Details of the Researcher

PHOTO

Mai Sakai
Section
Graduate School of Medicine
Job title
Assistant Professor
Degree

  • Doctor of Medical Science (Tohoku University)

e-Rad No.
20910425

Research History 1

  • 2021/04 - Present
    Graduate School of Medicine, Tohoku University

Education 3

  • Graduate School of Medicine, Tohoku University

    2017/04 - 2021/03

  • Tohoku University

    2015/04 - 2017/03

  • Tohoku University

    2011/04 - 2015/03

Awards 1

  1. Presidental Award

    2021/03　Tohoku University

Papers 34

  1. Maternal fasting during early gestation induces epigenetic alterations and schizophrenia-related phenotypes. International-journal Peer-reviewed

    Hongbo Wang, Miki Bundo, Yutaka Nakachi, Akinori Kanai, Yui Yamamoto, Hirofumi Miyazaki, Fumiko Toyoshima, Yasuyuki Shima, Mai Sakai, Zhiqian Yu, Hiroaki Tomita, Yutaka Suzuki, Kazuya Iwamoto, Yuji Owada, Motoko Maekawa

    Molecular psychiatry　2026/05/13

    DOI： 10.1038/s41380-026-03629-w 　

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    Schizophrenia is a severe neurodevelopmental disorder whose etiology remains incompletely understood. Epidemiological studies of the Dutch Hunger Winter demonstrated that maternal famine during early gestation increased the risk of schizophrenia in offspring, implicating the Developmental Origins of Health and Disease (DOHaD) framework. However, the molecular mechanisms underlying this association remain unclear. Here, we developed a novel DOHaD-based schizophrenia model by subjecting pregnant mice to transient fasting restricted to the peri-implantation period, a critical window of global epigenomic reprogramming. Male offspring of fasted dams exhibited schizophrenia-related phenotypes, including impaired sensorimotor gating, abnormal behavioral patterns, and reduced dendritic spine density in the medial prefrontal cortex. Multi-omics profiling, integrating bulk RNA sequencing, Visium HD spatial transcriptomics, and DNA methylation arrays, revealed convergent alterations in synaptic organization, protein homeostasis, and oxidative stress pathways. These findings highlight how brief maternal fasting reprograms the epigenome and reshapes neural circuitry. Our work establishes the first animal model that directly mirrors early gestational famine exposure linked to schizophrenia risk, providing a unique platform for uncovering epigenetic mechanisms underlying the developmental origins of psychiatric disorders.

  2. Maternal granulocyte colony-stimulating factor alters synaptic maturation and social behaviors in offspring. International-journal Peer-reviewed

    Hinako Kirikae, Karina Kimura, Jinghang Fu, Zhengkang Sun, Hongbo Wang, Haruka Shibuya, Yoshiyuki Kasahara, Hirofumi Miyazaki, Yui Yamamoto, Mai Sakai, Zhiqian Yu, Shohei Ochi, Fumito Naganuma, Takeo Yoshikawa, Takashi Namba, Noriko Osumi, Hiroaki Tomita, Yuji Owada, Motoko Maekawa

    Brain, behavior, and immunity　106534-106534　2026/03/11

    DOI： 10.1016/j.bbi.2026.106534 　

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    Neurodevelopmental disorders, including autism spectrum disorder (ASD), arise from complex interactions between genetic and environmental factors. Maternal immune activation (MIA) is a key environmental risk factor that disrupts embryonic neurodevelopment, primarily through inflammatory cytokines. However, the contribution of non-inflammatory cytokines, particularly hematopoietic growth factors, remains poorly understood. Here, we identified granulocyte colony-stimulating factor (G-CSF) as a candidate mediator of MIA-induced neurodevelopmental alterations. Polyinosinic:polycytidylic acid [poly(I:C)] administration to pregnant dams at embryonic day 12.5 (E12.5) significantly increased G-CSF levels in both maternal plasma and embryonic tissue. To assess its contribution to neurodevelopmental alterations, we administered human G-CSF (hG-CSF) to pregnant dams at E12.5. At the structural level, male offspring exposed to prenatal hG-CSF showed increased dendritic spine density and a higher proportion of immature spines in the medial prefrontal cortex. Behaviorally, both male and female offspring exhibited altered social preference. Bulk RNA-seq analysis of the prefrontal cortex revealed altered enrichment of pathways related to synapse organization, translation, and mitochondrial function in both sexes, with opposite directions of enrichment in males and females. In vitro, G-CSF attenuated synapse maturation and enhanced microglial phagocytic activity. These findings suggest that G-CSF may contribute to MIA-associated neurodevelopmental alterations, potentially through disrupted synapse maturation and microglial function. Our results highlight a hematopoietic pathway that may contribute to mechanisms underlying neurodevelopmental disorders, including ASD.

  3. Sex differences in the risk of autistic-related traits in toddlers born to mothers with perinatal depression: Evidence from human cohort and mouse study Peer-reviewed

    Changrong Duan, Zhiqian Yu, Xue Li, Mai Sakai, Yuko Maejima, Kenju Shimomura, Tomoyuki Furuyashiki, Saya Kikuchi, Natsuko Kobayashi, Kazuto Sasaki, Tasuku Matsuki, Hiroshi Komatsu, Mizuki Hino, Yasuto Kunii, Tomoko Kasahara, Mami Ishikuro, Keiko Murakami, Masatsugu Orui, Takaaki Abe, Fuji Nagami, Nobuo Fuse, Soichi Ogishima, Kengo Kinoshita, Masayuki Yamamoto, Naoki Nakaya, Atsushi Hozawa, Taku Obara, Shinichi Kuriyama, Hiroaki Tomita

    Molecular Psychiatry　2026/02/04

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41380-026-03456-z 　

    ISSN： 1359-4184

    eISSN： 1476-5578

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    Abstract Maternal perinatal depression (MPD) is associated with reduced maternal plasma oxytocin (OXT) levels and an increased risk of autism spectrum disorder (ASD) in offspring. Using data from 23,218 Japanese mother–child pairs, we evaluated the relationship between MPD—assessed with the Kessler Psychological Distress Scale (K6) and the Edinburgh Postnatal Depression Scale (EPDS)—and autistic-related traits (ART) in toddlers, measured by the Tokyo Autistic Behavior Scale (TABS). We also tested the potential causal relationship of maternal stress exposure on OXT, its receptor (OXTR), and offspring outcomes using a prenatal stress-exposed mouse model. In the human cohort study, higher K6 or EPDS scores during pregnancy and postpartum were significantly associated with increased TABS scores in toddlers. Offspring of mothers with MPD (K6 or EPDS score ≥ 9) during pregnancy or postpartum exhibited a higher risk of ART (TABS score ≥ 15; P  < 0.05). This risk was particularly pronounced in female toddlers exposed to MPD during pregnancy and postpartum (ORs: 5.805–9.367; P  < 0.05). Female toddlers born to mothers with MPD also had lower birth weight, and their ART were positively correlated with K6 scores during mid-gestation and with impaired maternal bonding postpartum. In the mouse model, chronically stressed dams displayed depressive-like behaviors, and their female juveniles exhibited increased self-grooming and impaired social interaction. Furthermore, OXTR mRNA levels were significantly reduced in the prefrontal cortex of female juveniles from stressed dams. These findings suggest that MPD increases the risk of ART, particularly in females, highlighting potential sex-specific mechanisms underlying ASD susceptibility.

  4. Orthorexia nervosa and psychological distress among nursing, medical, and non-health-related students Peer-reviewed

    Aoi Nikaido, Miharu Nakanishi, Mai Sakai, Hatsumi Yoshii

    Academia Mental Health and Well-Being　2　(4)　2025/12/25

    Publisher: Academia.edu Journals

    DOI： 10.20935/mhealthwellb8081 　

    eISSN： 2997-9196

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    <p lang="en">Orthorexia nervosa, characterized by obsessive healthy eating habits, has been reported in nursing students, implying that extensive health-related knowledge is a risk factor. This study aimed to investigate the difference in level of orthorexia nervosa and its association with psychological distress between students of nursing, medical, and non-health-related departments. This cross-sectional study included Japanese national university students, aged 18–25 years, who responded to an online questionnaire survey conducted in April 2024. Orthorexia nervosa traits were assessed using the Teruel Orthorexia Scale, autistic traits were assessed using the Autism Spectrum Quotient, and psychological distress was assessed using the Kessler 6-item Scale. We performed multiple linear regression analyses. The 211 participants included 54 (25.6%) nursing students, 52 (24.6%) medical students, and 105 (49.8%) students from other departments. After controlling for gender and autistic traits, nursing students did not differ in traits of orthorexia nervosa from either medical students or other students. The between-group difference was also non-significant in level of psychological distress. Students with orthorexia nervosa were more likely to present greater psychological distress; however, the level of strength of association did not vary according to type of department. Extensive health-related knowledge may not always trigger or escalate obsessive healthy eating among university students. Further investigation is warranted to identify risk factors for orthorexia nervosa among nursing students.</p>

  5. Effects of pharmacological inhibition of FABP4 during gestation and lactation on offspring neurodevelopment and behavior. International-journal Peer-reviewed

    Sun Zhengkang, Hinako Kirikae, He Xiaofeng, Fumiko Yoshimachi, Minori Ikuta, Tetsuo Ohnishi, Yui Yamamoto, Hirofumi Miyazaki, Yoshiyuki Kasahara, Mai Sakai, Zhiqian Yu, Noriko Osumi, Hiroaki Tomita, Yuji Owada, Motoko Maekawa

    Neuroscience letters　853　138199-138199　2025/03/28

    DOI： 10.1016/j.neulet.2025.138199 　

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    Fatty acid-binding protein 4 (FABP4), a key regulator of lipid metabolism and inflammation, has been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). This study investigated the effects of FABP4 inhibition during gestation and lactation on offspring neurodevelopment using the selective FABP4 inhibitor BMS309403. Female mice received BMS309403 (15 mg/kg) via oral gavage from two weeks before mating to postnatal day 28 (P28). Administration of BMS309403 to mouse dams resulted in autism-like phenotypes in male offspring (behavioral tests: n = 7-10 per group; spine analysis: 6 mice per group, n = 26-38 dendrites per group), characterized by increased dendritic spine density in the prefrontal cortex, impaired vocal communication, increased repetitive behaviors, and depression-like symptoms. Fatty acid analysis (n = 4-6 per group) revealed significant alterations in maternal and fetal lipid profiles, including elevated arachidonic acid levels in maternal plasma and increased n6PUFAs in the fetal brain, suggesting a pro-inflammatory lipid environment. Principal component analysis demonstrated distinct clustering of lipid profiles between control and BMS309403-treated groups. Cytokine analysis (n = 6 per group) indicated reductions in IL-10 and IL-12(p40) in maternal plasma and decreased TNFα in the fetal plasma, suggesting dysregulation in systemic inflammatory signaling. These findings suggest that FABP4 inhibition during the perinatal period perturbs lipid metabolism and may influence neurodevelopment through systemic metabolic changes. Although the direct effects of BMS309403 on the fetal brain cannot be excluded, alteration in maternal metabolism and placental function may have contributed to the observed neurodevelopmental changes in offspring.

  6. Experimenters' sex modulates anxiety-like behavior, contextual fear, and microglial oxytocin transcription in mice Peer-reviewed

    Mai Sakai, Zhiqian Yu, Rosanne Picotin, Tomoko Kasahara, Yoshie Kikuchi, Chiaki Ono, Mizuki Hino, Yasuto Kunii, Yuko Maejima, Kenju Shimomura, Miharu Nakanishi, Takaaki Abe, Hatsumi Yoshii, Hiroaki Tomita

    Behavioural Brain Research　115480-115480　2025/02

    Publisher: Elsevier BV

    DOI： 10.1016/j.bbr.2025.115480 　

    ISSN： 0166-4328

  7. Longitudinal associations between informal caring, social network, and psychological distress among adolescents and young adults: modelling within-person effects. International-journal Peer-reviewed

    Miharu Nakanishi, Satoshi Yamaguchi, Mai Sakai, Hatsumi Yoshii, Syudo Yamasaki, Atsushi Nishida, Takahiro Tabuchi

    BMC public health　25　(1)　260-260　2025/01/22

    DOI： 10.1186/s12889-025-21514-z 　

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    BACKGROUND: Informal caring is associated with mental health deterioration among young people and impacts their help-seeking ability. Social network can provide social support and mitigate the impact of informal care. However, young carers may avoid identification and withdraw from social networks. Evidence regarding the reciprocal associations between caring, social network, and mental health is scarce. We aimed to investigate the directionality and specificity of the associations among the three factors in young people. METHODS: This study used three consecutive assessment data (2021-2023; T0-T2) from the Japan COVID-19 and Society Internet Survey. We included 5539 young persons aged ≤ 25 years and 25,445 adults aged 26-59 years. Social network was measured using the Lubben Social Network Scale. Psychological distress was evaluated using the Kessler Psychological Distress Scale. Caring status was retrospectively reported at T2. We employed a random intercept cross-lagged model to detect within-person prospective associations between informal caring, social network, and psychological distress. RESULTS: Young persons showed significant directional relationships from increased social network and psychological distress at T0 to increased likelihood of caring at T1 (standardised coefficient: 0.131 and 0.176, respectively; 95% confidence interval, 0.015-0.247 and 0.071-0.282, respectively). Adults aged 26-59 years showed a reverse relationship from caring to increased psychological distress both from T0 to T1 (0.061, 0.009-0.112) and from T1 to T2 (0.042, 0.000-0.084). CONCLUSIONS: Increased psychological distress and social network preceded the onset of informal caring among young persons. Incorporating psychological distress assessment may benefit the early identification of and support for young carers. The long-term interplay between social networking and informal caring needs further clarification.

  8. Association between previous work experience in general healthcare and recovery orientation among mental health professionals during the COVID-19 pandemic in Japan Peer-reviewed

    Miharu Nakanishi, Tomohiro Takahashi, Keita Toshi, Mai Sakai, Hatsumi Yoshii

    Discover Global Society　2025/01/13

    DOI： 10.1007/s44282-024-00133-w 　

  9. Association between self-stigma and self-compassion in patients with schizophrenia: A longitudinal study from hospital admission to first follow-up after discharge. Peer-reviewed

    Keita Toshi, Miharu Nakanishi, Mai Sakai, Hatsumi Yoshii

    Japan journal of nursing science : JJNS　22　(1)　e12648　2025/01

    DOI： 10.1111/jjns.12648 　

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    AIM: Self-stigma is a major factor preventing the recovery of individuals with schizophrenia. Psychosocial interventions can reduce self-stigma, and mental health nurses may play a crucial role in leading them, but little is known about the modifiable factors that should be targeted. We aimed to investigate the association between self-stigma and self-compassion in patients with schizophrenia from admission to the first follow-up after discharge. METHODS: Twenty-three patients with schizophrenia were recruited from an acute psychiatric ward in a private psychiatric hospital in Japan. Participants filled out the Japanese versions of the Internalized Stigma of Mental Illness (ISMI) scale, the Self-Compassion Scale (SCS), and the Positive and Negative Syndrome Scale (PANSS) at the following three time points: 1 month after admission, discharge, and first follow-up after discharge at outpatient care. We used a linear mixed model to examine the association between self-stigma, self-compassion, and the symptoms. In the first model, we used self-stigma as a dependent variable and included time of assessment and positive and negative symptoms as independent variables. In the second model, we added self-compassion to the independent variables. RESULTS: Self-stigma did not change over time. Regarding the linear mixed model, the first model showed that participants with more positive symptoms tended to report worse self-stigma (p = .052). The second model showed a significant association between increasing self-stigma and higher over-identification (p = .001). CONCLUSIONS: Our results suggest that interventions focusing on over-identification can reduce self-stigma. Nurse-led intervention programs with a focus on over-identification should be further developed for effectiveness.

  10. Glial Markers of Suicidal Behavior in the Human Brain-A Systematic Review of Postmortem Studies. International-journal Peer-reviewed

    Mana Yamamoto, Mai Sakai, Zhiqian Yu, Miharu Nakanishi, Hatsumi Yoshii

    International journal of molecular sciences　25　(11)　2024/05/25

    DOI： 10.3390/ijms25115750 　

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    Suicide is a major public health priority, and its molecular mechanisms appear to be related to glial abnormalities and specific transcriptional changes. This study aimed to identify and synthesize evidence of the relationship between glial dysfunction and suicidal behavior to understand the neurobiology of suicide. As of 26 January 2024, 46 articles that met the inclusion criteria were identified by searching PubMed and ISI Web of Science. Most postmortem studies, including 30 brain regions, have determined no density or number of total Nissl-glial cell changes in suicidal patients with major psychiatric disorders. There were 17 astrocytic, 14 microglial, and 9 oligodendroglial studies using specific markers of each glial cell and further on their specific gene expression. Those studies suggest that astrocytic and oligodendroglial cells lost but activated microglia in suicides with affective disorder, bipolar disorders, major depression disorders, or schizophrenia in comparison with non-suicided patients and non-psychiatric controls. Although the data from previous studies remain complex and cannot fully explain the effects of glial cell dysfunction related to suicidal behaviors, they provide risk directions potentially leading to suicide prevention.

  11. Association Between Dementia, Change in Home-Care Use, and Depressive Symptoms During the COVID-19 Pandemic: A Longitudinal Study Using Data from Three Cohort Studies Peer-reviewed

    Miharu Nakanishi, Syudo Yamasaki, Taeko Nakashima, Yuki Miyamoto, Claudia Cooper, Marcus Richards, Daniel Stanyon, Mai Sakai, Hatsumi Yoshii, Atsushi Nishida

    Journal of Alzheimer's Disease　1-13　2024/04/17

    Publisher: IOS Press

    DOI： 10.3233/jad-240097 　

    ISSN： 1387-2877

    eISSN： 1875-8908

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    Background: The emotional impact of the coronavirus disease 2019 (COVID-19) pandemic on people with dementia has been quantified. However, little is known about the impact of change in home-care use owing to the pandemic. Objective: To determine the longitudinal association between dementia, change in home-care use, and depressive symptoms during the pandemic. Methods: We included data of 43,782 home-dwelling older adults from the English Longitudinal Study of Ageing (ELSA), Study of health, Ageing and Retirement in Europe (SHARE), and National Health and Aging Trends Study (NHATS). This study considered the latest main wave survey prior to the pandemic as the baseline, and the COVID-19 survey as follow-up. In a series of coordinated analyses, multilevel binomial logistic regression model was used to examine the association between baseline dementia, change in home-care use at follow-up, and presence of depressive symptoms. Results: Dementia, using the ELSA, SHARE, and NHATS datasets, was identified in 2.9%, 2.3%, and 6.5% of older adults, and home-care use reduced in 1.7%, 2.8%, and 1.1% of individuals with dementia, respectively. Dementia was significantly associated with the increased risk of depressive symptoms in all three cohorts. However, the interaction between dementia and period (follow-up) was non-significant in SHARE and NHATS. Across all three cohorts, home-care use during the pandemic, regardless of change in amount, was significantly associated with increased depressive symptoms, compared to the non-use of home care. Conclusions: These results highlight the need for tailoring dementia care at home to promote independence and provide sustainable emotional support.

  12. Depression and Anxiety in Older Adults with Dementia During the COVID-19 Pandemic Peer-reviewed

    Miharu Nakanishi, Asao Ogawa, Mai Sakai, Hatsumi Yoshii, Mitsuhiro Miyashita, Syudo Yamasaki, Atsushi Nishida

    Journal of Alzheimer's Disease Reports　7　(1)　1-9　2023/04/12

    Publisher: IOS Press

    DOI： 10.3233/adr-230019 　

    eISSN： 2542-4823

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    This study examined the longitudinal association between dementia, activity participation, the coronavirus disease 2019 pandemic period, and 1-year mental health changes. We obtained data from the National Health and Aging Trends Study in the United States. We included 4,548 older adult participants of two or more survey rounds between 2018 and 2021. We identified baseline dementia status, and assessed depressive symptoms and anxiety at baseline and follow-up. Dementia and poor activity participation were independently associated with an increased prevalence of depressive symptoms and anxiety. Dementia care and support should address emotional and social needs under continued public health restrictions.

  13. Association between advance care planning and depressive symptoms among community-dwelling people with dementia: An observational cross-sectional study during the COVID-19 pandemic in Japan Peer-reviewed

    Miharu Nakanishi, Taeko Nakashima, Yuki Miyamoto, Mai Sakai, Hatsumi Yoshii, Syudo Yamasaki, Atsushi Nishida

    Frontiers in Public Health　11　2023/03/30

    Publisher: Frontiers Media SA

    DOI： 10.3389/fpubh.2023.915387 　

    eISSN： 2296-2565

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    Objectives Advance care planning (ACP) is an increasing priority for people with dementia during the COVID-19 pandemic. This study evaluated the association between ACP initiation and depressive symptoms among home-dwelling people living with dementia. Methods An internet-based questionnaire survey was conducted with Japanese family caregivers of home-dwelling persons with dementia in June 2021. Family caregivers evaluated the level of depressive symptoms in persons with dementia using the Neuropsychiatric Inventory (NPI). Caregivers also rated the quality of life of persons with dementia using the EQ-5D-5L. Results A total of 379 family caregivers participated in the survey. Depressive symptoms were reported in 143 persons with dementia (37.7%). A total of 155 persons with dementia (40.9%) had initiated ACP, of which 88 (56.8%) had care professionals involved in ACP conversation. After adjusting for the characteristics of persons with dementia and caregivers, persons with professional involvement showed significantly more severe depressive symptoms compared to those who did not initiate ACP. There was no significant difference in the quality of life of persons with dementia according to ACP initiation. Conclusions Many home-dwelling persons with dementia experienced depressive symptoms during the COVID-19 pandemic, especially in cases where care professionals were involved in ACP conversations. Optimal and proactive ACP approaches need to be developed to prevent depressive symptoms in newly diagnosed persons.

  14. Quality of End-of-Life Care for Older Adults with Dementia during the COVID-19 Pandemic Peer-reviewed

    Miharu Nakanishi, Asao Ogawa, Mai Sakai, Hatsumi Yoshii, Syudo Yamasaki, Atsushi Nishida

    Journal of the American Medical Directors Association　24　(6)　906-910.e2　2023/03

    Publisher: Elsevier BV

    DOI： 10.1016/j.jamda.2023.03.001 　

    ISSN： 1525-8610

  15. N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling Peer-reviewed

    Mai Sakai, Zhiqian Yu, Masayuki Taniguchi, Rosanne Picotin, Nanami Oyama, David Stellwagen, Chiaki Ono, Yoshie Kikuchi, Ko Matsui, Miharu Nakanishi, Hatsumi Yoshii, Tomoyuki Furuyashiki, Takaaki Abe, Hiroaki Tomita

    International Journal of Molecular Sciences　24　(4)　3798-3798　2023/02/14

    Publisher: MDPI AG

    DOI： 10.3390/ijms24043798 　

    eISSN： 1422-0067

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    N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.

  16. Decreased β‐hydroxybutyrate and ketogenic amino acid levels in depressed human adults International-journal Peer-reviewed

    Shiho Sato, Zhiqian Yu, Mai Sakai, Ikuko N. Motoike, Daisuke Saigusa, Ryo Hirayama, Yoshie Kikuchi, Takaaki Abe, Kengo Kinoshita, Seizo Koshiba, Hiroaki Tomita

    European Journal of Neuroscience　57　(6)　1018-1032　2023/02/07

    Publisher: Wiley

    DOI： 10.1111/ejn.15931 　

    ISSN： 0953-816X

    eISSN： 1460-9568

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    β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.

  17. Microarray dataset of gene transcription in mouse microglia and peripheral monocytes in contextual fear conditioning Peer-reviewed

    Zhiqian Yu, Mai Sakai, Hotaka Fukushima, Chiaki Ono, Yoshie Kikuchi, Ryuta Koyama, Ko Matsui, Tomoyuki Furuyashiki, Satoshi Kida, Hiroaki Tomita

    Data in Brief　46　108862-108862　2023/02

    Publisher: Elsevier BV

    DOI： 10.1016/j.dib.2022.108862 　

    ISSN： 2352-3409

  18. Place of death from dementia as an underlying cause during the COVID-19 pandemic in Japan: a cross-sectional study from national death certificates Peer-reviewed

    Miharu Nakanishi, Syudo Yamasaki, Mai Sakai, Hatsumi Yoshii, Asao Ogawa, Atsushi Nishida

    Palliative Care and Social Practice　17　2023/01

    Publisher: SAGE Publications

    DOI： 10.1177/26323524231193039 　

    ISSN： 2632-3524

    eISSN： 2632-3524

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    Background: The coronavirus disease (COVID-19) pandemic has challenged palliative end-of-life care for people with dementia. The site of death can be considered as an end-of-life care quality indicator. Most people with dementia prefer to die at nursing or private homes; however, in Japan, they are often hospitalized in psychiatric hospitals for management of neuropsychiatric symptoms. As palliative end-of-life care for older adults with Alzheimer’s disease and related dementias has been further challenged by the COVID-19 pandemic, little is known about its effects on the place of death in patients with dementia. Objectives: This study aimed to investigate the shifts in place of death from dementia during the COVID-19 pandemic in Japan. Changes throughout the pandemic were compared between deaths from dementia and from senility. Design: Cross-sectional. Methods: Death certificate data of individuals aged 65 years or older who died in Japan between 1 January 2018, and 31 December 2021, were used to extract the cause and place of death. Differences in place of death between the periods were estimated using multinomial logistic analysis with reference to death in private homes. Results: Deaths from dementia mostly occurred in hospitals (59%), while deaths from senility were most frequent in nursing homes (37%). After adjusting for patient characteristics, the likelihood of hospital deaths significantly increased for patients with dementia during the pandemic. Meanwhile, the likelihood of senility deaths decreased in hospitals but increased in nursing homes during the pandemic. Conclusion: The shift to hospital deaths since the onset of the COVID-19 pandemic was uniquely observed in deaths from dementia. This hospital shift likely involved increased transfers from nursing and private homes to psychiatric hospitals. Further investigation is needed to examine the association between the pandemic-related change in long-term care workforce and palliative care practice in people with dementia.

  19. Plasma metabolic disturbances during pregnancy and postpartum in women with depression. International-journal Peer-reviewed

    Zhiqian Yu, Naomi Matsukawa, Daisuke Saigusa, Ikuko N Motoike, Chiaki Ono, Yasunobu Okamura, Tomomi Onuma, Yuta Takahashi, Mai Sakai, Hisaaki Kudo, Taku Obara, Keiko Murakami, Matusyuki Shirota, Saya Kikuchi, Natsuko Kobayashi, Yoshie Kikuchi, Junichi Sugawara, Naoko Minegishi, Soichi Ogishima, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Shinichi Kuriyama, Seizo Koshiba, Hiroaki Tomita

    iScience　25　(12)　105666-105666　2022/12/22

    DOI： 10.1016/j.isci.2022.105666 　

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    Examining plasma metabolic profiling during pregnancy and postpartum could help clinicians understand the risk factors for postpartum depression (PPD) development. This analysis targeted paired plasma metabolites in mid-late gestational and 1 month postpartum periods in women with (n = 209) or without (n = 222) PPD. Gas chromatogram-mass spectrometry was used to analyze plasma metabolites at these two time points. Among the 170 objected plasma metabolites, principal component analysis distinguished pregnancy and postpartum metabolites but failed to discriminate women with and without PPD. Compared to women without PPD, those with PPD exhibited 37 metabolites with disparate changes during pregnancy and the 1-month postpartum period and an enriched citrate cycle. Machine learning and multivariate statistical analysis identified two or three compounds that could be potential biomarkers for PPD prediction during pregnancy. Our findings suggest metabolic disturbances in women with depression and may help to elucidate metabolic processes associated with PPD development.

  20. Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia. International-journal Peer-reviewed

    Zhiqian Yu, Kazuko Ueno, Ryo Funayama, Mai Sakai, Naoki Nariai, Kaname Kojima, Yoshie Kikuchi, Xue Li, Chiaki Ono, Junpei Kanatani, Jiro Ono, Kazuya Iwamoto, Kenji Hashimoto, Kengo Kinoshita, Keiko Nakayama, Masao Nagasaki, Hiroaki Tomita

    Molecular neurobiology　60　(2)　1083-1098　2022/11/22

    DOI： 10.1007/s12035-022-03109-6 　

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    Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.

  21. Suicide rates during the COVID-19 pandemic in Japan from April 2020 to December 2021 International-journal Peer-reviewed

    Miharu Nakanishi, Syudo Yamasaki, Kaori Endo, Shuntaro Ando, Mai Sakai, Hatsumi Yoshii, Atsushi Nishida

    Psychiatry Research　316　114774-114774　2022/10

    Publisher: Elsevier BV

    DOI： 10.1016/j.psychres.2022.114774 　

    ISSN： 0165-1781

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    This study estimated the excess suicidal mortality during the COVID-19 pandemic in Japan. A Poisson regression model was used to assess the association between unemployment rates, expenditure for alcohol, eating out, and suicide, from January 2008 to March 2020. The excess suicidal mortality was assessed by applying the identified model to data from April 2020 to December 2021. The number of estimated excess deaths during COVID-19 was 3397 in men and 2390 in women. COVID-19 may have caused unprecedented psychological distress among people, owing to restricted social gatherings and prolonged uncertainties.

  22. Contextual fear conditioning regulates synapse-related gene transcription in mouse microglia. International-journal Peer-reviewed

    Zhiqian Yu, Mai Sakai, Hotaka Fukushima, Chiaki Ono, Yoshie Kikuchi, Ryuta Koyama, Ko Matsui, Tomoyuki Furuyashiki, Satoshi Kida, Hiroaki Tomita

    Brain research bulletin　189　57-68　2022/08/17

    DOI： 10.1016/j.brainresbull.2022.08.017 　

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    Microglia have been suggested to be involved in the underlying mechanism of conditional fear memory formation by regulating inflammatory cytokines. However, the mechanism linking microglia and neuronal activity related to fear conditioning remains unclear. This study characterized the transcription profile of microglia in a fear memory conditional mouse model. Compared with those in control mice microglia, the most significantly induced genes were synapse-related, whereas immune-related genes were reduced due to fear memory consolidation. Whilst the increased expression of synapse-related genes was reversed after fear memory extinction, that of immunological genes was not, strongly suggesting a connection between microglia, neurons, and a dysregulated immune response following contextual fear conditioning. Furthermore, in the hippocampal microglia, we found that the expression of neurotransmitter release regulators, γ-aminobutyric acid (GABA) receptor GABRB3 and synapsin 1/2, increased under fear memory consolidation and restored (decreased) after extinction. In addition, compared with the transcription profile in peripheral monocytes, few overlapping genes were not enriched in biological processes. Taken together, the identified conditional fear stress-induced changes in mouse microglial transcription profiles suggest that microglia-neuron communication mediates contextual fear conditioning.

  23. The Association Between COVID-19 Information Sources and Stigma Against Health Care Workers Among College Students: Cross-sectional, Observational Study Peer-reviewed

    Miharu Nakanishi, Mai Sakai, Gen Takagi, Keita Toshi, Koubun Wakashima, Hatsumi Yoshii

    JMIR Formative Research　6　(7)　e35806-e35806　2022/07/07

    Publisher: JMIR Publications Inc.

    DOI： 10.2196/35806 　

    eISSN： 2561-326X

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    Background The COVID-19 pandemic has triggered stigmatic attitudes against health care workers. Some forms of social media may play a role in disseminating stigmatizing messages. Objective We aimed to investigate the association between COVID-19 information sources and stigma against health care workers among college students during the pandemic. Methods A cross-sectional, observational study was conducted using a web-based platform in the Tohoku region of Japan. College students aged ≥20 years were asked to complete the questionnaire between August 18 and October 31, 2020. Stigma against health care workers was evaluated using a modified Japanese version of the Social Distance Scale. Participants were also asked to rate their perceived vulnerability to infection using the Japanese version of the Perceived Vulnerability to Disease scale. Results A total of 281 students from 8 colleges completed the web-based survey. There were 139 (49.5%) participants who used Twitter, 187 (66.5%) who used news websites, and 46 (16.4%) who used the websites of public health agencies as COVID-19 information sources. After adjusting for age, sex, department, and Perceived Vulnerability to Disease scores, the level of stigma did not differ between students who used Twitter and those who did not. Students who used the websites of public health agencies showed a significantly less stigmatic attitude than those who did not. Conclusions Fact-checking and directing visitors to credible information sources from public health agencies may have prevented the formation of stigmatic attitudes toward health care workers. An effective strategy to enable easy access to information provided by public agencies should be integrated into widespread web-based platforms.

  24. Depression and anxiety among nursing students during the COVID-19 pandemic in Tohoku region, Japan: A cross-sectional survey Peer-reviewed

    Sakai, M., Nakanishi, M., Yu, Z., Takagi, G., Toshi, K., Wakashima, K., Yoshii, H.

    Japan Journal of Nursing Science　19　(3)　2022/07

    DOI： 10.1111/jjns.12483 　

    ISSN： 1742-7924 1742-7932

  25. Adolescent Carers' Psychological Symptoms and Mental Well-being During the COVID-19 Pandemic: Longitudinal Study Using Data From the UK Millennium Cohort Study Peer-reviewed

    Miharu Nakanishi, Marcus Richards, Daniel Stanyon, Syudo Yamasaki, Kaori Endo, Mai Sakai, Hatsumi Yoshii, Atsushi Nishida

    Journal of Adolescent Health　70　(6)　877-884　2022/06

    DOI： 10.1016/j.jadohealth.2022.01.228 　

    ISSN： 1054-139X

    eISSN： 1879-1972

  26. Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance Peer-reviewed

    Mai Sakai, Zhiqian Yu, Ryo Hirayama, Masa Nakasato, Yoshie Kikuchi, Chiaki Ono, Hiroshi Komatsu, Miharu Nakanishi, Hatsumi Yoshii, David Stellwagen, Tomoyuki Furuyashiki, Masaaki Komatsu, Hiroaki Tomita, Mojgan Rastegar

    Neural Plasticity　2022　1-13　2022/02/16

    Publisher: Hindawi Limited

    DOI： 10.1155/2022/7503553 　

    ISSN： 2090-5904

    eISSN： 1687-5443

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    Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.

  27. Current status of psychosocial intervention on insight into illness in schizophrenia Peer-reviewed

    Mai Sakai, Yukimi Machida, Keita Toshi, Hatsumi Yoshii

    Japanese Journal of General Hospital Psychiatry　34　(1)　23-35　2022

    Publisher:

    ISSN： 0915-5872

  28. A single nucleotide polymorphism (−250 A/C) of the GFAP gene is associated with brain structures and cerebral blood flow Peer-reviewed

    Yuta Takahashi, Hikaru Takeuchi, Mai Sakai, Zhiqian Yu, Yoshie Kikuchi, Fumiaki Ito, Hiroo Matsuoka, Osamu Tanabe, Jun Yasuda, Yasuyuki Taki, Ryuta Kawashima, Hiroaki Tomita

    Psychiatry and Clinical Neurosciences　74　(1)　49-55　2020/01/01

    DOI： 10.1111/pcn.12932 　

    ISSN： 1323-1316

    eISSN： 1440-1819

  29. Polymorphisms in the microglial marker molecule CX3CR1 affect the blood volume of the human brain Peer-reviewed

    Mai Sakai, Hikaru Takeuchi, Zhiqian Yu, Yoshie Kikuchi, Chiaki Ono, Yuta Takahashi, Fumiaki Ito, Hiroo Matsuoka, Osamu Tanabe, Jun Yasuda, Yasuyuki Taki, Ryuta Kawashima, Hiroaki Tomita

    Psychiatry and Clinical Neurosciences　72　(6)　409-422　2018/06

    DOI： 10.1111/pcn.12649 　

    ISSN： 1323-1316

    eISSN： 1440-1819

  30. グリア線維酸性蛋白質遺伝子多型の脳構造への影響の検討 精神疾患感受性メカニズムの理解に向けて

    高橋 雄太, 伊藤 文晃, 竹内 光, 坂井 舞, 兪 志前, 松岡 洋夫, 瀧 靖之, 川島 隆太, 富田 博秋

    精神神経学雑誌　(2017特別号)　S622-S622　2017/06

    Publisher: (公社)日本精神神経学会

    ISSN： 0033-2658

  31. Pulmonary platelet accumulation induced by catecholamines: Its involvement in lipopolysaccharide-induced anaphylaxis-like shock Peer-reviewed

    Zhiqian Yu, Hiroko Saito, Hirotada Otsuka, Yosuke Shikama, Hiromi Funayama, Mai Sakai, Shigeo Murai, Masanori Nakamura, Takashi Yokochi, Haruhiko Takada, Shunji Sugawara, Yasuo Endo

    International Immunopharmacology　43　40-52　2017/02/01

    DOI： 10.1016/j.intimp.2016.11.034 　

    ISSN： 1567-5769

    eISSN： 1878-1705

  32. Microglial production of TNF-alpha is a key element of sustained fear memory Peer-reviewed

    Zhiqian Yu, Hotaka Fukushima, Chiaki Ono, Mai Sakai, Yoshiyuki Kasahara, Yoshie Kikuchi, Nicole Gunawansa, Yuta Takahashi, Hiroo Matsuoka, Satoshi Kida, Hiroaki Tomita

    Brain, Behavior, and Immunity　59　313-321　2017/01/01

    DOI： 10.1016/j.bbi.2016.08.011 　

    ISSN： 0889-1591

    eISSN： 1090-2139

  33. Linking Activation of Microglia and Peripheral Monocytic Cells to the Pathophysiology of Psychiatric Disorders Peer-reviewed

    Yuta Takahashi, Zhiqian Yu, Mai Sakai, Hiroaki Tomita

    Frontiers in Cellular Neuroscience　10　(JUN)　2016/06/03

    DOI： 10.3389/fncel.2016.00144 　

    ISSN： 1662-5102

  34. Microglial Gene Expression Alterations in the Brains of Patients with Psychiatric Disorders Peer-reviewed

    Mai Sakai, Yuta Takahashi, Zhiqian Yu, Hiroaki Tomita

    Advances in Neuroimmune Biology　6　(2)　83-93　2016

    DOI： 10.3233/NIB-160110 　

    ISSN： 1878-948X

    eISSN： 1878-9498

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Misc. 10

  1. 血漿メタボローム解析によるうつ様症状の病態解明

    兪志前, 兪志前, 小野千晶, 菊地淑恵, 坂井舞, 富田博秋, 富田博秋, 富田博秋

    日本生物学的精神医学会(Web)　46th　2024

  2. 自殺行動に関わるグリア細胞の機能異常-死後脳研究に基づくシステマティックレビュー-

    山本真菜, 坂井舞, 兪志前, 中西三春, 吉井初美

    日本自殺予防学会総会プログラム・抄録集　48th　2024

  3. 腫瘍壊死因子(TNF)-αを介したN-アセチルシステインのミクログリアに対する毒性

    兪志前, 坂井舞, 谷口将之, 菊地淑恵, 松井広, 古屋敷智之, 富田博秋, 富田博秋

    日本神経精神薬理学会プログラム・抄録集　53rd　2023

  4. 反復挫折ストレスに誘導されたうつ様行動におけるオートファジーの分子機構の解明

    坂井舞, 兪志前, 小野千晶, 菊地淑恵, 富田博秋

    日本神経化学会大会抄録集(Web)　65th　2022

  5. 恐怖記憶の形成および消去に伴うミクログリアにおける遺伝子発現変化

    兪志前, 坂井舞, 小野千晶, 富田博秋

    日本神経化学会大会抄録集(Web)　65th　2022

  6. 反復社会挫折ストレスにおける前頭前野の遺伝子発現

    兪志前, 坂井舞, 小野千晶, 富田博秋, 富田博秋

    日本生物学的精神医学会(Web)　41st　2019

  7. うつ病モデルマウスの前頭前皮質におけるミクログリアの炎症関連遺伝子発現変化

    坂井舞, 兪志前, 兪志前, 富田博秋, 富田博秋

    日本生物学的精神医学会(Web)　41st　2019

  8. 健常成人1212人におけるGFAP多型と脳機能画像との相関の検討

    高橋雄太, 高橋雄太, 坂井舞, 兪志前, 富田博秋

    日本生物学的精神医学会(Web)　38th　2016

  9. 恐怖記憶の持続におけるミクログリア由来TNF-αの発現

    兪志前, 兪志前, 福島穂高, 小野千晶, 坂井舞, 笠原好之, 高橋雄太, 松岡洋夫, 喜田聡, 富田博秋, 富田博秋

    日本生物学的精神医学会(Web)　38th　2016

  10. 精神疾患のリスク遺伝子CX3CR1多型と脳画像との相関解析

    坂井舞, 坂井舞, 竹内光, 菊地淑恵, 兪志前, 兪志前, 兪志前, 小野千晶, 瀧靖之, 瀧靖之, 川島隆太, 富田博秋, 富田博秋, 富田博秋

    日本生物学的精神医学会(Web)　38th　2016

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Research Projects 2

  1. うつ病の発症機序における血液脳関門とミクログリアの相互作用の分子基盤の解明

    坂井 舞

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究

    2025/04 - 2028/03

  2. クエン酸回路に着目した産後うつの病態解明研究

    坂井 舞

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 若手研究

    Institution: 東北大学

    2022/04/01 - 2025/03/31