Faculty Profiles - MATSUMOTO Yosuke

Papers - MATSUMOTO Yosuke

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Layer- and region-specific distribution of chondroitinase-resistant, lectin-binding extracellular matrix structures in the mouse somatosensory cortex and hippocampus. Reviewed International journal

Hiroshi Ueno, Eriko Kitano, Sachiko Mori, Yu Takahashi, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Neuroscience 2025.8

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

Extracellular matrix (ECM) structures in the brain, including perineuronal nets (PNNs), contribute to synaptic plasticity, neuroprotection, and circuit stability. Wisteria floribunda agglutinin (WFA) is widely used to label PNNs but detects only a subset of ECM glycoconjugates. To better understand ECM composition and organization, we used a panel of plant-derived lectins with distinct glycan-binding specificities to examine the spatial distribution of ECM in the mouse primary somatosensory cortex and hippocampus. Brain sections from adult male C57BL/6N mice (n = 6) were stained using seven biotinylated lectins (Jacalin, PSA, AAL, LCA, WGA, PHA-E, and PHA-L). Confocal imaging and quantitative fluorescence analysis revealed that each lectin exhibited a unique pattern of ECM labeling. Several lectins, such as Jacalin, WGA, and PHA-E, showed strong labeling in superficial cortical layers and select hippocampal subfields, while others displayed more diffuse or subregion-specific distributions. Co-labeling with WFA demonstrated partial overlap with some lectins but also revealed non-overlapping ECM components. Notably, most lectin signals, including those forming perineuronal net-like structures, remained intact after chondroitinase ABC digestion, in contrast to the loss of WFA staining. These results highlight the molecular heterogeneity and anatomical specificity of brain ECM structures, revealing a chondroitin sulfate-independent scaffold not visualized by WFA. These results highlight the molecular heterogeneity and anatomical specificity of brain ECM structures. Using diverse lectins provides complementary information to WFA-based labeling and reveals broader ECM architectures. This approach offers new insights into region- and layer-specific ECM organization, with implications for understanding the differential plasticity, resilience, and vulnerability of brain circuits.

DOI： 10.1016/j.neuroscience.2025.08.017

Postnatal expression of Cat-315-positive perineuronal nets in the SAMP10 mouse primary somatosensory cortex. Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Sachiko Mori, Eriko Kitano, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

IBRO neuroscience reports 18 244 - 256 2025.6

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

Perineuronal nets (PNNs) form at the end of the critical period of plasticity in the mouse primary somatosensory cortex. PNNs are said to have functions that control neuroplasticity and provide neuroprotection. However, it is not clear which molecules in PNNs have these functions. We have previously reported that Cat-315-positive molecules were not expressed in the PNNs of the senescence-accelerated model (SAM)P10 strain model mice at 12 months of age. To confirm whether the loss of Cat-315-positive molecules occurred early in life in SAMP10 mice, we examined Cat-315-positive PNNs in the primary somatosensory cortex during postnatal development. This research helps to elucidate the function of PNNs and the mechanism of cognitive decline associated with ageing. To confirm whether Cat-315-positive PNNs changed in an age-dependent manner in SAMP10 mice, we examined the primary somatosensory cortex at 21, 28, and 56 days after birth. We compared these results with those of senescence-accelerated mouse-resistant (SAMR) mice. In SAMP10 mice, Cat-315-positive PNNs were expressed in the primary somatosensory cortex early after birth, but their expression was significantly lower than that in SAMR1 mice. Many other molecules that calibrated the PNN were unchanged between SAMP10 and SAMR1 mice. This study revealed that the expression of the Cat-315 epitope was decreased in the primary somatosensory cortex of SAMP10 mice during postnatal development. SAMP10 mice have had histological abnormalities in their brains since early life. Furthermore, using SAMP10 will be useful in elucidating the mechanism of age-related abnormalities in brain function as well as in elucidating the function and structure of PNNs.

DOI： 10.1016/j.ibneur.2025.01.012

Postnatal sleep restriction in male mice impairs the development of parvalbumin-positive neurons in the prefrontal cortex and increases anxiety-like behaviour. Reviewed International journal

Eriko Kitano, Hiroshi Ueno, Yu Takahashi, Sachiko Mori, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Ayaka Ochi, Tsukasa Hatano, Motoi Okamoto, Takeshi Ishihara

Neuroscience 573 127 - 142 2025.5

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

Sleep is crucial for maintaining homeostasis and is conserved across the animal kingdom. Sleep restriction has emerged as a significant health concern, particularly in adolescents and adults. In infants and children, it is linked to disrupted brain development, impaired social-emotional growth, deficits in executive function, and increased anxiety and depression. However, the precise biological mechanisms remain unclear. This study aimed to investigate the effects of sleep restriction on parvalbumin (PV)-expressing inhibitory interneurons, which mature postnatally, and to clarify some of the developmental consequences of sleep restriction on brain function. Three hours of sleep restriction was induced daily from postnatal day (P) 10 until P14, P21, and P28. Behavioural abnormalities were assessed on P21, followed by brain histology and behavioural recovery analysis after sleep restoration. Our results showed that sleep restriction did not alter the development of PV-positive neurons in the somatosensory cortex or amygdala but significantly reduced PV-positive neurons in the prefrontal cortex. Moreover, sleep-restricted mice exhibited increased anxiety-like behaviour at P21. Upon sleep restoration, adult mice showed reduced activity in the open field test, indicating a persistent effect of early-life sleep restriction. These findings suggest that sleep restriction during postnatal development selectively affects certain brain regions, with potential long-lasting consequences. Early intervention to mitigate sleep restriction's impact on brain development may be crucial for reducing neurodevelopmental deficits.

DOI： 10.1016/j.neuroscience.2025.03.029

Rearing in an envy-like environment increases anxiety-like behaviour in mice. Reviewed International journal

Hiroshi Ueno, Eriko Kitano, Yu Takahashi, Sachiko Mori, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Translational neuroscience 16 ( 1 ) 20220364 - 20220364 2025.1

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

Interest in the societal and psychological harm caused by widespread envy and social comparison is increasing. Envy is associated with anxiety and depression, though the mechanism by which envy affects neuropsychiatric disorders, such as depression, remains unclear. Clarifying the neurobiological basis of envy's effects on behaviour and emotion regulation in experimental mice is essential for developing disease-prevention and treatment strategies. As mice recognize other mice in neighbouring cages, this study investigated whether they recognize neighbouring cages housed in environmentally enriched cages and suffer psychological stress due to envy. After being raised in an envy-like environment for 3 weeks, we revealed changes in the behaviour of the mice through a series of behavioural experiments. Mice raised in an envious environment showed increased body weight and anxiety-like behaviour but decreased social behaviour and serum corticosterone levels compared to control mice. Thus, mice recognize their neighbouring cages and experience psychological stress due to envy. This study revealed a part of the scientific basis for why envy increased anxiety. Using this novel experimental breeding environment, it may be possible to create an experimental animal model of anxiety disorders.

DOI： 10.1515/tnsci-2022-0364

Age-related behavioural abnormalities in C57BL/6.KOR-Apoe shl mice. Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Sachiko Mori, Eriko Kitano, Shinji Murakami, Kenta Wani, Tetsuji Miyazaki, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Translational neuroscience 16 ( 1 ) 20220363 - 20220363 2025.1

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

Spontaneously hyperlipidaemic (Apoeshl) mice were discovered in 1999 as mice lacking apolipoprotein E (ApoE) owing to a mutation in the Apoe gene. However, age-related behavioural changes in commercially available Apoeshl mice have not yet been clarified. The behavioural abnormalities of ApoE-deficient mice, which are genetically modified mice artificially deficient in ApoE, have been investigated in detail, and it has been reported that they can serve as a model of Alzheimer's disease (AD). To understand whether Apoeshl mice can also serve as a murine model of AD, it is necessary to investigate age-related behavioural abnormalities in Apoeshl mice. In this study, we conducted a series of behavioural experiments on 7- and 11-month-old Apoeshl mice to investigate the behavioural abnormalities associated with ageing in Apoeshl mice. In this study, 7-month-old Apoeshl mice showed decreased body weight and grip strength compared to age-matched wild-type mice. In the open field test, 7-month-old Apoeshl mice showed increased anxiety-like behaviour compared to wild-type mice, whereas 11-month-old Apoeshl mice showed decreased anxiety-like behaviour. Moreover, Apoeshl mice aged 7 and 11 months had increased serum cholesterol levels. These results indicate that the behaviour of Apoeshl mice changes with age. However, 11-month-old Apoeshl mice did not show a decline in cognitive function or memory ability similar to murine models of AD. Our findings indicate that Apoeshl mice can be used to investigate the function of ApoE in the central nervous system.

DOI： 10.1515/tnsci-2022-0363

【LGBTQ+の子どもたち～多様な性を知ろう～】性別違和感をもつ子どもと二次性徴抑制療法

長谷川高誠, 松本洋輔, 中塚幹也

チャイルドヘルス 27 ( 9 ) 679 - 682 2024.9

Forgetfulness in adult attention‐deficit/hyperactivity disorder masks transient epileptic amnesia: a case report Reviewed International journal

Takashi Fukao, Masaki Fujiwara, Yuto Yamada, Shinji Sakamoto, Yosuke Matsumoto, Manabu Takaki

Psychiatry and Clinical Neurosciences Reports 3 ( 3 ) e70003 2024.8

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

Abstract

Background

Inattention due to attention‐deficit/hyperactivity disorder (ADHD) can lead to forgetfulness. Transient epileptic amnesia (TEA) can cause forgetfulness, similar to ADHD. We report a patient with ADHD who developed TEA.

Case Presentation

The patient was a 40‐year‐old woman with ADHD. She has been prone to forgetfulness since childhood. Two years before visiting our outpatient clinic, she had begun to occasionally forget events that had occurred several days earlier. However, she was largely unaware of the emergence of new amnestic symptoms. She had also begun to experience various other amnestic symptoms 2 months before she visited our clinic, which prompted her to visit our outpatient clinic. The combination of a detailed interview, electroencephalography (EEG) examination, and consideration of TEA enabled us to diagnose her with TEA and provide treatment accordingly. In our patient, daily forgetfulness due to ADHD delayed the recognition of new additional forgetfulness attributed to TEA.

Conclusion

Psychiatrists need to consider TEA when patients with ADHD present with changes in or exacerbation of forgetfulness.

DOI： 10.1002/pcn5.70003

Trans men can achieve adequate muscular development through low-dose testosterone therapy: A long-term study on body composition changes. Reviewed International journal

Yusuke Tominaga, Tomoko Kobayashi, Yuko Matsumoto, Takatoshi Moriwake, Yoshitaka Oshima, Misa Okumura, Satoshi Horii, Takuya Sadahira, Satoshi Katayama, Takehiro Iwata, Shingo Nishimura, Kensuke Bekku, Kohei Edamura, Morito Sugimoto, Yasuyuki Kobayashi, Masami Watanabe, Yuzaburo Namba, Yosuke Matsumoto, Mikiya Nakatsuka, Motoo Araki

Andrology 13 ( 2 ) 275 - 285 2024.4

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

BACKGROUND: Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT. OBJECTIVES: To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose. MATERIALS AND METHODS: Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5 mg/wk) to a high-dose group (> 62.5 mg/wk). RESULTS: Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3 mo, P = 0.006, P < 0.001; 6 mo, P = 0.015, P < 0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia. CONCLUSION: Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass.

DOI： 10.1111/andr.13640

Mice Recognise Mice in Neighbouring Rearing Cages and Change Their Social Behaviour. Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Sachiko Mori, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Behavioural neurology 2024 9215607 - 9215607 2024

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

Mice are social animals that change their behaviour primarily in response to visual, olfactory, and auditory information from conspecifics. Rearing conditions such as cage size and colour are important factors influencing mouse behaviour. In recent years, transparent plastic cages have become standard breeding cages. The advantage of using a transparent cage is that the experimenter can observe the mouse from outside the cage without touching the cage. However, mice may recognise the environment outside the cage and change their behaviour. We speculated that mice housed in transparent cages might recognise mice in neighbouring cages. We used only male mice in this experiment. C57BL/6 mice were kept in transparent rearing cages with open lids, and the cage positions were maintained for 3 weeks. Subsequently, we examined how mice behaved toward cagemate mice, mice from neighbouring cages, and mice from distant cages. We compared the level of interest in mice using a social preference test. Similar to previous reports, subject mice showed a high degree of interest in unfamiliar mice from distant cages. By contrast, subject mice reacted to mice from neighbouring cages as familiar mice, similar to cagemate mice. This suggests that mice housed in transparent cages with open lids perceive the external environment and identify mice in neighbouring cages. Researchers should pay attention to the environment outside the mouse cage, especially for the social preference test.

DOI： 10.1155/2024/9215607

Effects of home-cage elevation on behavioral tests in mice. Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Brain and behavior 14 ( 2 ) e3269 2023.12

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

BACKGROUND: Research reproducibility is a common problem in preclinical behavioral science. Mice are an important animal model for studying human behavioral disorders. Experimenters, processing methods, and rearing environments are the main causes of data variability in behavioral neuroscience. It is likely that mice adapt their behavior according to the environment outside the breeding cage. We speculated that mice housed on elevated shelves and mice housed on low shelves might have differently altered anxiety-like behavior toward heights. PURPOSE: The purpose of this study was to investigate potential behavioral changes in mice raised at different heights for 3 weeks. Changes in behavior were examined using various experimental tests. RESULTS: Mice housed on elevated shelves showed reduced anxiety-like behavior in a light/dark traffic test compared with mice housed on low shelves. There were no significant differences between the two groups in terms of activity, exploratory behavior, muscle strength, or depression-like behavior. CONCLUSIONS: Our results indicate that different cage heights and corresponding light exposure may alter the anxiety-like behavior of mice in response to brightness. Researchers need to carefully control the cage height and light intensity experienced by the mice to produce reproducible test results.

DOI： 10.1002/brb3.3269

岡山大学病院ジェンダーセンターにおける二次性徴抑制療法の臨床的検討 Reviewed

小林知子, 松本裕子, 中塚幹也, 新井富士美, 長谷川高誠, 松本洋輔, 大島義孝, 佐藤俊樹, 難波祐三郎

GID(性同一性障害)学会雑誌 16 ( 1 ) 25 - 30 2023.12

生体移植ドナーの精神的・身体的サポート生体肝移植ドナーの併存精神疾患と精神科連携

木村宏之, 杉田尚子, 大橋綾子, 成田尚, 藤澤大介, 岡田剛史, 松本洋輔, 岸辰一, 川崎弘詔, 西村勝治, 小倉靖弘, 池田匡志, 日本総合病院精神医学会臓器不全・移植関連委員会

移植 58 ( 総会臨時 ) 116 - 116 2023.9

Component-specific reduction in perineuronal nets in senescence-accelerated mouse strains. Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Tetsuji Miyazaki, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

IBRO neuroscience reports 14 111 - 121 2023.6

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

With increased life expectancy, age-related diseases are a significant health concern in Western societies. Animal models (e.g., rodents) have been used to understand age-related changes in brain function-particularly through the senescence-accelerated mouse (SAM) strain. Previous reports have shown that the senescence-accelerated mouse propensity (SAMP)8 and SAMP10 strains have learning disabilities. In this study, we analyzed the prefrontal cortex, which is involved in cognitive function. We aimed to clarify the changes in parvalbumin-positive interneurons (PV-positive neurons), which are related to cognitive function, and perineuronal nets (PNNs), which are special extracellular matrix molecules formed around them. We performed histological analysis of PV-positive neurons and PNNs in the prefrontal cortex to elucidate the mechanism of behavioral abnormalities in SAMP8 and SAMP10 strains. Expression of Cat-315-positive PNN was not confirmed in the prefrontal cortex of SAMP10 mice. However, the density of AB1031-positive PNN, tenascin-R-positive PNN, and brevican-positive PNN decreased in the prefrontal cortex of SAMP8 and SAMP10 mice compared to that of the senescence-accelerated mouse resistance (SAMR1) mice. In addition, the density of PV-positive neurons was lower in SAMP8 mice than in SAMR1 mice. These mice, which exhibited behavioral and neuropathological phenotypes with age, showed different PV-positive neurons and PNNs in the prefrontal cortex compared with the SAMR1 mice. We believe that the results of this study will be useful for elucidating the mechanisms of age-related decline in cognitive and learning functions using SAM.

DOI： 10.1016/j.ibneur.2023.01.002

Comprehensive behavioral study of C57BL/6.KOR-ApoE^shl mice Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Tetsuji Miyazaki, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Translational Neuroscience 14 ( 1 ) 20220284 - 20220284 2023.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Walter de Gruyter GmbH

Abstract

Background

Apolipoprotein E (ApoE) is associated with Alzheimer’s disease (AD) and cognitive dysfunction in elderly individuals. There have been extensive studies on behavioral abnormalities in ApoE-deficient (Apoe^shl) mice, which have been described as AD mouse models. Spontaneously hyperlipidemic mice were discovered in 1999 as ApoE-deficient mice due to ApoE gene mutations. However, behavioral abnormalities in commercially available Apoe^shl mice remain unclear. Accordingly, we aimed to investigate the behavioral abnormalities of Apoe^shl mice.

Results

Apoe^shl mice showed decreased motor skill learning and increased anxiety-like behavior toward heights. Apoe^shl mice did not show abnormal behavior in the Y-maze test, open-field test, light/dark transition test, and passive avoidance test.

Conclusion

Our findings suggest the utility of Apoe^shl mice in investigating the function of ApoE in the central nervous system.

DOI： 10.1515/tnsci-2022-0284

Other Link： https://www.degruyter.com/document/doi/10.1515/tnsci-2022-0284/pdf

Fingolimod increases parvalbumin-positive neurons in adult mice Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

IBRO Neuroscience Reports 13 96 - 106 2022.12

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

In recent years, it has been shown that central nervous system agents, such as antidepressants and antiepileptic drugs, reopen a critical period in mature animals. Fingolimod, which is used for the treatment of multiple sclerosis, also restores neuroplasticity. In this study, we investigated the effects of parvalbumin (PV)-positive neurons and perineuronal nets (PNN) on fingolimod administration with respect to neuroplasticity. Fingolimod was chronically administered intraperitoneally to mature mice. PV-positive neurons and PNN in the hippocampus, prefrontal cortex, and somatosensory cortex were analyzed. An increase in PV-positive neurons was observed in the hippocampus, prefrontal cortex, and somatosensory cortex of the fingolimod-treated mice. An increase in Wisteria floribunda agglutinin-positive PNN was confirmed in mice treated with fingolimod in the somatosensory cortex only. Fingolimod increased the density of PV-positive neurons in the brains of mature mice. The results indicate that fingolimod may change the critical period in mature animals.

DOI： 10.1016/j.ibneur.2022.06.005

The Prevention of Home-Cage Grid Climbing Affects Muscle Strength in Mice Reviewed International journal

Ueno H, Takahashi Y, Murakami S, Wani K, T Miyazaki, Matsumoto Y, Okamoto M, Ishihara T

Scientific Reports 12 ( 15263 ) 15263 - 15263 2022.9

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

Experimenters and treatment methods are the major contributors to data variability in behavioral neuroscience. However, home cage characteristics are likely associated with data variability. Mice housed in breeding cages spontaneously exhibit behavioral patterns such as biting into the wire grid and climbing on the grid lid. We aimed to clarify the effect of covering the stainless steel wire grid lid in commonly used home cage with Plexiglas to prevent climbing on muscle strength in mice. Furthermore, we investigated the effects of climbing prevention on activity and anxiety-like behavior, and the impact of climbing prevention during the postnatal development period and adulthood on muscle strength. Muscle strength, anxiety-like behavior, and locomotor activity were assessed by a battery of tests (wire hang, suspension, grip strength, rotarod, elevated-plus maze, and open field tests). Mice prevented from climbing the wire grid during postnatal development displayed lower muscle strength than those able to climb. Moreover, mice prevented from climbing for 3 weeks following maturity had weakened muscles. The muscle strength was decreased with 3 weeks of climbing prevention in even 1-year-old mice. In summary, the stainless steel wire grid in the home cage contributed to the development and maintenance of muscle strength in mice.

DOI： 10.1038/s41598-022-19713-4

Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-Based Internet Survey Using the Utrecht Gender Dysphoria Scale Reviewed International journal

Yoshitaka Oshima, Yosuke Matsumoto, Seishi Terada, Norihito Yamada

The Journal of Sexual Medicine 19 ( 7 ) 1185 - 1195 2022.7

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

BACKGROUND: Several studies have attempted to estimate the prevalence of gender dysphoria (GD) from a general population sample. However, no previous studies used reliable questionnaires. AIM: To estimate the prevalence of GD in Japan by gender and age using the Utrecht Gender Dysphoria Scale (UGDS). METHODS: A cross-sectional observational study was conducted with 20,000 respondents between the ages of 20 and 69 who were registered with an internet research company. The study consisted of two phases. First, the participants were asked to self-identify their gender on two 5-point Likert scales. Second, the screened participants completed the UGDS. OUTCOMES: Self-identified gender and GD were defined as follows: ambivalent gender (equally feeling like the birth gender and another gender), incongruent gender (a stronger sense of the latter vs the former), narrow GD (incongruent gender + UGDS score ≥ 41), and broad GD (ambivalent or incongruent gender + UGDS score ≥ 41). RESULTS: Among the eligible participants, the age-adjusted proportions of those classified as male (n = 7827) and female (n = 8903) at birth were 6.0% and 5.9%, respectively, for ambivalent gender, and 0.93% and 1.0%, respectively, for incongruent gender. The age-adjusted prevalence of GD was 0.27% (95% confidence interval, 0.18-0.42) and 0.35% (95% confidence interval, 0.25-0.50) for narrow GD and 0.87% (95% confidence interval, 0.69-1.1) and 1.1% (95% confidence interval, 0.86-1.3) for broad GD, respectively. No significant gender differences were found within the age groups, except for broad GD in respondents in their 50s (P = .016). However, for both genders, significant differences were found between age groups such that GD was more prevalent in younger vs older respondents, except for broad GD in respondents classified as female at birth (P = .063). CLINICAL IMPLICATIONS: Clinicians should be aware that the prevalence of GD is not negligible and that it varies with age. GD should be assessed in detail from various perspectives in addition to self-identified gender. STRENGTHS & LIMITATIONS: This study used a reliable questionnaire to examine the prevalence of GD in a large population. However, the participants did not represent the general population because this was an internet survey. CONCLUSION: The prevalence of GD was much higher than previously estimated by clinic-based studies, and was more frequently associated with participant age vs gender. Oshima Y, Matsumoto Y, Terada S, et al. Prevalence of Gender Dysphoria by Gender and Age in Japan: A Population-based Internet Survey Using the Utrecht Gender Dysphoria Scale. J Sex Med 2022;19:1185-1195.

DOI： 10.1016/j.jsxm.2022.03.605

Effect of simultaneous testing of two mice in the tail suspension test and forced swim test Reviewed International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Scientific Reports 12 ( 1 ) 9224 - 9224 2022.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

In mouse studies, the results of behavioural experiments are greatly affected by differences in the experimental environment and handling methods. The Porsolt forced swim test and tail suspension test are widely used to evaluate predictive models of depression-like behaviour in mice. It has not been clarified how the results of these tests are affected by testing single or multiple mice simultaneously. Therefore, this study evaluated the differences between testing two mice simultaneously or separately. To investigate the effect of testing multiple mice simultaneously, the Porsolt forced swim test and tail suspension test were performed in three patterns: (1) testing with an opaque partition between two mice, (2) testing without a partition between two mice, and (3) testing a single mouse. In the Porsolt forced swim test, the mice tested simultaneously without a partition demonstrated increased immobility time as compared to mice tested alone. No difference in immobility time was observed between the three groups in the tail suspension test. Our results showed that the environment of behavioural experiments investigating depression-like behaviour in mice can cause a difference in depression-like behaviour. The results of this experiment indicated that it is necessary to describe the method used for behavioural testing in detail.

DOI： 10.1038/s41598-022-12986-9

Other Link： https://www.nature.com/articles/s41598-022-12986-9

Mice can recognise water depths and will avoid entering deep water. International journal

Hiroshi Ueno, Yu Takahashi, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Translational neuroscience 13 ( 1 ) 1 - 10 2022.1

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

Rodents are averse to bodies of water, and this aversion has been exploited in experiments designed to study stress in mice. However, a few studies have elucidated the characteristics of murine water aversion. In this study, we investigated how mice behave in and around areas filled with water. Using variants of the open field test that contained pools of water at corners or sides of the field, we recorded the movements of mice throughout the field under various conditions. When the water was 8 mm deep, the mice explored the water pool regardless of whether an object was placed within it, but when the water was 20 mm deep, the mice were less willing to enter it. When the mice were placed on a dry area surrounded by 3 mm-deep water, they explored the water, but when they were surrounded by 8 mm-deep water, they stayed within the dry area. Our results indicate that mice exhibit exploratory behaviours around water, they can recognise water depths and avoid unacceptably deep water, and their willingness to enter water may be reduced by situational anxiety. Our experimental method could be used to investigate water-related anxiety-like behaviours in mice.

DOI： 10.1515/tnsci-2020-0208

Chronic Inhibition of Aggressive Behavior Induces Behavioral Change in Mice. International journal

Hiroshi Ueno, Yu Takahashi, Shinji Murakami, Kenta Wani, Tetsuji Miyazaki, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Behavioural neurology 2022 7630779 - 7630779 2022

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

Suppression of anger is more common than its expression among Asian individuals. Emotional suppression is considered an unhealthy emotional regulation. Most studies on emotional suppression have concluded that suppression adversely affects social outcomes, with approximately 5% of the world's population suffering from emotional disorders. However, anger suppression has not received academic attention, and details of the effects of chronic anger suppression on the central nervous system remain unclear. In this study, we performed the resident-intruder test to investigate the effect of chronic suppression of aggressive behavior in mice using a behavioral test battery and to clarify whether suppression of this aggressive behavior is stressful for mice. Mice chronically inhibited aggressive behavior and lost weight. Mice with inhibited aggressive behavior showed a reduced percentage of immobility time during the tail suspension test as well as no changes in activity, anxiety-like behavior, muscle strength, or temperature sensitivity. This study provides scientific evidence for the effects of chronic aggressive behavior inhibition on the body and central nervous system.

DOI： 10.1155/2022/7630779

臓器移植希望者(レシピエント)の心理社会的評価に関する提言

西村勝治, 井上真一郎, 大橋綾子, 岡田剛史, 桂川修一, 木村宏之, 小林清香, 成田尚, 中西健二, 松本洋輔, 日本総合病院精神医学会臓器不全・臓器移植関連委員会

総合病院精神医学 33 ( 3 ) 246 - 285 2021.7

Collective Housing of Mice of Different Age Groups before Maturity Affects Mouse Behavior. Reviewed International journal

Hiroshi Ueno, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yu Takahashi, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Behavioural neurology 2020 6856935 - 6856935 2020.11

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

BACKGROUND: Although population housing is recommended by many animal management and ethical guidelines, the effect of collective housing of mice of different age groups on mouse behavior has not been clarified. Since the development of the central nervous system continues to occur before sexual maturation, the stress of social ranking formation among male individuals in mixed housing conditions can affect postmaturation behavior. To assess these effects, sexually immature mice of different ages were housed in the same cage and a series of behavioral tests were performed after maturation. RESULTS: The findings for three groups of mice-junior mice housed with older mice, senior mice housed with younger mice, and mice housed with other mice of the same age-were compared. Junior mice showed higher body weight and activity as well as lower grip strength and anxiety-like behaviors than other mice. In contrast, senior mice showed lower body temperature and increased aggression, antinociceptive effect, and home-cage activity in the dark period in comparison with other mice. CONCLUSIONS: Thus, combined housing of immature mice of different age groups affects mouse behavior after maturation. Appropriate prematuration housing conditions are crucial to eliminate the uncontrollable bias caused by age-related social stratification.

DOI： 10.1155/2020/6856935.

Hexanal inhalation affects cognition and anxiety-like behavior in mice International journal

Hiroshi Ueno, Atsumi Shimada, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yu Takahashi, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

Zeitschrift fur Naturforschung - Section C Journal of Biosciences 75 ( 11-12 ) 409 - 415 2020.11

てんかん発作後に精神病症状と生活史健忘を認め、遷延する健忘がてんかん性か解離性かの区別に苦慮した1例. Reviewed

深尾貴志、藤原雅樹、松本洋輔、山田了士

精神神経学雑誌 122 ( 9 ) 703 - 703 2020.9

自閉スペクトラム症を背景にもち断食を試みた自殺企図に対し、治療および社会支援を導入した1例. Reviewed

加藤朱万理、植田真司、藤原雅樹、松本洋輔、山田了士

精神神経学雑誌 122 ( 9 ) 700 - 701 2020.9

Effects of haloperidol inhalation on MK-801- and memantine-induced locomotion in mice. Reviewed International journal

Hiroshi Ueno, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yu Takahashi, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

The Libyan journal of medicine 15 ( 1 ) 1808361 - 1808361 2020.8

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

UNLABELLED: The administration of therapeutic agents is difficult in many patients, such as patients with post-operative delirium or dementia or patients with schizophrenia, who are upset in an emergency room. Therefore, the development of a new method for administering therapeutic agents to the central nervous system is desired. In this study, we investigated if inhalation was an effective route of administration for haloperidol, a commonly used, strong antipsychotic. Dizocilpine, also known as MK-801, is a noncompetitive antagonist of the N-methyl-D-aspartate receptor. MK-801 or memantine-induced motor hyperactivity was evaluated in mice following either intraperitoneal injection or inhalation of haloperidol or the histamine neuroactivator betahistine. Pretreatment with haloperidol inhalation inhibited the MK-801-induced or memantine-induced increase in locomotor activity. This effect was similar to that of the intraperitoneal administration of haloperidol. However, pretreatment with inhaled betahistine or the intraperitoneal administration of betahistine did not suppress the MK-801-induced or memantine-induced increase in locomotor activity. Thus, haloperidol when inhaled acts on the central nervous system of mice and suppresses the MK-801-induced increase in mouse locomotor activity. Our findings suggest that inhalation may be a novel method for administering haloperidol. ABBREVIATIONS: ANOVA: analysis of variance.

DOI： 10.1080/19932820.2020.1808361

Pentylenetetrazol kindling induces cortical astrocytosis and increased expression of extracellular matrix molecules in mice. Reviewed

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Yu, Matsumoto Y, Okamoto M, Ishihara T

Brain Res Bull 163 120 - 134 2020.7

Alpha-pinene and dizocilpine (MK-801) attenuate kindling development and astrocytosis in an experimental mouse model of epilepsy. Reviewed

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Yu, Matsumoto Y, Okamoto M, Ishihara T

IBRO Rep 9 102 - 114 2020.7

Behavioural Changes in Mice after Getting Accustomed to the Mirror Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Behavioural Neurology 4071315 4071315 - 4071315 2020

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

Patients with brain function disorders due to stroke or dementia may show inability to recognize themselves in the mirror. Although the cognitive ability to recognize mirror images has been investigated in many animal species, the animal species that can be used for experimentation and the mechanisms involved in recognition remain unclear. We investigated whether mice have the ability to recognize their mirror images. Demonstrating evidence of this in mice would be useful for researching the psychological and biological mechanisms underlying this ability. We examined whether mice preferred mirrors, whether plastic tapes on their heads increased their interest, and whether mice accustomed to mirrors learnt its physical phenomenon. Mice were significantly more interested in live stranger mice than mirrors. Mice with tape on their heads spent more time before mirrors. Becoming accustomed to mirrors did not change their behaviour. Mice accustomed to mirrors had significantly increased interest in photos of themselves over those of strangers and cage-mates. These results indicated that mice visually recognized plastic tape adherent to reflected individuals. Mice accustomed to mirrors were able to discriminate between their images, cage-mates, and stranger mice. However, it is still unknown whether mice recognize that the reflected images are of themselves.

DOI： 10.1155/2020/4071315.

Increased anxiety-related behavior in mice following b-citronellol inhalation Reviewed International journal

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Yu Takahashi, Matsumoto Y, Okamoto M, Ishihara T

Libyan Journal of Medicine in press ( 1 ) 1767275 - 1767275 2020

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

β-Citronellol is a monoterpene alcohol found in essential oils of various aromatic plant species. The physiological effects of β-citronellol inhalation on the central nervous system remain unclear. We investigated the effects of β-citronellol inhalation on mouse behavior. First, we examined whether the odor of β-citronellol was attractive or repellent to mice. Then, following 30 minutes of β-citronellol inhalation, a series of behavioral tests (elevated plus maze, open field, Y-maze, tail suspension, and forced swim tests) were performed. Mice were neither attracted to nor repelled by β-citronellol. Mice that inhaled β-citronellol showed an increase in anxiety-like behavior in the elevated plus maze and open field tests. Performance in the Y-maze and forced swim tests was not affected. These results indicate that β-citronellol acts on the central nervous system of mice following inhalation and increases anxiety. Essential oils and cosmetics containing β-citronellol should be used with caution.

DOI： 10.1080/19932820.2020.1767275

Effects of repetitive gentle handling of male C57BL/6NCrl mice on comparative behavioural test results Reviewed International journal

Ueno H, Takahashi Y, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Scientific Reports 10 ( 3509 ) 3509 - 3509 2020

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

Mice are the most commonly used laboratory animals for studying diseases, behaviour, and pharmacology. Behavioural experiment battery aids in evaluating abnormal behaviour in mice. During behavioural experiments, mice frequently experience human contact. However, the effects of repeated handling on mice behaviour remains unclear. To minimise mice stress, methods of moving mice using transparent tunnels or cups have been recommended but are impractical in behavioural tests. To investigate these effects, we used a behavioural test battery to assess differences between mice accustomed to the experimenter's handling versus control mice. Repeatedly handled mice gained slightly more weight than control mice. In behavioural tests, repeatedly handled mice showed improved spatial cognition in the Y-maze test and reduced anxiety-like behaviour in the elevated plus-maze test. However, there was no change in anxiety-like behaviour in the light/dark transition test or open-field test. Grip strength, rotarod, sociability, tail suspension, Porsolt forced swim, and passive avoidance tests revealed no significant differences between repeatedly handled and control mice. Our findings demonstrated that mice repeatedly handled by the experimenter before behavioural tests showed reduced anxiety about high altitudes and improved spatial cognition, suggesting that repeated contact can affect the results of some behavioural tests.

DOI： 10.1038/s41598-020-60530-4

Hexanal inhalation affects cognition and anxiety-like behavior in mice Reviewed

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Zeitschrift für Naturforschung C in press 409 - 415 2020

Caffeine Inhalation Effects on Locomotor Activity in Mice Reviewed International journal

Ueno H, Takahashi Y, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Drug Development and Industrial Pharmacy in press ( 5 ) 778 - 794 2020

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

It is estimated that 80% of the world's population consumes caffeine from beverages and food every day. The traditional form of caffeine intake is oral, but more recently people have been inhaling caffeine using nasal sprays. However, the effects of caffeine inhalation are not well understood. The purpose of this study was to determine whether caffeine inhalation affects mouse behavior. To test this, we compared spontaneous activity of mice following inhalation and intraperitoneal administration of caffeine. Next, we investigated whether spontaneous activity changed with the time and/or concentration of caffeine inhaled. We found that mice that inhaled caffeine increased their spontaneous activity similar to mice that were administered caffeine intraperitoneally. Furthermore, spontaneous activity increased in an inhalation time-dependent and concentration-dependent manner. These results show that caffeine-induced stimulation also occurs by inhalation in mice, which suggests that caffeine can reach the brain even by inhalation. This study is useful not only for creating new administration methods of caffeine but also for adjusting caffeine storage and management.

DOI： 10.1080/03639045.2020.1753064

Conformity-like Behaviour in Mice Observing the Freezing of Other Mice: A Model of Empathy Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

BMC Neuroscience in press ( 1 ) 19 - 19 2020

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

BACKGROUND: Empathy refers to the ability to recognise and share emotions with others. Several research groups have recognised observational fear in mice as a useful behavioural model for assessing their ability to empathise. However, in these observation systems, it remains unclear whether the observer mouse truly recognises the movements of, and empathises with, the demonstrator mouse. We examined changes in the behaviour of an observer mouse when a demonstrator mouse was anaesthetised, when the demonstrator's activity was increased, and when the interval of electrical stimulation was altered. If mice exhibit an ability to empathise, then the observer should display empathic behaviour when the demonstrator experiences pain or discomfort under any circumstances. RESULTS: Relative to low-frequency stimulation, frequent electrical stimulation reduced immobility time among observer mice. Moreover, when demonstrators exhibited excessive activity, the activity of the observers significantly increased. In addition, the proportion of immobility time among observer mice significantly increased when demonstrator mice exhibited fear learning and excessive immobility. CONCLUSION: Although our results indicate that observer mice change their behaviour based on the movements of demonstrator mice, increases in immobility time may reflect conformity-like behaviour rather than emotional empathy. Thus, not only visual but also auditory and odour information additionally influenced the conformity-like behaviour shown by observer mice. Thus, our findings suggest that methods other than the fear observation system should be used to investigate rodent empathy-like behaviour.

DOI： 10.1186/s12868-020-00566-4

Alpha-Pinene and Dizocilpine (MK-801) Attenuate Kindling Development and Astrocytosis in an Experimental Mouse Model of Epilepsy Reviewed International journal

Hiroshi Ueno, Atsumi Shimada, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Yu Takahashi, Yosuke Matsumoto, Motoi Okamoto, Takeshi Ishihara

IBRO Reports 9 102 - 114 2020

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

Understanding the molecular and cellular mechanisms involved during the onset of epilepsy is crucial for elucidating the overall mechanism of epileptogenesis and therapeutic strategies. Previous studies, using a pentylenetetrazole (PTZ)-induced kindling mouse model, showed that astrocyte activation and an increase in perineuronal nets (PNNs) and extracellular matrix (ECM) molecules occurred within the hippocampus. However, the mechanisms of initiation and suppression of these changes, remain unclear. Herein, we analyzed the attenuation of astrocyte activation caused by dizocilpine (MK-801) administration, as well as the anticonvulsant effect of α-pinene on seizures and production of ECM molecules. Our results showed that MK-801 significantly reduced kindling acquisition, while α-pinene treatment prevented an increase in seizures incidences. Both MK-801 and α-pinene administration attenuated astrocyte activation by PTZ and significantly attenuated the increase in ECM molecules. Our results indicate that astrocyte activation and an increase in ECM may contribute to epileptogenesis and suggest that MK-801 and α-pinene may prevent epileptic seizures by suppressing astrocyte activation and ECM molecule production.

DOI： 10.1016/j.ibror.2020.07.007

Pentylenetetrazol kindling induces cortical astrocytosis and increased expression of extracellular matrix molecules in mice Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Brain Research Bulletin 163 120 - 134 2020

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

Although epilepsy is one of the most common chronic neurological disorders with a prevalence of approximately 1.0 %, the underlying pathophysiology remains to be elucidated. Understanding the molecular and cellular mechanisms involved in the development of epilepsy is important for the development of appropriate therapeutic strategy. In this study, we investigated the effects of status epilepticus on astrocytes, microglia, and extracellular matrix (ECM) molecules in the somatosensory cortex and piriform cortex of mice. Activation of astrocytes was observed in many cortices except the retrosplenial granular cortex after pentylenetetrazol (PTZ)-induced kindling in mice. Activated astrocytes in the cortex were found in layers 1-3 but not in layers 4-6. In the somatosensory and piriform cortices, no change was observed in the number of parvalbumin (PV)-positive neurons and PV-positive neurons covered with perineuronal nets. However, the amount of ECM in the extracellular space increased. The expression of VGLUT1- and GAD67-positive synapses also increased. Thus, in the PTZ-kindling epilepsy mice model, an increase in the number of ECM molecules and activation of astrocytes were observed in the somatosensory cortex and piriform cortex. These results indicate that PTZ-induced seizures affect not only the hippocampus but also other cortical areas. Our study findings may help to develop new therapeutic approaches to prevent seizures or their sequelae.

DOI： 10.1016/j.brainresbull.2020.07.019

Region-Specific Reduction of Parvalbumin Neurons and Behavioral Changes in Adult Mice Following Single Exposure to Cranial Irradiation Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

International journal of radiation biology 95 ( 5 ) 611 - 625 2019.1

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

PURPOSE: Ionizing irradiation has several long-term effects including progressive cognitive impairment. Cognitive deterioration generally appears to be caused by abnormalities in the hippocampal dentate gyrus, with abnormal function of parvalbumin-expressing interneurons (PV neurons) in the cerebral cortex. PV neurons are vulnerable to oxidative stress, which can be caused by ionizing irradiation. We speculated that selective impairment of specific brain regions due to ionizing irradiation may alter the degree of cognitive impairment. METHODS: We irradiated mature mouse brains with 20 Gy-ionizing irradiation. Subsequently, we analyzed behavioral abnormalities and changes in the number of PV neurons. RESULTS: PV neuron density was significantly lower in some cortical regions of irradiated mice than in control mice. Within 1 week of irradiation, both body weight and temperature of irradiated mice decreased. In the forced swim test, irradiated mice spent significantly less time immobile than did control mice. However, irradiated mice did not display any abnormalities in the elevated plus maze test, Y-maze test, tail suspension test, and social interaction test between 3 to 6 days after irradiation. CONCLUSIONS: These results suggest that high-dose irradiation is less likely to cause brain dysfunction in the subacute phase. Moreover, the vulnerability of PV neurons appears to be brain-region specific.

DOI： 10.1080/09553002.2019.1564081

Layer-Specific Expression of Extracellular Matrix Molecules in the Mouse Somatosensory and Piriform Cortices Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

IBRO Reports 6 1 - 17 2019

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

In the developing central nervous system (CNS), extracellular matrix (ECM) molecules have regulating roles such as in brain development, neural-circuit maturation, and synaptic-function control. However, excluding the perineuronal net (PNN) area, the distribution, constituent elements, and expression level of granular ECM molecules (diffuse ECM) present in the mature CNS remain unclear. Diffuse ECM molecules in the CNS share the components of PNNs and are likely functional. As cortical functions are greatly region-dependent, we hypothesized that ECM molecules would differ in distribution, expression level, and components in a region- and layer-dependent manner. We examined the layer-specific expression of several chondroitin sulfate proteoglycans (aggrecan, neurocan, and brevican), tenascin-R, Wisteria floribunda agglutinin (WFA)-positive molecules, hyaluronic acid, and link protein in the somatosensory and piriform cortices of mature mice. Furthermore, we investigated expression changes in WFA-positive molecules due to aging. In the somatosensory cortex, PNN density was particularly high at layer 4 (L4), but not all diffuse ECM molecules were highly expressed at L4 compared to the other layers. There was almost no change in tenascin-R and hyaluronic acid in any somatosensory-cortex layer. Neurocan showed high expression in L1 of the somatosensory cortex. In the piriform cortex, many ECM molecules showed higher expression in L1 than in the other layers. However, hyaluronic acid showed high expression in deep layers. Here, we clarified that ECM molecules differ in constituent elements and expression in a region- and layer-dependent manner. Region-specific expression of ECM molecules is possibly related to functions such as region-specific plasticity and vulnerability.

DOI： 10.1016/j.ibror.2018.11.006

Feeding Behavior of Mice Under Different Food Allocation Regimens Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Behavioural Neurology 1581304 1 - 10 2019

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

Social interaction, a basic survival strategy for many animal species, helps maintain a social environment that has limited conflict. Social dominance has a dramatic effect on motivation. Recent evidence suggests that some primate and nonprimate species display aversive behavior toward food allocation regimens that differ from their peers. Thus, we examined the behaviors displayed by mice under different food allocation regimens. We analyzed changes in food intake using several parameters. In the same food condition, the mice received the same food; in the quality different condition, the mice received different foods; in the quantity different condition, one mouse did not receive food; and in the no food condition, none of the mice received food. To test differences based on food quality, one mouse received normal solid food as a less preferred reward, and the other received chocolate chips as a high-level reward. No behavioral change was observed in comparison to the same food condition. To test differences based on food quantity, one mouse received chocolate chips while the other received nothing. Mice who received nothing spent more time on the other side of the reward throughout the experiment. Interestingly, highly rewarded mice required more time to consume the chocolate chips. Thus, under different food allocation regimens, mice changed their behavior by being more hesitant. Moreover, mice alter food intake behavior according to the social environment. The findings help elucidate potential evolutionary aspects that help maintain social cohesion while providing insights into potential mechanisms underlying socially anxious behavior.

DOI： 10.1155/2019/1581304

Region-Specific Reduction of Parvalbumin Neurons and Behavioral Changes in Adult Mice Following Single Exposure to Cranial Irradiation Reviewed

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

International Journal of Radiation Biology 2 1 - 17 2019

Helping-Like Behaviour in Mice Towards Conspecifics Constrained Inside Tubes Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Scientific Reports 9 ( 5817 ) 5817 - 5817 2019

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

Prosocial behaviour, including helping behaviour, benefits others. Recently, helping-like behaviour has been observed in rats, but whether it is oriented towards rescue, social contact with others, or other goals remains unclear. Therefore, we investigated whether helping-like behaviour could be observed in mice similar to that in rats. Because mice are social animals widely used in neuroscience, the discovery of helping-like behaviour in mice would be valuable in clarifying the psychological and biological mechanisms underlying pro-sociability. We constrained mice inside tubes. Subject mice were allowed to move freely in cages with tubes containing constrained conspecifics. The subject mice released both cagemates and stranger mice but did not engage in opening empty tubes. Furthermore, the same behaviour was observed under aversive conditions and with anesthetised conspecifics. Interestingly, hungry mice opened the tubes containing food before engaging in tube-opening behaviour to free constrained conspecifics. Mice showed equal preferences for constrained and freely moving conspecifics. We demonstrated for the first time that mice show tube-opening behaviour. Furthermore, we partly clarified the purpose and motivation of this behaviour. An effective mouse model for helping-like behaviour would facilitate research on the mechanisms underlying prosocial behaviour.

DOI： 10.1038/s41598-019-42290-y

Alteration of Parvalbumin Expression and Perineuronal Nets Formation in the Cerebral Cortex of Aged Mice Reviewed International journal

Ueno H, Fujii K, Takao K, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Molecular and Cellular Neuroscience 95 31 - 42 2019

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

Aging is associated with decline in cognitive function, but the underlying mechanisms have not been elucidated. Normal activity of pyramidal cells and parvalbumin-expressing interneurons (PV neurons) is essential for cognitive function. PV neurons participate in the regulation of pyramidal-cell firing. Abnormal function of PV neurons may occur with aging. We analyzed the density and the percentage of PV neurons surrounded by perineuronal nets (PNNs) in the entire cortex of adult (3-month-old) and aged (24-month-old) mice. PNNs are extracellular matrix molecules that cover PV neurons and control synaptic plasticity. PV-neuron density decreased in some cortical areas of aged compared to adult mice. In particular, in the retrosplenial granular cortex (RSG) of aged mice, pyramidal cells expressed PV protein at high levels. This study suggests that the RSG of aged mice is in an abnormal activated state. RSG function abnormality may be part of the cognitive decline mechanism.

DOI： 10.1016/j.mcn.2018.12.008

Anti-depressive-like effect of 2-phenylethanol inhalation in mice Reviewed International journal

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Biomedicine & Pharmacotherapy 111 1499 - 1506 2019

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

Rose oil has traditionally been used to treat psychiatric disorders, but the scientific basis of this treatment remains poorly understood. The main odor component of rose oil is 2-phenylethanol (2-PE), but the neuropsychological effects of 2-PE have not been investigated in detail. Thus, we aimed to investigate the effects of 2-PE on mouse behavior. We first investigated whether 2-PE is attractive or repulsive to mice. After 2-PE inhalation, the mice underwent a series of behavioral experiments, such as the elevated plus maze, open field, Y-maze, tail-suspension, and Porsolt forced-swim tests. Mice did not have a strong interest in 2-PE but were not repelled by it nor were fearful. In the open field test, mice that had inhaled 2-PE spent less time in the center area, while in the tail suspension test, their immobility time decreased. There was no change in cognitive function, activity level, muscle strength, or aggression in these mice. Our results suggest that 2-PE elicits neuropsychological effects that alter the behavior of mice and may also elicit anti-depressive effects. Inhalation of rose oil containing 2-PE may be effective against depression and stress-related diseases.

DOI： 10.1016/j.biopha.2018.10.073

Anti-stress effects of the hydroalcoholic extract of Rosa gallica officinalis in mice Reviewed International journal

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Fujiwara Y, Ishihara T

Heliyon 5 ( 6 ) e01945 - e01945 2019

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

Rosa gallica, a plant of the Rosa genus, has been used widely since the 13th century and is cultivated in many areas as a medicinal plant for the preparation of herbal medicines. However, details of the neuropsychological effects of R. gallica remain unclear; therefore we aimed to investigate the neuropsychological effects of a water-soluble extract of R. gallica in male C57BL/6N mice under normal conditions and under chronic stress. We administered a water-soluble extract of R. gallica to mice and performed a series of behavioral experiments to compare the treated animals with the untreated controls. No significant differences in activity level, anxiety-like behavior, depression-like behavior, body weight, and body temperature were observed between R. gallica-treated mice and control mice. However, in mice subjected to chronic stress, the observed decrease in activity was smaller in the R. gallica-treated mice than in the control mice. The oral administration of R. gallica did not affect the normal behavior of mice. However, when the mice were subjected to stress, R. gallica exerted an anti-stress effect. Therefore, R. gallica has potential as a medicinal plant for the purpose of stress prevention.

DOI： 10.1016/j.heliyon.2019.e01945

Attenuation Effects of Alpha-Pinene Inhalation on Mice with Dizocilpine-Induced Psychiatric-like Behaviour Reviewed International journal

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Ishihara T

Evidence-Based Complementary and Alternative Medicine 2745453 1 - 12 2019

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

α-Pinene, an organic terpene compound found in coniferous trees, is used as a safe food additive and is contained in many essential oils. Moreover, some studies have shown that α-pinene suppresses neuronal activity. In this study, we investigated whether inhalation of α-pinene suppresses dizocilpine (MK-801-) induced schizophrenia-like behavioural abnormalities in mice. Mice inhaled α-pinene 1 h before the first MK-801 injection. Thirty minutes after MK-801 injection, the open field, spontaneous locomotor activity, elevated plus maze, Y-maze, tail suspension, hot plate, and grip strength tests were conducted as behavioural experiments. Inhalation of α-pinene suppressed the activity of mice in the spontaneous locomotor activity test and although it did not suppress the MK-801-induced increased locomotor activity in the open field test, it remarkably decreased the time that the mice remained in the central area. Inhalation of α-pinene suppressed the MK-801-induced increased total distance travelled in the Y-maze test, whereas it did not alter the MK-801-induced reduced threshold of antinociception in the hot plate test. In the tail suspension and grip strength tests, there was no effect on mouse behaviour by administration of MK-801 and inhalation of α-pinene. These results suggest that α-pinene acts to reduce MK-801-induced behavioural abnormalities resembling those seen in neuropsychiatric disorders. Therefore, both medicinal plants and essential oils containing α-pinene may have potential for therapeutic treatment of schizophrenia.

DOI： 10.1155/2019/2745453

Behavioural Effects of Inhalation Exposure to Dizocilpine (MK-801) in Mice Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Biomedicine & Pharmacotherapy 117 ( 109038 ) 109038 - 109038 2019

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

The complex pathophysiology of brain disorders and the difficulty of delivering therapeutic agents to the brain remain major obstacles in the research and development of new therapeutic methods for brain disorders. Therefore, delivering existing therapeutic agents to the central nervous system is expected to provide benefits in various diseases. In this study, we investigated whether inhaled central nervous system drugs reached the brain and affected mouse behaviour. Dizocilpine (MK-801), which increases locomotor activity in mice, was mainly used to study this hypothesis. First, we administered MK-801, an N-methyl-d-aspartate receptor antagonist, to mice via inhalation and examined whether it induced excessive activity similar to that observed after intraperitoneal administration. We also examined the time- and dose-dependency of drug induced changes in mouse behaviour after MK-801 inhalation. Next, we investigated whether inhalation of scopolamine, pentobarbital, and imipramine also affected mouse behaviour. Mice that inhaled MK-801 showed MK-801-induced hyperactivity similar to that observed following intraperitoneal administration. Furthermore, the extent of activity changed in a time- and dose-dependent manner after MK-801 inhalation. Inhalation of pentobarbital, scopolamine, and imipramine also changed mouse behaviour. These results demonstrate that inhalation of MK-801 exerts effects similar to those achieved with intraperitoneal and oral administration in mice. Thus, central nervous system agonists can reach the brain efficiently via inhalation. This finding may facilitate the development of improved therapies for brain disorders.

DOI： 10.1016/j.biopha.2019.109038

Comprehensive Behavioral Study of the Effects of Vanillin Inhalation in Mice Reviewed International journal

Ueno H, Shimada A, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Yu, Matsumoto Y, Okamoto M, Fujiwara Y, Ishihara T

Biomedicine & Pharmacotherapy 115 ( 108879 ) 108879 - 108879 2019

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

Vanillin is widely used in food and cosmetics, among other substances, for its sweet smell. However, the neuropsychological effects of vanillin inhalation have not been elucidated. In this study, we investigated the effect of vanillin inhalation on mouse behavior. First, we investigated whether the aroma of vanillin was attractive or repulsive for mice. Thereafter, the mice inhaled vanillin for 20 min before each test in a series of behavioral tests (elevated plus maze, open field, Y-maze, tail suspension, cotton bud biting, and Porsolt forced swim tests). In these tests, the mice showed a neutral response to vanillin. Mice that inhaled vanillin had a suppressed pain response in the hot plate test. In addition, the grip strength of the forelimbs of mice that inhaled vanillin was decreased. No significant differences were found between the mice inhaling vanillin and control mice in the open field, Y-maze, tail suspension, forced swimming, and aggression tests. These results show that vanillin inhalation has anti-nociceptive effects, similar to other routes of administration. The results also show that vanillin inhalation does not cause significant behavioral effects.

DOI： 10.1016/j.biopha.2019.108879

Rescue-like Behaviour in Mice is Mediated by Their Interest in the Restraint Tool Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Scientific Reports 10648 ( 1 ) 10648 - 10648 2019

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

Acting without the expectation of compensation is called prosocial behaviour. Since prosocial behaviour requires high cognitive and social abilities, it has been thought to be only shown by primates. Although prosocial behaviour has been recently reported in rats, there are still questions regarding this finding. We demonstrated rescue-like behaviour in mice in a previous report. In this study, we investigated the motives underlying rescue-like behaviour for constrained cage-mates among mice. We prepared either a tube containing a ball of yarn or an opaque tube and assessed whether mice displayed the same rescue-like behaviour shown in the case of tube-restrained cage-mates. Mice did not open the lid of the tube containing the ball of yarn but opened the opaque tube lid. Mice showed a high interest in the tube in which the cage-mate had been restrained and prioritized staying in this tube rather than rescuing additional cage-mates. Oxytocin, which increases empathy, had no effect on the lid-opening behaviour. Thus, the rescue-like behaviour of mice is not based on empathy but is related to social interest in the cage-mate and the tube itself. These results suggest that rodent lid-opening behaviour may not conclusively prove the presence of prosocial behaviour.

DOI： 10.1038/s41598-019-46128-5

Alteration of extracellular matrix molecules and perineuronal nets in the hippocampus of pentylenetetrazol-kindled mice Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Takahashi Y, Matsumoto Y, Okamoto M, Ishihara T

Neural Plasticity 8924634 1 - 14 2019

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

The pathophysiological processes leading to epilepsy are poorly understood. Understanding the molecular and cellular mechanisms involved in the onset of epilepsy is crucial for drug development. Epileptogenicity is thought to be associated with changes in synaptic plasticity; however, whether extracellular matrix molecules-known regulators of synaptic plasticity-are altered during epileptogenesis is unknown. To test this, we used a pentylenetetrazole- (PTZ-) kindling model mouse to investigate changes to hippocampal parvalbumin- (PV-) positive neurons, extracellular matrix molecules, and perineuronal nets (PNNs) after the last kindled seizure. We found an increase in Wisteria floribunda agglutinin- (WFA-) and Cat-315-positive PNNs and a decrease in PV-positive neurons not surrounded by PNNs, in the hippocampus of PTZ-kindled mice compared to control mice. Furthermore, the expression of WFA- and Cat-315-positive molecules increased in the extracellular space of PTZ-kindled mice. In addition, consistent with previous studies, astrocytes were activated in PTZ-kindled mice. We propose that the increase in PNNs after kindling decreases neuroplasticity in the hippocampus and helps maintain the neural circuit for recurrent seizures. This study shows that possibility of changes in extracellular matrix molecules due to astrocyte activation is associated with epilepticus in PTZ-kindled mice.

DOI： 10.1155/2019/8924634

Hyaluronic Acid is Present on Specific Perineuronal Nets in the Mouse Cerebral Cortex Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Aoki S, Ishihara T

Brain Research 1698 139 - 150 2018.11

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

In the central nervous system (CNS), extracellular matrix (ECM) molecules comprise more than 20% of the volume and are involved in neuronal plasticity, synaptic transmission, and differentiation. Perineuronal nets (PNNs) are ECM molecules that highly accumulate around the soma of neurons. The components of the ECM in the CNS include proteins, proteoglycans, and glycosaminoglycans. Although hyaluronic acid (HA) is considered a constituent element of PNNs, the distribution of HA in the cortex has not been clarified. To elucidate the cortical region-specific distribution of HA, we quantitatively analyzed HA binding protein (HABP)-positive PNNs in the mature mouse cerebral cortex. Our findings revealed that HABP-positive PNNs are present throughout the mouse cortex. The distribution of many HABP-positive PNNs differed from that of Wisteria floribunda agglutinin-positive PNNs. Furthermore, we observed granular-like HABP-positive PNNs in layer 1 of the cortex. These findings indicate that PNNs in the mouse cortex show region-dependent differences in composition. HABP-positive PNNs in layer 1 of the cortex may have different functions such as neuronal differentiation, proliferation, and migration unlike what has been reported for PNNs so far.

DOI： 10.1016/j.brainres.2018.08.011

精神疾患併存が肝移植レシピエントの生存に与える影響

木村宏之, 岸辰一, 岡田剛史, 成田尚, 田中輝明, 町野彰彦, 松本洋輔, 藤澤大介, 大橋綾子, 光安博志, 野間俊一, 西村勝治, 川嵜弘詔, 小倉靖弘, 尾崎紀夫

移植 53 ( 総会臨時 ) 531 - 531 2018.9

Empathic behavior according to the state of others in mice International journal

Hiroshi Ueno, Shunsuke Suemitsu, Shinji Murakami, Naoya Kitamura, Kenta Wani, Motoi Okamoto, Yosuke Matsumoto, Shozo Aoki, Takeshi Ishihara

Brain and Behavior 8 ( 7 ) e00986 2018.7

戸籍の性別の「変更」ではなく「訂正」が認められた46、XX副腎皮質過形成症の2例. Reviewed

大島義孝、松本洋輔、佐藤俊樹、山田了士

GID(性同一性障害)学会雑誌 10 ( 1 ) 41 - 48 2018.3

Juvenile stress induces behavioral change and affects perineuronal net formation in juvenile mice Reviewed International journal

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Matsumoto Y, Okamoto M, Aoki S, Ishihara T

BMC Neuroscience 19 ( 41 ) 41 - 41 2018

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

BACKGROUND: Many neuropsychiatric disorders develop in early life. Although the mechanisms involved have not been elucidated, it is possible that functional abnormalities of parvalbumin-positive interneurons (PV neurons) are present. Several previous studies have shown that juvenile stress is implicated in the development of neuropsychiatric disorders. We aimed to clarify the effects of juvenile stress on behavior and on the central nervous system. We investigated behavioral abnormalities of chronically-stressed mice during juvenilehood and the effect of juvenile stress on PV neurons and WFA-positive perineuronal nets (PNNs), which are associated with vulnerability and plasticity in the mouse brain. RESULTS: Due to juvenile stress, mice showed neurodevelopmental disorder-like behavior. Juvenile stressed mice did not show depressive-like behaviors, but on the contrary, they showed increased activity and decreased anxiety-like behavior. In the central nervous system of juvenile stressed mice, the fluorescence intensity of WFA-positive PNNs decreased, which may signify increased vulnerability. CONCLUSION: This study suggested that juvenile stressed mice showed behavioral abnormalities, resembling those seen in neuropsychiatric disorders, and increased brain vulnerability.

DOI： 10.1186/s12868-018-0442-z

Empathic Behaviour According to the State of Others in Mice Reviewed

Ueno H, Suemitsu S, Murakami S, Kitamura N, Wani K, Okamoto M, Matsumoto Y, Aoki S, Ishihara T

Brain and Behavior 8 ( e00986 ) e00986 - e00986 2018

Vaginoplasty in gender identity disorder male-to-female transsexuals

Yuzaburv Namba, Yoshihiro Kimala, Yosuke Matsumoto, Morito Sugimoto, Mikiya Nakatsuka

Japanese Journal of Plastic Surgery 57 ( 8 ) 867 - 873 2014

非けいれん性てんかん発作重積を呈した1例

千田真友子, 松本洋輔, 水木寛, 高木学, 岡部伸幸, 内富庸介

精神神経学雑誌 115 ( 6 ) 681 - 682 2013.6

Factors predicting psychiatric co-morbidity in gender-dysphoric adults. Reviewed

Terada S, Matsumoto Y, Sato T, Okabe N, Kishimoto Y, Uchitomi Y

Psychiatry Res 200 ( 2-3 ) 469 - 474 2012.12

A Case of Adult-onset Adrenoleukodystrophy with Frontal Lobe Dysfunction：A Novel Point Mutation in the ABCD1 Gene Reviewed

Inoue S, Terada S, Matsumoto T, Ujike H, Uchitomi Y

Intern Medicine 51 ( 11 ) 1403 - 1406 2012.1

岡山大学病院ジェンダークリニックにおける性同一性障害治療の現状と一般精神科臨床と同障害の関わりについて

松本洋輔, 岡部伸幸, 佐藤俊樹, 山本文子, 太田順一郎, 中島豊爾, 横山茂生, 大西勝, 井戸由美子, 黒田重利

精神神経学雑誌 111 ( 6 ) 711 - 711 2009.6

岡山大学病院における性同一性障害を対象としたジェンダークリニックの現状報告と今後の課題について

佐藤俊樹, 松本洋輔, 岡部伸幸, 山本文子, 横山茂生, 太田順一郎, 中島豊爾, 大西勝, 大谷恭平, 黒田重利

精神神経学雑誌 ( 2009特別 ) S - 441 2009.5

岡山大学病院ジェンダークリニックの精神科医療分野における性同一性障害診療臨床場面で問題となる症例と一般精神科臨床との関連についての考察

松本洋輔, 佐藤俊樹, 岡部伸幸, 山本文子, 横山茂生, 太田順一郎, 中島豊爾, 大西勝, 大谷恭平, 黒田重利

精神神経学雑誌 ( 2009特別 ) S - 441 2009.5

Primary and secondary kindling in the cat perirhinal cortex Reviewed

A. Orita, T. Moriwake, N. Yamada, K. Ootsuki, T. Norikiyo, K. Miyanagi, Y. Matsumoto, K. Morimoro, S. Kuroda

Epilepsia 37 ( 3 ) 112 1996

Excitatory Changes of Rat Perirhinal Cortex by Amygdala‐Kindling: A Study with In Vitro Slice Technique Reviewed

Yosuke Matsumoto, Norihito Yamada, Kiyoshi Morimoto, Yukito Shimizu, Tazuko Namba, Yoshihiro Kitamura, Shigetoshi Kuroda

Psychiatry and Clinical Neurosciences 48 ( 2 ) 293 - 298 1994

Epileptogenesis in Perirhinal Cortex In Vitro Reviewed

Norihito Yamada, Yosuke Matsumoto, Kiyoshi Morimoto, David K. Bilkey

Psychiatry and Clinical Neurosciences 47 ( 2 ) 320 - 321 1993

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