研究者詳細 - 溝口　博之

論文 - 溝口　博之

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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 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

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: Relndel/del: n = 4. Correct: Relndel/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: Relndel/del: n = 3. Correct: Relndel/del: n = 4. 3. Statistics table. Current:Figure S2BWT = 10Treatment (between columns): F (2, 22) = 14.32, P = 0.0001Body weight: WT vs. Relndel/+:P = 0.9446Relndel/+ = 10Body weight: WT vs. Relndel/del:P = 0.0001Relndel/del = 5 Correct:(Figure presented)Figure S2BWT = 9Gene: F (2, 21) = 13.79, P = 0.0001Body weight: WT vs. Relndel/+:P = 0.9174Relndel/+ = 10Body weight: WT vs. Relndel/del:P = 0.0002Relndel/del = 5 Current:Figure S2DWT = 3Treatment (between columns): F (2, 7) = 5.742, P = 0.0334Relndel/+ = 3Relndel/del = 4 Correct:Figure S2DWT = 3Gene: F (2, 7) = 5.742, P = 0.0334Relndel/+ = 3Relndel/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

Cortical excitatory and inhibitory neuron deficits may underlie the cognitive and social impairments in a mouse model of schizophrenia with exonic Reln 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

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

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

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

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

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

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

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

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

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. Twf1Y309F 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

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

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

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

Open Access

Web of Science

Scopus

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

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

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

A hyper-activatable CAMK2A 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

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

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

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

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

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

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

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

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

Scopus

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

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

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

Mice with deficiency in Pcdh15, 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

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

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

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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