有り

Takeuchi K, Tanaka A, Suzuki K, and Mizoguchi H

Current Pharmaceutical Design   7 巻 ( 1 ) 頁： 49-69   2001年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

一酸化窒素遊離型インドメタシンの小腸傷害性についての検討

溝口博之, 田中晶子, 竹内孝治

Ulcer Research   28 巻   頁： 157-160   2001年

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担当区分：筆頭著者   記述言語：日本語  

Prostaglandin E inhibits indomethacin-induced gastric lesions through EP1 receptors. 査読有り

Suzuki K, Araki H, Mizoguchi H, Furukawa O, and Takeuchi K

Digestion   63 巻 ( 2 ) 頁： 92-101   2001年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The roles of nitric oxide and prostaglandins in alterations of ulcerogenic and healing responses in adjuvant-induced arthritic rat stomachs 査読有り

Kato S, Tanaka A, Kunikata T, Mizoguchi H, and Takeuchi K.

Alimentary Pharmacology & Therapeutics   14 巻 ( s1 ) 頁： 18-25   2000年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Regulatory mechanism of acid secretion in the damaged stomach: role of endogenous nitric oxide 査読有り

Takeuchi K, Araki H, Kawauchi S, Kunikata T, Mizoguchi H, and Tashima K.

Journal of Gastroenterology and Hepatology   15 巻 ( s1 ) 頁： 37-45   2000年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

インドメタシン誘起小腸傷害の発生における一酸化窒素の二面作用 招待有り

田中晶子, 溝口博之, 加藤伸一, 竹内孝治

Ulcer Research   27 巻   頁： 176-179   2000年

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記述言語：日本語  

プロスタグランジンEによるインドメタシン誘起胃損傷の抑制: EP受容体サブタイプとの関連 招待有り

鈴木敬三, 荒木秀夫, 溝口博之, 竹内孝治

Cytoprotection & biology   8 巻   頁： 31-34   2000年

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記述言語：日本語  

一酸化窒素遊離型インドメタシンの小腸傷害性について 招待有り

田中晶子, 溝口博之, 鈴木敬三, 加藤伸一, 竹内孝冶

Cytoprotection & biology   8 巻   頁： 27-30   2000年

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記述言語：日本語  

Protective effect of Irsogladine on monochloramine-induced gastric mucosal lesions in rats: a comparative study with rebamipide 査読有り

Yamamoto H, Umeda M, Mizoguchi H, Kato S, Takeuchi K.

World J. Gastroenterol.   5 巻 ( 6 ) 頁： 477-482   1999年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

Roles of endogenous prostaglandins and nitric oxide in gastroduodenal ulcerogenic responses induced in rats by hypothermic stress 査読有り

Takeuchi K, Suzuki K, Araki H, Mizoguchi H, Sugamoto S, and Umdeda M.

Journal of Physiology-Paris   93 巻 ( 5 ) 頁： 423-431   1999年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dual action of nitric oxide in pathogenesis of indomethacin-induced small intestinal ulceration in rats 査読有り

Tanaka A, Kunikata T, Mizoguchi H, Kato S, and Takeuchi K.

Journal of Physiology and Pharmacology   50 巻 ( 3 ) 頁： 405-417   1999年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses 査読有り

Takeuchi K, Suzuki K, Yamamoto H, Araki H, Mizoguchi H, and Ukawa H.

Journal of Physiology and Pharmacology   49 巻 ( 4 ) 頁： 501-513   1998年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）