論文 - 溝口　博之

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

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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

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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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