| Late-Breaking Abstracts |
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| 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-001
低悪性度脳腫瘍に起因するてんかん脳内の細胞内情報伝達機構の解析
Analysis of intracellular signaling mechanisms in the epileptic brain caused by low-grade epilepsy-associated tumors
*陶山 京香(1)、宮下 聡(2)、飯島 圭哉(3)、橋詰 晃一(1)、田部 直央(1)、岩崎 真樹(3)、田谷 真一郎(1)、星野 幹雄(1)
1. 国立精神・神経医療研究センター・神経研究所・病態生化学、2. 新潟大学・脳研究所・システム脳病態学分野、3. 国立精神・神経医療研究センター・病院・脳神経外科
*Kyoka Suyama(1), Satoshi Miyashita(2), Keiya Iijima(3), Koichi Hashizume(1), Nao Tabe(1), Masaki Iwasaki(3), Shinichiro Taya(1), Mikio Hoshino(1)
1. Department of Biochemistry and Cellular biology, National Institute of Neuroscience, NCNP, 2. Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, 3. Department of Neurosurgery, National Center Hospital, NCNP
Keyword: Epilepsy, Low-grade epilepsy-associated tumor, RNA-sequencing
Epilepsy affects approximately 1% of the world's population, and genetic and environmental factors are thought to play a role in its development. Despite the large number of people with epilepsy, proper disease classification, diagnosis, and treatment are not yet well established. Antiepileptic drugs are used to control seizures, but more than 30% of patients have drug-resistant epilepsy. Some patients with drug-resistant epilepsy may undergo surgery to remove the epileptic focus. Low-grade epilepsy-associated tumor (LEAT) is known to cause epileptic seizures in humans. In patients with this disease, surgery can control the seizures, but a certain percentage of epilepsy flares up. The mechanism by which tumors cause epileptic seizures is still poorly understood, and the NCNP biobank has a large collection of surgically resected specimens of epilepsy, including LEAT (N=40). In this study, we attempted to use surgically resected LEAT specimens to investigate changes in intracellular signaling pathways in LEAT and to elucidate the molecular mechanisms by which LEAT causes epilepsy. In the experiment, non-tumor sites, also surgically dissected, were used as control. LEAT has been reported to be genetically classified into three subgroups: BRAFV600E mutants, FGFR mutants, and others. In order to determine the changes in gene expression in each LEAT subgroup, RNA-sequencing (RNA-seq) was performed from five non-tumor regions and 40 tumor regions derived from LEAT patients. First, gene expression was compared between samples from non-tumor (control) and tumor regions. As a result, we identified two gene subsets whose expression was specifically increased in LEAT. Gene Ontology analysis based on RNA-seq data from controls and LEAT samples suggested that the most significantly different molecular cascade in LEAT is the MAPK cascade. Differentially expressed gene analysis was then performed among the different LEAT subgroup samples (21 BRAFV600E mutants, 7 FGFRs mutants, and 12 others). The RNA-seq results are currently being validated by immunoblotting and immunostaining, and will help to elucidate the molecular mechanisms of LEAT-induced epileptogenesis in the future. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-002
抗てんかん薬の前臨床試験に用いる実用的な難治てんかん動物モデル
A practical intractable epilepsy model for preclinical evaluation of antiepileptic medications
*浅井 真人(1,2)、飯田 真智子(1)、田中 基樹(1)、浅井 直也(2)、髙橋 雅英(2)
1. 愛知県医療療育総合センター 発達障害研究所障害モデル研究部、2. 名古屋大学大学院医学系研究科腫瘍病理学
*Masato Asai(1,2), Machiko Iida(1), Motoki Tanaka(1), Naoya Asai(2), Masahide Takahashi(2)
1. Aichi Developmental Disability Center, Institute For Developmental Research , 2. Nagoya Univ Grad Sch Med, Nagoya, Japan
Keyword: Epilepsy, Animal model, preclinical study, Girdin/ccdc88a
Girdin/ccdc88a is an actin-binding protein, where loss-of-function causes developmental epileptic encephalopathy (DEE) and severe central hypotonia in humans in a genetically recessive manner (Nahorski 2016). Global Girdin knockout mice (gKO) die before weaning. However, implementation of a specific feeding regimen over their lifetime can completely overcome the lethal phenotype, whereby gKO body weights catch up to those of wild-type (wt) littermates (female n=16, p=0.93; male n=24, p=0.63, age 2-5 months). All gKOs develop generalized tonic-clonic seizures (GTCSs) at P21-30 (n=29). Overt gKO behavior before GTCS onset is characterized as jumpy and restless. In comparison, following GTCS onset, gKOs gradually develop a generalized muscle weakness, with characteristic postures at rest and when walking. Mean grip strength in gKOs is 31.7% lower than wt (mean±SD: wt, 238.6±33.2; gKO, 162.9±24.1 gram-weight, t-test p=2.29×10^-7, wt, n=16; gKO, n=13, age 422-462 days old), while mean distance traveled is 48.6% lower than wt (gKO, 393.3±138.5; wt, 202.2±138.5 m/day, t-test p=0.029, n=11 each, age 62-501 days). Despite severe disability, gKOs demonstrate sufficient viability. Two-thirds of gKOs survive over a year and withstand various challenges such as long-distance automobile transport, EEG electrode-placement surgery, and months of EEG recordings. The video-verified GTCSs of gKOs correspond almost perfectly to the fast wave rhythm on EEG (n=78). Regardless of light or dark phase, all gKOs continuously show interictal slow spikes and waves. Automated measurements show that the mean spike frequency of gKOs is 331 spikes/h (n=4, 16.3 spikes/h for wt), which is reduced in a dose-dependent manner following antiepileptic drug administration (Tukey p<0.0001 at 1 mg/kg p.o. perampanel, p=0.0059 at 100 mg/kg p.o. levetiracetam). In addition, video observations indicate a 44.9% reduction in GTCS frequency in carbamazepine-treated mice (non-treated, 98+3.5; carbamazepine mixed fed, 54+10.6 GTCSs/2 weeks) (t-test p=0.002, n=3). As reported separately, gKO mice represent a model of intractable epilepsy that encompasses multiple epilepsy syndromes including DEE, Lennox-Gastaut, and mesial-temporal lobe epilepsy with hippocampal sclerosis. Given the abundant GTCSs and interictal spikes, both of which can respond to clinically validated antiepileptic drugs, gKO mice are a practical intractable epilepsy model for preclinical studies of antiepileptic medication efficacy. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-003
Nkx2-1リネージ介在ニューロンにおけるGirdin欠損が難治てんかんを誘発する
A deficiency of Girdin in Nkx2-1-lineage interneurons generates intractable epilepsy
*飯田 真智子(1)、田中 基樹(1)、浅井 直也(2)、髙橋 雅英(2)、浅井 真人(1,2)
1. 愛知県医療療育総合センター 発達障害研究所 障害モデル研究部、2. 名古屋大学大学院医学系研究科 腫瘍病理学
*Machiko Iida(1), Motoki Tanaka(1), Naoya Asai(2), Masahide Takahashi(2), Masato Asai(1,2)
1. Institute For Developmental Research, Aichi Developmental Disability Center, Aichi, Japan, 2. Nagoya Univ Grad Sch of Med, Nagoya, Japan
Keyword: Girdin/ccdc88a, Developmental and epileptic encephalopathies, Mesial temporal lobe epilepsy, Migration defects of interneuron
Girdin/ccdc88a is a substrate of Akt and an actin-binding protein. Girdin global homozygous knockout mice (gKO) exhibit significant developmental defects (e.g. microcephaly and corpus callosum deficiency) and die before weaning with growth retardation. With the new feeding regimen, we overcame complete preweaning lethality and obtained a long-term survival over a year. gKO exhibit early-onset (P21-30) spontaneous generalized tonic-clonic seizures (GTCSs) with 100% genetic penetrance (n=29). Progressive, severe motor dysfunction was observed in gKO from around the epilepsy onset. Video-electroencephalogram (EEG) analyses revealed EEG patterns in adult gKO reminiscent of epileptic encephalopathies, including high-amplitude and continuous diffuse irregular slow spike-and-wave complexes over 24 h. During GTCSs, a low-voltage fast wave with the tonic seizure onset followed by a recruiting rhythm with a clonic seizure are detected. These findings suggest developmental and epileptic encephalopathy (DEE)-like epilepsy. Following the GTCS onset, typical histological characteristics of mesial temporal lobe epilepsy (MTLE) begin to appear in the bilateral hippocampi of gKO, representing classical hippocampal sclerosis (HS), including progressive pyramidal cell loss and astrogliosis. Gliosis eventually extends to the amygdala and cerebral cortex. We performed immunohistochemistry of embryonic brains and found that tangentially migrating Gad65/67-positive INs from the medial ganglionic eminence (MGE) to the cerebral cortex were significantly depleted at embryonic day 14.5 gKO, presumably resulting in severe loss of MGE-derived INs in the adult hippocampus. To examine whether or not the migration defects in MGE-derived INs were sufficient for inducing intractable epilepsy, we generated Nkx2-1-lineage Girdin conditional KO mice (cKO). Nkx2-1 is a key transcription factor expressed in MGE and is required for the specification of two major subgroups of cortical INs: parvalbumin (PV)-INs and somatostatin (SST)-INs. cKO exhibit late-onset (adolescent-adult) spontaneous GTCSs (n=5) with PV-IN depletion and mild astrogliosis in the bilateral hippocampi. These results suggest that depletion of hippocampal INs in Nkx2-1-lineage is sufficient to cause intractable epilepsy. Furthermore, the fact that differential ranges of Girdin knockout led to two different phenotypes—DEE and MTLE with HS, which are usually considered independent—suggests an underlying pathological continuity. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-004
新生児低酸素性虚血性脳症モデルにおけるニューロセルピンの神経保護効果
Neuroprotective effect of neuroserpin in a mouse model of neonatal hypoxic-ischaemic encephalopathy
*河下 映里(1,2)、Fischer Jan(1)、福崎 由美(1,3)、Millar Lancelot(1)、Zhong Peiyun(4)、Hoerder-Suabedissen Anna(1)、Shi Lei(4)、Molnár Zoltán(1)
1. Dept of Physiology, Anatomy and Genetics, Univ of Oxford, Oxford, UK、2. 京都薬科大学 病態生化学分野、3. Dept of Neurology, UCSF, CA、4. JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangdong, China
*Eri Kawashita(1,2), Jan Fischer(1), Yumi Fukuzaki(1,3), Lancelot Millar(1), Peiyun Zhong(4), Anna Hoerder-Suabedissen(1), Lei Shi(4), Zoltán Molnár(1)
1. Dept of Physiology, Anatomy and Genetics, Univ of Oxford, Oxford, UK, 2. Dept of Pathological Biochemistry, Kyoto Pharmaceutical University, Kyoto, Japan, 3. Dept of Neurology, UCSF, CA, 4. JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangdong, China
Keyword: NEONATAL HYPOXIC-ISCHAEMIC ENCEPHALOPATHY, NEUROSERPIN, CORTICAL DEVELOPMENT, HYPOXIA
Background: Neonatal hypoxic-ischaemic encephalopathy (HIE) is one of the most prevalent causes of infant morbidity and mortality, and therapeutic hypothermia is the only clinically approved treatment. Neuroserpin, a physiological inhibitor of tissue plasminogen activator, has been shown to reduce brain damage in an adult mouse stroke model. However, in neonatal HIE the protective effects of endogenous and exogenous neuroserpin on brain damage is still unknown. In this study, we aimed to determine the expression pattern of neuroserpin during neonatal brain development and test the protective effects of neuroserpin on HI-induced brain damage in the Rice-Vannucci model by either performing the experiments on neuroserpin KO mice or by administering exogenous neuroserpin into the brains during HI. Methods: We analysed the expression pattern of neuroserpin in the mouse (P4-P14) cerebral cortex by immunohistostaining. Neuroserpin knockout mice and wild-type (WT) mice were subjected to HI procedures according to a modified Rice-Vannucci HI model at P8, and then the size of ischaemic damage was determined by triphenyltetrazolium chloride staining at P10. To evaluate the effects of the exogenous neuroserpin on brain damage in the neonatal HIE model, we injected 100 ng of recombinant neuroserpin protein into the lateral ventricle of the brain of WT mice just after HI procedures at P8, and the cortical thickness and number of NeuN-positive cells were measured at P12. Moreover, the effect of neuroserpin on oxygen-glucose deprivation/reoxygenation-induced cell death in cortical neuronal culture was examined. Results: In WT mice, the density of neuroserpin-positive cells was high in cortical layers 5 and 6b and peaks at P8-P10 (n=4 at each age). Since neuroserpin alleviated cell death in neuronal culture, (n=3), we expected that neuroserpin knockout mice would show more severe ischaemic damage compared with WT mice, but the degree of brain damage was similar between the knockout mice and WT mice (n=29 and n=14, respectively). However, the reduction in the cortical thickness and number of NeuN-positive cells after HI injury was suppressed in the pups that received neuroserpin injection into the brain (n=3). Conclusions: Endogenous neuroserpin is not sufficient to provide a protective effect against HI-induced brain damage but applying exogeneous neuroserpin at the time of HI could be a promising neuroprotective candidate for pharmacotherapy of neonatal HIE. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-005
脳出血後の運動と薬理的ヒストン脱アセチル酵素阻害による大脳皮質半球間のエピジェネティクス修飾の相違
Different epigenetic modifications between ipsilateral and contralateral motor cortex caused by exercise and pharmacological inhibition of histone deacetylases after intracerebral hemorrhage
*前島 洋(1)、岡村 未里(2)、井上 貴博(2)、高松 泰行(1)
1. 北海道大学大学院保健科学研究院リハビリテーション科学分野、2. 北海道大学大学院保健科学院
*Hiroshi Maejima(1), Misato Okamura(2), Takahiro Inoue(2), Takamatsu Yasuyuki(1)
1. Dept Rehab Sci, Faculty of Health Sci, Hokkaido Univ, Sapporo Japan, 2. Grad Sch Health Sci, Hokkaido Univ, Sapporo, Japan
Keyword: intracerebral hemorrhage, epigenetics, motor cortex, exercise
Exercise beneficially modulates the expression of genes related to neuroplasticity in the brain accompanying epigenetic regulation. In particular, acetylation level of specific lysine residues in histones is one of the potent epigenetic targets and is essential for transcriptional regulation. We have preliminarily reported that inhibition of histone deacetylase (HDAC) could beneficially improve epigenetic condition specifically in the acetylation level of histone H4 in the ipsilateral motor cortex after intracerebral hemorrhage (ICH) in Neuro 2021. However, it was controversial whether the epigenetic modification in histones was specific to ipsilateral cortex or bilateral cortex. Therefore, we here assessed the effect of epigenetic treatment using a histone deacetylase (HDAC) inhibitor and aerobic exercise on the epigenetic markers in the contralateral cortex in addition to ipsilateral cortex after ICH, to find the interhemicerebral difference in epigenetic alternations. Forty-one 7-week-old Wistar male rats were randomly divided into a sham operated group (n=8) and an ICH group (n=33). The rats in the ICH group were divided into two groups: those who did not participate in exercise and those who participated in exercise. Each group was subdivided into two other groups: the one who received vehicle and the one who received HDAC inhibitor, sodium butyrate (NaB). Thus, the ICH rats were distributed among 4 groups: a control group (n = 9), an exercise group (n = 8), a NaB group (n = 8), and a NaB plus exercise group (n=8). ICH was systematically induced by the injection of collagenase in the left striatum near the internal capsule (AP: -2.0 mm, ML: 3.7 mm, DV: -6.0 mm). Intraperitoneal administration of an HDAC inhibitor (300 mg/kg NaB) and treadmill exercise (at 11 m/min for 30 min) were conducted five days a week for four weeks starting from 3 days after ICH. Total brain was excised 24h after the last intervention. Regarding histone H3, ICH had no significant effect on the acetylation level bilaterally, whereas exercise significantly increased the acetylation level bilaterally in the ICH model rats. Meanwhile, regarding histone H4, ICH significantly decreased the acetylation level in the ipsilateral cortex, but not in the contralateral cortex. NaB administration significantly increased the acetylation level of histone H4 and attenuate the effect of ICH only in the ipsilateral cortex, but not in contralateral cortex. In the contralateral cortex, exercise increased the acetylation level of histone H4 as found in the modification of histone H3. Therefore, this study showed that exercise acetylated histones in bilateral cortex, whereas HDAC inhibition could target on histone H4 specifically in the ipsilateral cortex, which could enrich epigenetic condition in the motor cortex for neurorehabilitation after ICH. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-006
放射線照射前の高気圧酸素療法による神経保護効果
Neuroprotective effect of hyperbaric oxygenation treatment before radiotherapy.
*片桐 千秋(1,2)、高木 博(2)、石内 勝吾(2)
1. 北海道大学 遺伝子病制御研究所、2. 琉球大学 大学院医学研究科
*Chiaki Katagiri(1,2), Hiroshi Takagi(2), Shogo Ishiuchi(2)
1. Hokkaido University, 2. Grad Sch Med, Univ of Ryukyus, Okinawa, Japan
Keyword: Radiation injury, Hyperbaric Oxygen Therapy
Radiation therapy is one of the standard therapy for the patients with brain tumors. After surgery, the patient receives up to 60 Gy of radiation. However, radiation is also slightly exposed to brain tissue other than the treatment site. Already well known as that irradiation reduces neurogenesis in the hippocampus, and at the same time damages white matter integrity. In our clinical research, we found that a treatment method combining Hyperbaric Oxygen Therapy (HBO) just before irradiation enhanced radiosensitivity of hypoxic cancer cells. However, it still remains obscure whether HBO operates neuroprotective effect on surrounds brain tissue or not. In this study, the effect of HBO on the reduction of cognitive function due to radiation disorder was evaluated by an animal behavioral analysis and calcium imaging of hippocampus. Eight week BL6/J mice were separated three groups, then radiation therapy for the whole brain was occurred 2Gy per day for 5 days with or without HBO (2.5 atmosphere with 100% oxygen for 40min) just before irradiation. Non-irradiated mice spent the same time in the irradiation machine. In context fear conditioning test, irradiated mice reduced freezing time significantly compared to non-irradiated mice. Unexpectedly, mice treatment with HBO before irradiation showed freezing time similar to non-irradiated mice. These results suggested that HBO treatment would restore memory impairment of irradiated mice up to the level of non-irradiated ones. Results of calcium imaging analysis, irradiation of the whole brain at 10 Gy completely abolished the NMDA response of hippocampal CA1 and DG. An NMDA response in the DG region was observed in mice treated with HBO prior to irradiation. These results suggested that HBO treatment prevents radiation-induced cognitive decline by preserving neural activity in the DG region of the hippocampus. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-007
抗うつ薬および過活動膀胱治療薬の中枢コリン作動系への影響．薬物誘発認知症のメカニズム解明
Effects of antidepressants and overactive bladder drugs on the central cholinergic system: Elucidation of the mechanism of drug-induced dementia
*稲津 正人(1,3)、長倉 知輝(2)、山中 力(3)、内野 博之(2)
1. 東京医科大学 医学総合研究所、2. 東京医科大学 麻酔科学分野、3. 東京医科大学 分子予防医学
*Masato Inazu(1,3), Tomoki Nagakura(2), Tsuyoshi Yamanaka(3), Hiroyuki Uchino(2)
1. Inst Med Sci, Tokyo Med Univ, Japan, 2. Dept Anesthesiology, Tokyo Med Univ, Japan, 3. Dept Mol Prev Med, Tokyo Med Univ, Japan
Keyword: dementia, choline, acetylcholine, transporter
Anticholinergic drugs are mainly associated with decreased cognitive function in non-demented older adults and an increased risk of cognitive impairment and dementia in older adults. The use of antidepressants and overactive bladder drugs with a high anticholinergic cognitive burden (ACB) scale in the elderly increases the risk of drug-induced dementia. Abnormalities of the central cholinergic system and cognitive deficits are deeply related and include alterations or modifications in choline transport, acetylcholine synthesis and release, nicotinic and muscarinic receptor function, and axonal transport. This study investigated the effects of antidepressants and overactive bladder drugs on the central cholinergic system. Choline uptake in mouse brain slices is mediated by both high-affinity choline transporter 1 (CHT1) and choline transporter-like protein 1 (CTL1). However, acetylcholine synthesis and release were linked to choline uptake via CHT1, and CTL1 was not involved. CTL1 was involved in choline uptake in astrocytes but not in neurons. The effects of antidepressants and overactive bladder drugs on choline uptake and acetylcholine synthesis and release in mouse brain slices were examined. Drugs with high ACB scores were found to inhibit choline uptake and acetylcholine synthesis and release. There was a correlation between the inhibitory effects of both drugs on choline uptake and acetylcholine synthesis and release (r=0.594, p=0.0018). These results suggest that antidepressants and overactive bladder drugs may have inhibited acetylcholine synthesis and release by directly inhibiting CHT1 function. Drugs that inhibit choline uptake via CHT1, the rate-limiting step in the central cholinergic system, are associated with a risk of drug-induced dementia. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-008
男性健常高齢者の足関節運動機能と認知機能の関係
The relationship between ankle motor and cognitive function in healthy older adult men
*宮﨑 敦子(1,2)、奥山 卓(1,3)、森 隼人(4)、佐藤 和久(5)、熊本 圭吾(6)、檜山 敦(1,7)
1. 東京大学、2. 理化学研究所、3. 神戸大学、4. 有限会社スーパーリハ、5. 株式会社ケア２１、6. 東京保健医療専門職大学、7. 一橋大学
*Atsuko Miyazaki(1,2), Takashi Okuyama(1,3), Hayato Mori(4), Kazuhisa Sato(5), Keigo Kumamoto(6), Atsushi Hiyaam(1,7)
1. The University of Tokyo, 2. RIKEN, 3. Kobe University, 4. Super Reha, LLC., 5. Care 21 Co., Ltd., 6. Tokyo Professional University of Health Sciences, 7. Hitotsubashi University
Keyword: COGNITIVE FUNCTION, MOTOR FUNCTION, DETECTING COGNITIVE DECLINE, COGNITIVE FRAIL
Gait speed decreases 12 years before mild cognitive impairment (Buracchio et al. 2010) and 7 years before dementia diagnoses (Dumurgier et al. 2017). The gait style of older adults changes from an ankle strategy to a hip strategy with age (Horak et al. 1990). However, the link between ankle joint function and cognitive function is unclear. Plantarflexion assesses muscle strength (Andre et al. 2016), while dorsiflexion causes gait delay (Kemoun et al. 2002). Given the high association between performance speed and cognitive function, we examined the association between ankle motor function, specifically toe lifting, and cognitive function in healthy older men.
Participants were 58 healthy older men 68.55 (SD=5.80) years old without dementia, diabetes, cerebrovascular disease, frailty, or sarcopenia. Participants performed toe and heel raises with their hands on the wall. Respectively, the mean angles were 14.49 (SD=3.77) and 38.26 (SD=4.24) degrees, confirming Spearman's correlations with other measures (one-sided). There was no correlation between cognitive (MMSE, MoCA) and physical function (maximal gait speed 10m, grip strength), which previous studies have shown to be associated with cognitive decline. However, toe lift angle was correlated with cognitive and physical function (grip strength, 5Time Sit-to-Stand Test, one-leg stand). Heel lift angle was correlated with body composition such as lower limb muscle mass and BMI, but not with cognitive or physical function indices.
Permutation multiple regression analyses were conducted to examine the relationship between cognitive function and toe lift angle. Age, education, grip strength, and gait speed were treated as covariates. Significant regression equations were obtained for MMSE (standardized β=0.2225 , t=1.7249, p=0.0205, and FDR q=0.041) and MoCA (standardized β=0.2219, t=2.0726, p=0.0126, and FDR q=0.041).
Results suggest that toe lift angle is related to cognitive function in healthy older adults. It is possible that toe lift angle might be an indicator of earlier cognitive decline prior to physical function performance decline. Leg circumference, a simple measure of physical frailty (Fujii et al. 2019), was not related to cognitive function, so this becomes a comprehensive measure of frailty if evaluated in conjunction with toe lift angle. Alternatively, when assessing the driving ability of older drivers, assessing ankle joint motor function along with cognitive function assessment is suggested. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-009
神経細胞内アミロイドβオリゴマーによる認知機能障害は回転かごによる自発的な運動によって改善する
Cognitive impairment caused by intracellular amyloid β oligomers is ameliorated by voluntary exercise with a running wheel
*落石 知世(1)、角 正美(2)、清末 和之(1)
1. 国立研究開発法人産業技術総合研究所、2. 植草学園大学保険医療学部
*Tomoyo Ochiishi(1), Masami Kaku(2), Kazuyuki Kiyosue(1)
1. National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, JAPAN, 2. Fac of Health and Sci, Uekusa Gakuen Univ, Chiba, Japan
Keyword: Alzheimer's disease, exercise, amyloid β protein oligomer, cognitive function
It is well known that habitual exercise improves cognitive function in the elderly. Since this is no exception for Alzheimer's disease (AD) patients, habitual exercise is attracting attention as a part of prevention against the onset of AD or as a new therapeutic intervention, even though drug treatments for AD have yet to be established. However, the mechanism by which habitual exercise and other activities can improve the efficiency of synaptic transmission is unknown. In AD, memory impairment precedes senile plaque formation and neuronal loss. Recently it suggested that oligomers of intracellular amyloid β (Aβ) are strongly cytotoxic, and play crucial roles in the synaptic transmission and cognitive function in AD. To investigate the effects of the voluntary exercise loading in early stage of AD, we used Aβ-GFP transgenic mouse (Aβ-GFP Tg mouse) that we developed previously. This mouse model express fusion protein of Aβ and GFP that consisting of only low molecular weight of Aβ oligomers inside neurons entire life, and exhibits the attenuated LTP, morphological changes of spines, cognitive disorders, and oxidative stresses at young age (about 3 months of age). Therefore Aβ-GFP Tg mouse is specialized for investigating the toxicity of Aβ oligomer inside neurons in early stage of AD. After 7 weeks of voluntary exercise loading to the Aβ-GFP Tg mouse with a running wheel, a novel object recognition test was performed. Normally, Aβ-GFP mice showed recognition deficits compared to non-transgenic mice in both short (1 hour) and long (24 hours) retention, but these deficits were significantly improved after voluntary exercise loading. In addition, a comprehensive DNA microarray analysis of genes whose expression fluctuated before and after exercise loading revealed changes in synaptic-related proteins. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-010
ストループ課題中の音声スペクトル分布の時間変化は軽度認知障害の影響を反映する
Degree of temporal change in vocal spectral profile during Stroop test is affected by mild cognitive impairment
*中村 光晃(1)、樋口 政和(1)、大宮 康宏(1,2)、篠原 修二(3)、高野 毅(2)、水口 大輔(2)、光吉 俊二(1)、徳野 慎一(1,4)
1. 東京大学大学院工学系研究科、2. PST株式会社研究開発部、3. 東京電機大学理工学部、4. 神奈川県立保健福祉大学ヘルスイノベーション研究科
*Mitsuteru Nakamura(1), Masakazu Higuchi(1), Yasuhiro Omiya(1,2), Shuji Shinohara(3), Takeshi Takano(2), Daisuke Mizuguchi(2), Shunji Mitsuyoshi(1), Shinichi Tokuno(1,4)
1. Grad Sch Eng, Univ of Tokyo, 2. Research and Develop Dept, PST inc, 3. Sch Sci and Eng, Tokyo Denki Univ, 4. Grad Sch Health Innov, Kanagawa Univ of Human Service
Keyword: Mild cognitive impairment, Stroop test, Vocal analysis, Screening
Detection of Mild Cognitive Impairment (MCI) in its earlier stage is important for preventive medicine in cognitive disorders. It is reported that people with cognitive disorders have difficulty in execution of dual tasks. We examined effects by MCI in individuals’ vocal behavior when they conduct Stroop test as an analog to dual tasks without limb motor function, to examine feasibility of casual screening technology for MCI. We recruited 89 native Japanese speakers aged 65 years or older as participants of the study. Their cognitive function was evaluated by Montreal Cognitive Assessment (MoCA) Japanese version. They were asked to read out characters showing colors’ name printed in black as a control task and conduct Stroop test as a test task; each task consisted of 64 stimuli. We recorded and analyzed the participants’ voice during their tasks. We focused on spectral roll-off point of 50% (R), representing distribution of acoustic power in the frequency axis, and examined temporal change in R (VR) at the initial period and the final period of the both tasks. We calculated the mean of absolute values of VR (μ(|VR|)) as a degree of temporal variability of vocal spectrum. Also we compensated individual variability in vocal features by subtraction of μ(|VR|) in the control task from that in the test task. We examined the relation between compensated μ(|VR|) and MoCA score. As the results, we found that there is almost no correlation (correlation coefficient r = -0.01) between the compensated μ(|VR|) and MoCA score at the initial period of the tasks, while there is small correlation (r = -0.23) between them at the final period of the tasks. Also, we confirmed that the duration to complete the test task was larger than that to complete the control task in almost all the participants, showing that the mental load by the test task was larger than that by the control task. The results infer that the participants with deteriorated cognitive function were affected largely by the mental load of dual-task like task than the participants with normal cognitive function, and the change in vocal spectrum by the test task also became larger in the participants with deteriorated cognitive function than in the participants with normal cognitive function. The results demonstrate possibility of casual screening tool for MCI in daily life, implementable on popular devices such as smartphones. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-011
Immune-in-resin CLEMによる神経セロイドリポフスチン症モデルマウス脳組織のグリア細胞の超微形態イメージング
Revealing the ultrastructure of activated microglia and astrocytes in neuronal ceroid lipofuscinosis mouse model brain by immune-in-resin CLEM
*三井 駿(1)、山口 隼司(1,2)、鈴木 ちぐれ(1)、谷田 以誠(1)、内山 安男(1)
1. 順天堂大・医・老研センター、2. 順天堂大・医・形態解析イメージング
*Shun Mitsui(1), Junji Yamaguchi(1,2), Chigure Suzuki(1), Isei Tanida(1), Yasuo Uchiyama(1)
1. Institute for Diseases of Old Age, Juntendo Univ Grade Sch Med, Tokyo, Japan, 2. Laboratory of Morphology and Image Analysis, Juntendo Univ Grade Sch Med, Tokyo, Japan
Keyword: CLEM, Cathepsin D, glial cell, neurodegenerative disease
Cathepsin D (CtsD) deficient mice are characterized by a severe and progressive neurodegenerative phenotype similar to that observed in Neuronal Ceroid Lipofuscinoses (NCLs), a group of pediatric neurodegenerative diseases known as Batten Disease. Central nervous system (CNS)-specific CtsD deficient (CtsDflox/flox;Nestin-Cre) mice show a neurodegenerative disease phenotype with accumulation of ceroid lipofuscin in lysosomes of the brain neurons. Abnormal neurons, activated astrocytes and microglia are increased in the brain of CtsDflox/flox;Nestin-Cre mice. To clarify the complicated ultrastructure of activated glial cells and the relationship between biomolecules and ultrastructures in the brain of CNS-specific CtsD deficient mice, we newly established immune-in-resin correlative light and electron microscopy (immune-in-resin CLEM) of an epon-embedded sample of thin sections based on direct correlation of immunofluorescence microscopy with electron microscopy. Immune-in-resin CLEM of the thalamus of CtsDflox/flox;Nestin-Cre mice using anti-GFAP antibody showed that GFAP-positive astrocytes were detected in the ultrathin sections of the epon-embedded thalamus by a fluorescence microscope. Using the same sections, ultrastructures of increased GFAP-positive filaments were easily observed by a scanning electron microscope. Similarly to the GFAP-positive astrocytes, iba1-positive microglia was detected in the sections by a fluorescent microscope, and granular osmiophilic deposits (GROD) of degenerated neurons were detected in the cytoplasm of iba1-positive microglia in the thalamus of CtsDflox/flox;Nestin-Cre mice by a scanning electron microscope. Furthermore, we identified the ultrastructures of microglia that phagocytosed TUNEL-positive degenerated cells in the thalamus of CtsDflox/flox;Nestin-Cre mice. Therefore, immune-in-resin CLEM make it possible to distinguish microglia, astrocytes, and neurons in epon-embedded ultrathin sections of the thalamus of CtsDflox/flox;Nestin-Cre mice with fluorescence microscopy, and at the same time, to investigate ultrastructures of activated astrocyte and microglia. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-012
アクチン結合蛋白フィラミンAはタウ凝集を促進し、進行性核上性麻痺の病理に関連する
Actin-binding protein filamin-A promotes tau aggregation and contributes to progressive supranuclear palsy pathology
*辻河 高陽(1)、濱中 耕平(2)、陸 雄一(1,3)、服部 祐季(4)、井口 洋平(1)、小林 憲太(5)、池内 健(6)、宮田 卓樹(4)、松本 直通(2)、佐橋 健太郎(1)、勝野 雅央(1)
1. 名古屋大学大学院医学系研究科神経内科学、2. 横浜市立大学大学院医学研究科遺伝学、3. 愛知医科大学加齢医科学研究所、4. 名古屋大学大学院医学系研究科細胞生物学、5. 自然科学研究機構生理学研究所ウイルスベクター開発室、6. 新潟大学脳研究所遺伝子機能解析学
*Koyo Tsujikawa(1), Kohei Hamanaka(2), Yuichi Riku(1,3), Yuki Hattori(4), Yohei Iguchi(1), Kenta Kobayashi(5), Takeshi Ikeuchi(6), Takaki Miyata(4), Naomichi Matsumoto(2), Kentaro Sahashi(1), Masahisa Katsuno(1)
1. Department of Neurology, Nagoya University Graduate School of Medicine, 2. Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3. Department of Neuropathology, Institute for Medical Science of Aging,, 4. Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, 5. Section of Viral Vector Development, National Institute for Physiological Sciences, 6. Department of Molecular Genetics, Brain Research Institute, Niigata University
Keyword: tau, filamin-A, progressive supranuclear palsy, neurodegeneration
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by tau aggregation in neurons and glial cells. While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including PSP, are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate has remained elusive.
Here, we showed that filamin-A is abundant and co-localized with the aggregated tau in the brains with PSP. We also identified gene duplication and rare single nucleotide variants of filamin-A gene in cases with PSP. An association study using the dataset of 312 cases with PSP and 499 normal controls demonstrated that the rare variants of filamin-A gene can contribute to the risk of PSP with the odds ratio of 3.91.
We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. Also, reduction of filamin-A corrected aberrant tau levels in the culture cells from cases with PSP.
To induce overexpression of filamin-A in the adult murine brains, we designed an adeno-associated virus vector expressing the truncated versions of filamin-A that contains essential domains for the interaction with tau (AAV-ΔFLNA). We performed stereotaxic injections of AAV-ΔFLNA into the frontal cortex of 2-month-old wild-type mice, and found increased murine tau. Similarly, we evaluated the effect of AAV-ΔFLNA on human tau protein in transgenic mice that harbor human tau in the absence of murine tau and found the increased protein levels of human tau in the ΔFLNA-transduced neurons. We further generated transgenic mice expressing full-length human filamin-A (FLNA-Tg). The brains of the 5-month-old FLNA-Tg mice showed augmented sarkosyl-insoluble tau and co-localization of filamin-A with tau in the neurons and glial cells, similar to the brains with PSP. Finally, primary cortical neurons from the FLNA-Tg mice showed tau phosphorylation and defective neurite outgrowth, which were rescued by lentiviral short hairpin RNA-mediated knockdown of filamin-A.
Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-013
脊髄小脳変性症患者2例における小脳-運動前野の連合性対刺激による小脳機能改善: Proof of concept study
Cerebellar dysfunction improved by the premotor-cerebellar paired associative stimulation in two cases with spinocerebellar degeneration: Proof of concept study
*小金丸 聡子(1)、島 淳(1)、田中 和樹(1)、小川 明莉(1)、三宅 智彬(1)、美馬 達哉(2)
1. 京都大学大学院医学研究科、2. 立命館大学先端総合学術研究科
*Satoko Koganemaru(1), Atsushi Shima(1), Kazuki Tanaka(1), Akari Ogawa(1), Tomoaki Miyake(1), Tatsuya Mima(2)
1. Grad Sch Med, Kyoto University, Kyoto, Japan, 2. The Graduate School of Core Ethics and Frontier Sciences, Ritsumeikan University, Kyoto, Japan
Keyword: spinocerebellar degeneration, paired associative stimulation, transcranial magnetic stimulation, plasticity
Background: Paired associative stimulation (PAS) can induce LTP-like effects on the target cortical area through spiking-timing dependent plasticity. In patients with spinocerebellar degeneration (SCD), cerebellar dysfunction has been reported such as decreased cerebellar brain inhibition (CBI). Therefore, PAS targeting the cerebellum may improve the cerebellar dysfunction in SCD patients who has few treatment opportunities in the modern medicine. We investigated whether the PAS from the contralateral premotor cortex to the cerebellar cortex (PM-crb PAS) could improve the abnormal CBI in the two SCD patients by comparing unpaired single stimulation or sham stimulation.
Methods: Two SCD patients were recruited (#1. 57 y.o., male, sporadic adult-onset ataxia of unknown etiology, disease duration 1 year; #2. 61 y.o., male, SCA6, disease duration 5 years). PM-crb PAS was performed with two figure-eight TMS coils with paired stimulation from the contralateral premotor cortex to the cerebellum hemisphere with interstimulus interval of 20 milliseconds. Each paired stimulation with a 6-second interval was repeated 120 times on one side and the stimulation side was changed. As controlled sessions, we performed 120 times of unpaired TMS over the cerebellum or the premotor cortex or sham stimulation on the both side of hemisphere. CBIs with ISI of 3, 5 and 10 milliseconds were assessed using paired TMS from the cerebellum to the primary motor cortex (M1) before and after each intervention.
Result: After the PM-crb PAS intervention, the abnormal CBIs were partially improved (#1. Averaged CBI: ltM1 pre 1.35, post 0.79, rtM1 pre 1.35, post 0.85, #2. Averaged CBI: ltM1 pre 1.20, post 0.99, rtM1 pre 1.09, post 0.89), suggesting that cerebellar function was improved. There was almost no change after the unpaired stimulation or sham stimulation.
Conclusion: The PM-crb PAS improved the cerebellar function in two patients with SCD. In future, it would be necessary to study in a larger number of patients to investigate it as a possible treatment for SCD patients. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-014
脳画像統計解析を用いた難聴モデル霊長類の病態評価
Evaluation of pathophysiology in a primate deafness model using statistical analysis of brain MRI
*野武 幸子(1)、畑 純一(1,2)、平林 源希(1)、力武 聖月(2)、黒川 華怜(2)、吉丸 大輔(1)、栗原 渉(1)、岡野 ジェイムス洋尚(1)
1. 東京慈恵会医科大学、2. 東京都立大学
*Sachiko Notake(1), Junichi Hata(1,2), Genki Hirabayashi(1), Mitsuki Rikitake(2), Karen Kurokawa(2), Daisuke Yoshimaru(1), Sho Kurihara(1), Hirotaka James Okano(1)
1. The Jikei University School of Medicine, 2. Tokyo Metropolitan University
Keyword: HEARING LOSS, BRAIN DEGENERATION
Purpose and Background
Most studies have focused on changes in the auditory cortex in human subjects although studies on brain function in people with hearing loss have been conducted for some time. MRI is very useful in visualizing brain degeneration over time because it is less invasive and can capture quantitative and qualitative features. However, in humans, there are several problems: the frequency of MRI imaging for hearing loss is low; it is hard to make comparisons before and after hearing loss because of the difficulty in predicting the time of onset; and the long process of hearing loss may involve confounding factors, such as aging. In contrast, analysis of animal models of hearing loss allows us to estimate the effects of hearing loss on the brain with only minimal bias. In addition, the common marmoset, a small primate, has a similar cranial nerve structure to humans, making it a useful experimental animal for preclinical studies. In this study, we created a model of hearing loss in the common marmoset and used Voxel Based Morphometry (VBM) and Voxel Based Meta-analysis (VBA), statistical analysis, before and after hearing loss. The purpose of this study is to show quantitative and qualitative changes in various brain regions and to understand the relationship between the changes and auditory deprivation.
Material and Methods
MRI data of T1WI, T2WI, and DWI were acquired on a 9.4T-MRI system (Bruker) before, 1 month, 3 months, and 6 months after sound exposure in a marmoset model of hearing loss (n=4). In the VBM analysis, T2WI was used for statistical analysis (before vs. after sound exposure) using the Paired t test from SPM, and the P value threshold was set to 0.001. For VBA analysis, the same statistical analysis as for VBM was performed on four types of images: T1w/T2w Myelin map calculated using Mrtrix3, and RD, AD, and FA images analyzed by tensor analysis using the Diffusion Toolkit.
Results and Conclusions
In both VBM and VBA, significant differences were found in motor- and vision-related areas such as supplementary motor area, primary motor area, visual cortex, cerebellum, caudate nucleus, visual association area, cingulate cortex, and lateral patella. No significant differences were found in auditory-related areas. These results indicate that there is a compensatory response in the visual and balance senses to the auditory deprivation marmoset model, and that motor performance is impaired. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-015
神経変性疾患関連因子の睡眠表現型スクリーニングによる新規睡眠覚醒制御因子の同定
Identifi cation of a novel sleep-regulating factor by in vivo screening ofneurodegenerative disease-related factors
*山浦 港生(1,2)、戸根 大輔(3)、山田 陸裕(2)、三谷 智樹(1,2)、上田 泰己(1,2,3)
1. 大阪大学大学院医学系研究科、2. 理化学研究所生命機能研究センター、3. 東京大学大学院医学系研究科
*Kosei Yamaura(1,2), Daisuke Tone(3), Rikuhiro Yamada(2), Tomoki Mitani(1,2), Hiroki Ueda(1,2,3)
1. Grad Sch Med, Osaka Univ, Osaka, Japan, 2. RIKEN Ctr for Biosystems Dynamics Research, 3. Grad Sch Med, Univ of Tokyo, Tokyo, Japan
Keyword: NEURODEGENERATIVE DISEASE, SLEEP, AAV
Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are known to be accompanied by sleep disorders (Raman, Sleep Med. Clin., 2018). Conversely, in recent years, the sleep disorders have been shown to be a risk factor for the neurodegenerative diseases (Sabia et al., Nat. Commun., 2021). Although these findings suggest a link between neurodegenerative diseases and sleep disorders, the molecular mechanisms involved here are yet to be elucidated. In this study, we addressed the molecular mechanisms that link these two processes by analyzing the contribution of neurodegenerative diseases-related factors to sleep regulation. For this purpose, we analyzed the effects of more than 50 neurodegenerative disease-related factors and their mutants on sleep by combining the adeno-associated viral vector which delivers genes throughout the whole mouse brain (Chan et al., Nat. Neurosci., 2017; Challis, Nat. Protoc., 2019), and the Snappy Sleep Stager (SSS) method which measures sleep in a high-throughput manner from mouse respiratory pattern (Sunagawa et al., Cell Rep., 2015). As a result, we have identified a novel sleep-regulating factor that alters sleep duration in mice significantly. We further found from EEG/EMG analyses that inhibition of the factor leads to a decrease in REM sleep duration and changes in theta power in each vigilance state. The factor might provide insights into the molecular basis linking sleep regulation and pathogenesis of neurodegenerative diseases. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-016
Glymphatic systemの調節によるタウタンパク質蓄積の改善効果
The therapeutic impacts of modulating glymphatic clearance on pathological accumulation of tau protein
*石田 和久(1)、山田 薫(1)、西山 里瑳(1)、五十嵐 博中(3)、阿部 陽一郎(2)、安井 正人(2)、岩坪 威(1)
1. 東京大学大学院医学系研究科、2. 慶應義塾大学医学部、3. 新潟大学脳研究所
*Kazuhisa Ishida(1), Kaoru Yamada(1), Risa Nishiyama(1), Hironaka Igarashi(3), Youichiro Abe(2), Masato Yasui(2), Takeshi Iwatsubo(1)
1. Grad Sch Med, Univ of Tokyo, Tokyo, Japan, 2. Sch Med, Keio University, Tokyo, Japan, 3. Brain Res Inst, Niigata Univ, Niigata, Japan
Keyword: Tau, glymphatic system, aquaporin-4, alzheimer's disease
Tau is a microtubule-associated protein whose accumulation causes neuronal death in a set of neurodegenerative diseases called tauopathies. Although tau aggregation occurs intracellularly, it also spreads between neurons via extracellular space. This led to the idea that facilitating extracellular tau clearance could be therapeutic, however, the mechanism that eliminates extracellular tau from brain remains to be elucidated.
Glymphatic system is a brain-wide system for waste clearance driven by flows of brain interstitial fluid and cerebrospinal fluid (CSF) along perivascular spaces. Glymphatic convective flows are facilitated by a water channel, aquaporin-4 (AQP4), which is highly expressed in perivascular astrocytes. Substances drained to CSF by glymphatic system are then absorbed by dural lymphatic vessels and transported to deep cervical lymph nodes (dcLNs) by lymphatic system. In this study, we hypothesized that extracellular tau is cleared by glymphatic/lymphatic system and investigated how it is involved in the accumulation of intracellular tau.
To examine whether tau is cleared by glymphatic/lymphatic system, we first injected human tau into the striatum or CSF of wild type (WT) or AQP4 knock out (AQP4KO) and analyzed the efflux clearance into CSF or drainage to dcLNs. We found that the glymphatic clearance of tau to CSF as well as tau drainage from CSF to dcLN were both suppressed in AQP4KO mice, which led to significantly higher levels of tau retention in brains and CSF.
Next to see how long-term deficiency of AQP4 impacts intracellular tau accumulation and neurodegeneration, we crossed AQP4KO mice with P301S tau transgenic mice (PS19) that develop age-dependent tau pathology and neurodegeneration. At 9-months of age, PS19 x AQP4 (-/-) mice showed higher level of tau accumulation as well as severe brain atrophy compared to PS19 x AQP4 (+/+) mice.
Based on these observations that AQP4 deficiency aggravates tau aggregation, we next examined whether tau accumulation could be suppressed by enhancing AQP4 function. When a BBB-permeable AQP4 facilitator, TGN-073 was administered to PS19 for 3 months by drinking water, we found that the levels of both soluble and insoluble tau were significantly reduced in PS19 treated with TGN-073.
The current study revealed the critical roles of AQP4 not only in extracellular tau clearance but also in intracellular tau accumulation and associated neurodegeneration. More importantly, we have demonstrated that tau accumulation is suppressed by AQP4 facilitator TGN-073, suggesting that promoting glymphatic system could mitigate intracellular tau accumulation. Although the detailed mechanisms of how extracellular tau clearance impact intracellular accumulation of tau remain to be elucidated, this study provides a proof of concept of targeting glymphatic/lymphatic systems as a potential therapeutic strategy in tauopathies. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-017
進行性格上性麻痺におけるタンパク質SUMO化によるTauタンパク質の機能制御
SUMO1 Modification of Tau in Progressive Supranuclear Palsy
*高村 明孝(1,2)、中山 宜昭(3)、伊藤 秀文(3)、片山 泰一(1)、Paul E Fraser(2,4)、松崎 伸介(1,5)
1. 大阪大学大学院連合小児発達学研究科、3. 和歌山県立医科大学神経内科、5. 森ノ宮医療大学医療技術学部放射線診療学科
*Hironori Takamura(1,2), Yoshiaki Nakayama(3), Hidefumi Ito(3), Taiichi Katayama(1), Paul E Fraser(2,4), Shinsuke Matsuzaki(1,5)
1. United Graduate School of Child Development, Osaka University, Osaka, Japan, 2. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada, 3. Department of Neurology, Wakayama Medical University, Wakayama, Japan, 4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, 5. Department of Radiological Sciences, Faculty of Health Sciences, Morinomiya University of Medical Sciences, Osaka, Japan
Keyword: Tauopathy, SUMO, Neurodegeneration, Protein aggregation
Many findings have reported the importance of small ubiquitin-like modifiers (SUMOs), especially SUMO1 and SUMO2/3, and SUMO1 shares ~50% homology with SUMO2 and SUMO3 while SUMO2/3 are virtually identical. A recently generated SUMO1 transgenic model has demonstrated a significant contribution of SUMOylation to the development and maintenance of dendritic spines. SUMO have also been implicated in several neurodegenerative diseases. SUMO1 conjugation has been shown to promote aggregation and regulate phosphorylation of the microtubule associated protein tau linked to Alzheimer’s disease and related tauopathies. The current study has demonstrated that SUMO1 co-localizes with intraneuronal tau inclusions in progressive supranuclear palsy (PSP). Immunoprecipitation of isolated and solubilized tau fibrils from PSP tissues revealed SUMO1 conjugation to a cleaved and N-terminally truncated tau. The effects of SUMOylation were examined using tau-SUMO fusion proteins which showed a higher propensity for tau oligomerization of PSP-truncated tau and accumulation on microtubules as compared to the full-length protein. This was found to be specific for SUMO1 as the corresponding SUMO2 fusion protein did not display a significantly altered cytoplasmic distribution or aggregation of tau. Blocking proteasome-mediated degradation promoted the aggregation of the tau fusion proteins with the greatest effect observed for truncated tau-SUMO1. The SUMO1 modification of the truncated tau in PSP may represent a detrimental event that promotes aggregation and impedes the ability of cells to remove the resulting protein deposits. This combination of tau truncation and SUMO1 modification may be a contributing factor in PSP pathogenesis. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-018
幼年期の髄膜炎による注意欠陥・多動性障害の誘導とそのメカニズム
Neonatal meningitis induces hyperactivity and attention-deficits behavior by increasing dopaminergic inputs
*田辺 章悟(1)、村松 里衣子(1)
1. 国立精神・神経医療研究センター 神経研究所 神経薬理研究部
*Shogo Tanabe(1), Rieko Muramatsu(1)
1. Dept Mol Pharmacol, Natl Inst Neurosci, National Center of Neurology and Psychiatry
Keyword: NEURODEVELOPMENTAL DISORDER, IMMUNE SYSTEM, DOPAMINE
Immune cells, localized in the meningeal space and choroid plexus, contribute to brain development by regulating neurogenesis, gliogenesis, and synaptic formation. Abnormalities in immune system are associated with neurodevelopmental disorders such as autism spectrum disorders (ASD) and attention-deficits hyperactivity disorders (ADHD), and neonatal meningitis is a potent risk factor in causing ADHD behavior. However, the pathological mechanism of neonatal meningitis-induced neurodevelopmental disorder has been still unclear. In this study, we established mouse model of neonatal meningitis-induced neurodevelopmental disorders and investigated its pathological mechanisms. To determine whether neonatal meningitis leads to neurodevelopmental disorders, we injected carrageenan, an inflammatory reagent, into the cisterna magna at neonatal stage, and detected large number of macrophages in the brain. Carrageenan-treated mice exhibited hyperactivity and attention-deficits in the adulthood assessed by behavioral test. Histological analysis and adeno-associated virus (AAV)-based neurotracing experiments showed neurons in the nucleus accumbens were highly activated due to the increase of dopaminergic inputs from ventral tegmental area. Moreover, macrophage depletion prevented carrageenan-induced hyperactivity and attention-deficits, and hyperactivation of nucleus accumbens. These results demonstrated that inflammatory macrophages are associated with neurodevelopmental diseases induced by neonatal meningitis by increasing dopaminergic inputs. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-019
Prucalopride restores the delayed gastrointestinal transit in preclinical mouse model of 15q duplication syndrome
*Gayathri Balasuriya(1,2), Kota Tamada(1), Jun Nomura(1), Toru Takumi(1)
1. Graduate School of Medicine, Department of Physiology and Cell Biology, Kobe University, 2. Japan Society for the Promotion of Science (JSPS), Tokyo, JAPAN
Keyword: Enteric Nervous System, Gastrointestinal Dysfunction, 15q duplication, Serotonin
Chromosome 15q duplication Syndrome is a neurodevelopmental disorder that includes autism patients and involves increased copy numbers of the chromosome 15q11.2-q13 region. Approximately 80% of individuals with 15q duplications (15q dup) have gastrointestinal (GI) dysfunction, with frequent symptoms including gastroesophageal reflux and constipation. The duplicated region consists of genes encoding for GABA receptor A subunits and GABA is an important neurotransmitter in the Enteric Nervous System (ENS)t. 15q duplication causes reduced concentration of serotonin in the brain, resulting in altered neuronal firing, sensory tuning and social behaviour. The gut produces over 90% of the body's serotonin, and it is well documented that serotonin plays a vital role in the enteric neuronal circuitry that regulates gut motility. Therefore, we investigated GI dysfunction and the GABA and serotonin mediated neurotransmission in this Enteric nervous system of this model. The total GI transit was investigated by gavaging the animals with carmine red dye and measuring the time it taken for red pellets to emerge, which demonstrated that both male and female adult 15q dup mice had a delayed GI transit. The small intestinal transit was unaffected. We investigated colonic motility using a video imaging approach in which colonic contractions were assessed in an ex vivo preparation using a video camera and in-house software. When 15q dup mice were treated with Bicuculine(10uM), a GABA receptor A antagonist, colonic contractions were slower and travelled for a shorter distance. Since the 15q dup neurones were under a hypo-serotonin condition, the potential of Prucalopride (5-HT4 receptor agonist, FDA approved to treat chronic constipation) to restore the delayed GI transit was investigated. Prucalopride at a dosage of 2mg/kg per day for 6 days, reversed the delayed GI transit in 15q dup mice. The results suggest that enteric neurones in 15q dup mice are more susceptible to GABA receptor inhibition and targeting serotonin receptors is an effective way to treat GI dysfunction in 15q dup syndrome. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-020
軸索起始部解析をもとにおこなうmPFCを中心とするASDモデル動物異常神経回路探索
Alteration of axon initial segment in the pyramidal neuron of medial prefrontal cortex revealed abnormal neural circuitry.
*岩﨑 華奈(1)、大谷 嘉典(1)、高橋 温志(1)、山中 由芽(1)、藤谷 昌司(1)
1. 島根大学医学部
*Hana Iwasaki(1), Yoshinori Otani(1), Atushi Takahashi(1), Yume Yamanaka(1), Masashi Fujitani(1)
1. Faculty of medicine, Shimane University
Keyword: Autism spectrum disorder, Axon initial segment, Neural Circuit
The axon initial segment (AIS) is located at the proximal axon and has a high density of ion channels, which occurs action potential initiation. In addition, the AIS regulates the excitability of neurons by changing the structures which include length and position. Many studies reported abnormalities in AIS are risk factors that cause various neurological diseases, such as autism spectrum disorder (ASD). ASD is a developmental disorder involving impairments in social communication, reciprocal social interaction, and restricted repetitive behaviors or interests. Duplication of the human chromosome 15q11-13(15q) region is the most frequently seen chromosomal abnormality and a risk factor for the development of ASD. The medial prefrontal cortex (mPFC) regulates various types of behavior including social communication. Therefore, we hypothesize that neuronal circuit of mPFC are critical for phenotypes of 15q duplication (15q dup) mice. To address, we analyzed abnormal neural circuits related ASD by measuring the length of AIS by projection site specific method in 15q dup and wild type mice. Previously, we reported that amount of serotonin was abnormal in the brain of 15q11-13 duplication ASD mice and there was significant difference in the length of AIS of pyramidal neurons in the layer 5 of medial prefrontal cortex (mPFC) toward dorsal raphe nucleus (DRN) in 15q dup mice. In this study, we revealed novel abnormal neuronal circuit of mPFC-nucleus accumbens and lateral habenular nucleus in 15q dup ASD mice by measuring the length of AIS. Therefore, we found potential abnormal neuronal circuits in 15q dup mouse by using measuring AIS. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-021
F70W ameliorates behavioral deficits and restores synaptic function via upregulation of AMPK in a mouse model of autism
*Ming-Chia Chu(1), Chi-Wei Lee(1), Ching-Hsiang Chang(1), Chieh-Yu Chang(1), Tzu-Ning Peng(1), Tzu-Jung Yang(1), Yen-Cheng Lin(1), Hsiang Chi(1), Guang-Huar Young(2), Hui-Ching Lin(1,3)
1. Department and institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221 Taiwan, 2. Energenesis Biomedical Co. Ltd, Taipei, 11492 Taiwan, 3. Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
Keyword: Autism spectrum disorder, Synaptic dysregulation
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder worldwide marked by impaired social interactions, communication deficits, and stereotypical behaviors. Synaptic dysregulation in critical brain regions is the major basis of ASD pathophysiology. Increasing evidence revealed that AMP-activated protein kinase (AMPK), the intracellular energy sensor, plays a pivotal role in regulating synaptic integrity and function. Given that limited benefit for the core symptoms of ASD is offered by the treatments available, we aim to investigate the effect of F70W, a compound purified from bamboo shoot extract, on the valproate-induced (VPA) mouse model of ASD. In the present study, the VPA-induced ASD offspring were orally treated with F70W treatments (15 mg/kg/day) by drinking water. We found that social deficiency and repetitive behaviors in the VPA-induced offspring were alleviated following 7-day F70W treatment in three-chamber social test and marble burying test. Moreover, aberrant long-term potentiation in the CA1 region of the hippocampus from the VPA-induced offspring was rescued following 7-day F70W treatment during electrophysiological recordings. Mechanistically, decreased phosphorylation levels of AMPK in the VPA-induced offspring were improved following 7-day F70W treatment. Taken together, treatment with F70W ameliorates behavioral and synaptic abnormalities in the ASD animal model, shedding new light on the potential utility of AMPK upregulation in the pharmacotherapeutic strategies of ASD. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-022
C57BL6J雄マウスの自発運動量は異種他個体のBALB/cCrSlc雄マウスの存在により増加する
Voluntary exercise of C57BL/6J male mice was enhanced in the presence of heterospecific BALB/cCrSlc male mice
*吉崎 嘉一(1)、田中 基樹(1)、飯田 真智子(1)、浅井 真人(1)
1. 愛知県医療療育総合センター発達障害研究所
*Kaichi Yoshizaki(1), Motoki Tanaka(1), Machiko Iida(1), Masato Asai(1)
1. Institute for Developmental Research, Aichi Developmental Disability Center
Keyword: social facilitation, voluntary exercise, others' recognition, self-presence
Social facilitation is a psychological phenomenon that an individual’s performance, such as food consumption and cognitive behavior, improves in frequency and intensity due to mere presence of other individuals. Intriguingly, performance of a Theory of Mind was impaired in children with autism spectrum disorder (ASD) than that in typically developing children under social context, while their performances were similar when the task was performed under non-social context. This suggests that social facilitation is attenuated in ASD children. However, the underlying mechanisms of attenuated social facilitation in ASD are still unclear. We previously developed a special breeding cage installed a running wheel on one of two section of a normal breeding cage and reported that voluntary exercise of more social C57BL/6J male mice, but not less social BALB/cCrSlc male mice, was enhanced in the presence of conspecific observer male mice, implicating functional deficiencies in either or both of self-presence and others’ recognition in BALB/cCrSlc male mice. To clarify the underlying mechanism of impaired social facilitation in BALB/cCrSlc male mice, we examined voluntary exercise of more social C57BL/6J and less social BALB/cCrSlc in the presence of heterospecific observer male mice. Voluntary exercise of more social C57BL/6J male mice was enhanced in the presence of heterospecific BALB/cCrSlc male mice. In contrast, voluntary exercise of less social BALB/cCrSlc male mice was not affected in the presence of heterospecific C57BL/6J male mice. These results suggest that BALB/cCrSlc male mice promote social facilitation in C57BL/6J male mice, but C57BL/6J male mice do not affect social facilitation in BALB/cCrSlc male mice, implicating that others’ recognition, but not self-presence, is disabled in BALB/cCrSlc male mice. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-023
自閉スペクトラム症動物モデルの社会性行動に対する新規抗てんかん薬の効果に関する検討
Anti-epileptic drugs attenuate behavioral changes and hyperactive ERK signaling in the prefrontal cortex of offspring from mice exposed to valproic acid during pregnancy
*守屋 友加(1)、毛利 彰宏(2,5)、宮地 麻衣(1)、倉橋 仁美(2)、不破 武弥(2)、西川 貴也(2)、鍋島 俊隆(3,5)、齋藤 邦明(4,5)、長谷川 洋一(1)
1. 名城大学薬学部、2. 藤田医科大学大学院保健学研究科 レギュラトリーサイエンス部門、3. 藤田医科大学大学院保健学研究科 先進診断システム探索部門、4. 藤田医科大学大学院保健学研究科 病態制御解析学、5. NPO 医薬品適正使用推進機構
*Yuka MORIYA(1), Akihiro MOURI(2,5), Mai MIYACHI(1), Hitomi KURAHASHI(2), Takemi Fuwa(2), Takaya NISHIKAWA(2), Toshitaka NABESHIMA(3,5), Kuniaki SAITO(4,5), Yoichi HASEGAWA(1)
1. Faculty of Pharmacy, Meijo University, Japan, 2. Department of Regulatory Science for Evaluation & Development of Pharmaceuticals & Devices, Fujita Health University Graduate School of Health Science, Japan, 3. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Science, Japan, 4. Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Science, Japan, 5. Japanese Drug Organization of Appropriate Use and Research, Japan
Keyword: Autism spectrum disorder
Autism spectrum disorder (ASD) is the developmental disorders characterized by social disability and restricted interest and repetitive behaviors. The imbalance of excitation and inhibition in neural circuitry is hypothesized for the pathophysiology of ASD, which results in symptoms like those of epilepsy. It is epidemiologically reported that administration of valproic acid (VPA) during pregnancy increases the risk of ASD in the offspring. In this study, we investigated therapeutic potential of anti-epileptic drugs for ASD using prenatal VPA-induced ASD animal model. Pregnant mice were injected with VPA (500 mg/kg, i.p.) on gestational day 12. The male but not female offspring from mice exposed to VPA during pregnancy showed decrease in social interaction time in social interaction test, decrease in exploratory time for novel object in the novel object recognition test. In the prefrontal cortex of offspring from mice exposed to VPA during pregnancy, the protein levels of NMDA receptor NR2B subunit and phosphorylated ERK were increased. The offspring were injected with anti-epileptic drugs (levetiracetam, lacosamide, and perampanel) before each behavioral test, they attenuated these behavioral changes and increase of phosphorylation of ERK in offspring from mice exposed to VPA during pregnancy. Behavioral changes in offspring from mice exposed to VPA during pregnancy are associated with the symptom of ASD (decrease in social interaction time: social disability, decrease in approach time for novel object: cognitive dysfunction). Hyperactivity of glutamatergic system represented by the up-regulation of NR2B and phosphorylation of ERK in the prefrontal cortex. The ameliorating effects of anti-epileptic drugs on the ASD-like behaviors suggested that modulation of glutamatergic nervous system is therapeutic target for ASD, which should be subjected for further investigation to verify the clinical relevance. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-024
統合失調症モデルで認められた感覚刺激後に出現する皮質領域間位相同期性の障害
Cortical connectivity in animal models for schizophrenia: Impaired inter-regional phase coherence after sensory stimulation in awake electroencephalography
*難波 寿明(1)、稲葉 洋芳(2)、那波 宏之(1,2)
1. 和歌山県立医科大学、2. 新潟大学脳研究所
*Hisaaki Namba(1), Hiroyoshi Inaba(2), Hiroyuki Nawa(1,2)
1. Wakayama Medical University, 2. Brain Res Inst, Niigata University
Keyword: EEG, auditory cortex, schizophrenia
Communication between brain areas has been implicated in wide range of cognitive function and sensory perception, and is impaired in some neuropsychiatric disorders. For the analyzes of inter-regional connectivity in neocortex at the electrophysiological level, phase synchronization in a certain frequency range in electroencephalography (EEG) can be assessed to determine the cortical connectivity. Here, we recorded epidural EEG in frontal, somatosensory, auditory and visual cortical areas in awake rats and analyzed phase coherence of each frequency band between these areas evoked by auditory and visual stimuli. We found three continual auditory or visual stimuli induced enhanced phase coherence between cortical areas during post-stimulus period. Auditory stimulation of three continual tones of 10 kHz (duration 500 ms, interval 1 s, 80 dB) induced sustained phase locking for ~ 4 s at theta and low beta bands between auditory and frontal cortical areas. Sustained phase locking was not detected between auditory and somatosensory cortical areas or auditory and visual cortical areas. Visual stimulation of three continual light pulses (duration 500 ms, interval 1 s) also induced similar sustained phase locking during post-stimulus period between visual and frontal cortical areas and visual and somatosensory cortical areas. Three continual tones of rather lower sound frequency (3 kHz) and typical paired tone paradigm with rather shorter duration (10 kHz, 20 ms, interval 500 ms) did not induced marked phase locking in any frequency bands. In addition, using cytokine-induced rat models for schizophrenia, we detected diminished phase coherence between auditory and frontal cortical areas evoked by auditory stimulation. Though further analyzes are needed to assess the role of inter-regional phase synchronization at theta and low beta bands for cognitive and perceptual function, diminished phase coherence in the animal model suggests some impairments in cortical connectivity and/or auditory perception. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-025
メスのVRK2欠失ゼブラフィッシュは神経樹状突起形態の変化を介して異常行動を示す。
Female VRK2-deficient zebrafish exhibit malbehavior via an alteration of the morphology of nerve dendrites.
*梅田 涼平(1)、清水 誠之(2)、波田 一誠(2)、寺西 仁志(1)、鹿野 健史朗(1)、比嘉 涼子(1)、漆畑 博太郎(2)、白石 裕士(2)、花田 俊勝(2)、花田 礼子(1)
1. 大分大学医学部神経生理学、2. 大分大学医学部細胞生物学
*Ryohei Umeda(1), Nobuyuki Shimizu(2), Kazumasa Hada(2), Hitoshi Teranishi(1), Kenshiro Shikano(1), Ryoko Higa(1), Hirotaro Urushibata(2), Hiroshi Shiraishi(2), Toshikatsu Hanada(2), Reiko Hanada(1)
1. Dept Neurophysiol, Fac Med, Oita univ, Oita, Japan , 2. Dept Cell BIol, Fac Med, Oita univ, Oita, Japan
Keyword: VRK2, zebrafish, aggression, GABA
Vaccinia-related kinase 2 (VRK2) VRK2 is one of the serine/threonine kinases that was originally identified in highly proliferative cells such as thymocytes and fetal liver cells. And VRK2 plays an important role in cell division and cell cycle regulation. In humans, it was reported that VRK2 was a potential candidate molecule for neuropsychiatric diseases such as schizophrenia by several GWAS. However, little is known about the molecular mechanism and physiological function of VRK2 on the central nervous systems. In this study, we established vrk2 deficient zebrafish (VRK2 KO) and found that VRK2 KO grew normal and the brain size was comparable to their control zebrafish (WT). In the behavioral study, we performed a series of behavior tests such as a novel tank diving test, mirror test, and social preference test. We observed that the aggressive behavior was significantly enhanced in female VRK2 KO on the mirror test, and abnormal behavior was observed in the social preference test. Additionally, to investigate what mechanism causes these malbehavior, we measured neurotransmitters in the whole brain of VRK2KO and WT. VRK2 KO female zebrafish showed low gamma-aminobutyric acid (GABA) content in the brain. Moreover, to examine morphological changes in dendrite-spine formation, we performed Golgi-Cox staining in the forebrain area. We found a high density of neuronal dendrites in VRK2 KO female zebrafish when compared with WT. These findings suggest that there is a tight relationship between VRK2 and the malbehavior mediated by the alteration of the morphology of nerve dendrites in the forebrain on female zebrafish. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-026
Cuprizone短期投与によりプレパルス抑制が障害されたマウスにおける統合失調症関連分子の免疫組織化学的研究
Immunohistochemical analyses for molecules relating to schizophrenia in short-term treated mice by cuprizone with impairment of prepulse inhibition
*佃 京華(1)、窪田 剛志(2)、千葉 葵(4)、冨永 貴志(1)、岸本 泰司(3)、中島 健太郎(1)
1. 徳島文理大学 神経科学研究所、2. 徳島文理大学 香川薬学部 薬理学講座、3. 帝京大学 薬学部 物理化学教室、4. 徳島文理大学 香川薬学部 生命物理化学講座
*Kyoka Tsukuda(1), Takashi Kubota(2), Aoi Chiba(4), Takashi Tominaga(1), Yasushi Kishimoto(3), Kentaro Nakashima(1)
1. Institute of Neuroscience, Tokushima Bunri University, Kagawa, Japan, 2. Laboratory of Pharmacol., Kagawa Sch. Phrmaceut. Sci., Tokushima Bunri Univ., Kagawa, Japan, 3. Laboratory of Physical Chemistry, Faculty of Pharma Sciences, Teikyo University, Tokyo, Japan, 4. Department of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Kagawa, Japan
Keyword: Neuroinflammation, Cuprizone, Schizophrenia, Demyelination
Cuprizone (CPZ), a copper chelator, has been employed to build a mouse model for demyelinating diseases such as multiple sclerosis. A long-term feeding diet containing CPZ induces demyelination in the brain (mainly corpus callosum and cingulum of white matter). On the other hand, it has recently been reported that short-term CPZ treatment induces neuroinflammation without demyelination and psychobehavioral disorders like symptoms of schizophrenia. These results suggest that short-term CPZ treatment may serve as a new animal model for the study of psychiatric disorders with neuroinflammation. However, there have been few reports on the behavioral characteristics of short-term CPZ-treated mice without demyelination. In this study, we evaluated the behavioral characteristics of this mouse by spontaneous behavior, social behavior, and prepulse inhibition (PPI), which is a measure of sensorimotor gating and is known to be reduced in schizophrenic patients. These results showed significant impairment of PPI in short-term CPZ-treated mice as compared with control mice. Neuroinflammation without demyelination in these mice was shown by immunohistochemical analyses using anti-MBP and anti-Iba1 antibodies, a marker of oligodendrocytes and microglia, respectively. These results suggest that neuroinflammation induced by short-term CPZ treatment may participate in psychiatric symptoms observed in schizophrenia, such as impaired PPI. To date, human brain imaging studies using functional MRI in schizophrenia patients have demonstrated the involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. In addition, post-mortem studies and PET brain imaging study have also reported that the density or the activity of NMDAR, one of the glutamate receptors, is reduced in the hippocampus of schizophrenia patients. In this presentation, besides the results of behavioral analyses, we will report the results of immunohistological analyses of NMDAR and dopaminergic neurons in short-term CPZ-treated mice. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-027
統合失調症における予測的推論と瞳孔にリンクした覚醒システム
Predictive inference and pupil-linked arousal systems in schizophrenia
*白間 綾(1)、住吉 太幹(1)
1. 国立精神・神経医療研究センター
*Aya Shirama(1), Tomiki Sumiyoshi(1)
1. National Center of Neurology and Psychiatry
Keyword: schizophrenia, pupillometry, inference, arousal
Several symptoms of schizophrenia, such as hallucinations, delusion, and impaired social functioning, have been suggested to be produced by maladaptive inferences. However, little is known about the neural mechanisms underlying the disturbance of inference processes in schizophrenia. In this study, we conducted a predictive inference task where participants were instructed to predict each subsequent number to be presented in a series such that the average error made on all predictions would be minimized. Participants were also required to update their prediction at several discrete change points in which an outcome generation criterion changed. We compared performance on the predictive inference task between patients with schizophrenia and healthy controls, and concurrently measured pupil diameters, a parameter that is thought to reflect uncertainty of belief when performing the task. Patients with schizophrenia showed a significantly higher learning rate than healthy controls, indicating more frequent updating of prediction during the task. Moreover, there was a difference in average pupil diameter during an outcome-viewing period in the task between patients and healthy controls. Specifically, average pupil diameter temporarily decreased on change point trials, and then remained at a relatively high level for several trials after a change point in healthy controls, whereas such change was absent in patients. These findings may represent aberrant regulation of arousal while making an inference in schizophrenia. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-028
意思決定の計算論的指標による抑うつ症状の早期予測
Computational markers of decision-making predict depressive symptoms
*陳 冲(1)、望月 泰博(2)、萩原 康輔(1)、弘津 正子(1)、松原 敏郎(1)、中川 伸(1)
1. 山口大学大学院医学系研究科、2. 早稲田大学データ科学総合研究教育センター
*Chong Chen(1), Yasuhiro Mochizuki(2), Kosuke Hagiwara(1), Masako Hirotsu(1), Toshio Matsubara(1), Shin Nakagawa(1)
1. Grad Sch Med, Yamaguchi Univ, Ube, Japan, 2. Center for Data Science, Waseda Univ, Tokyo, Japan
Keyword: depression, decision-making, computational psychiatry, uncertainty
Background: Early prediction of high depressive symptoms is crucial for selective intervention and the minimization of functional impairment. Recent cross-sectional studies indicated decision-making deficits in depression, which may be an important contributor to the disorder. Our goal was to test whether description- and experience-based decision making, two major neuroeconomic paradigms of decision-making under uncertainty, predict future depressive symptoms in young adults. Methods: One hundred young adults performed two decision-making tasks, one description-based, in which subjects chose between two gambling options given explicitly stated rewards and their probabilities, and the other experience-based, in which subjects were shown rewards but had to learn the probability of those rewards (or cue-outcome contingencies) via trial-and-error experience. We evaluated subjects’ depressive symptoms with BDI-II at baseline (T1) and half a year later (T2). Results: Comparing subjects with low versus high levels of depression at T2 showed that the latter performed worse on the experience- but not description-based task at T1. Computational modeling of the decision-making process suggested that subjects with high levels of depression had a more concave utility function, indicating enhanced risk aversion. Furthermore, a more concave utility function at T1 increased the odds of high depression at T2, even after controlling depression at T1, perceived stress at T2, and several covariates (OR=0.251, 95% CI [0.085, 0.741]). Conclusions: This is the first study to demonstrate a prospective link between experience-based decision-making and depression. Our results suggest that enhanced risk aversion in experience-based decision-making may be an important contributor to the development of depression. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-029
The Antidepressant Effects and Signaling Pathways of Ketamine and Ketamine Enantiomers in Antidepressant-Resistant Rat Model
*Chieh-Yu Chang(1), Chi-Wei Lee(1), Ming-Chia Chu(1), Tzu-Jung Yang(1), Ching-Hsiang Chang(1), Tzu-Ning Peng(1), Yen-Cheng Lin(1), Hsiang Chi(1), Hsun-Shuo Chang(3), Hui-Ching Lin(1,2)
1. Department and Institute of Physiology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, 2. Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, 3. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Keyword: Treatment-resistant depression, Ketamine, (S)-ketamine, (R)-ketamine
Treatment-resistant depression (TRD) is defined as major depression disorder (MDD) patients with greater resistance to traditional antidepressants. Moreover, traumatic event-induced depression rats model showed the resistance to selective serotonin reuptake inhibitor antidepressant have demonstrated in our previous study. The function of prefrontal cortex including regulation of emotion, cognitive behavior and discission-making. Moreover, the hypoactivation of prefrontal cortex in TRD patients was revealed in clinical studies. Previous studies showed that the activities of mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinases (ERK) were decreased in several MDD patients. Growing studies revealed that low-dose ketamine has rapid antidepressant effects on TRD. Nevertheless, the psychotomimetic effects and dissociative symptoms caused by (R,S)-ketamine are still concerned. Ketamine is composed of two enantiomers, (S)-ketamine and (R)-ketamine. However, the antidepressant effect and mechanism of (R)-ketamine and (S)-ketamine are still unclear. In this study, we applied tone-shock pairings as traumatic event to induce depressive-like behavior on Sprague Dawley rat. First, we found that the depressive-like behaviors, including altered hedonic behavior and active coping behavior, were ameliorated in traumatic event group among (R,S)-ketamine, (S)-ketamine and (R)-ketamine treatment by sucrose preference test, tail suspension test and forced swim test. Second, the phosphorylation of mTOR was only ameliorated after (S)-ketamine and (R,S)-ketamine treatments in prefrontal cortex of traumatic event group; whereas, the phosphorylation of ERK was only ameliorated after (R)-ketamine and (R,S)-ketamine treatments in prefrontal cortex of traumatic event group. Taken together, we revealed that three types of ketamine have antidepressant-effect acting through different signaling pathways in antidepressant-resistant model. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-030
Brain interoception network structures linked with cardiac dysfunction in depression
*Fermin Alan(1)、Chan Hui-Ling(1)、Ichikawa Naho(1)、Takamura Masahiro(1)、Yokoyama Satoshi(1)、Machizawa Maro(1)、Yoshino Atsuo(1)、Matani Ayumu(1)、Yamawaki Shigeto(1)、Okada Go(1)、Okamoto Yasumasa(1)
*Alan S. R. Fermin(1), Hui-Ling Chan(1), Naho Ichikawa(1), Masahiro Takamura(1), Satoshi Yokoyama(1), Maro G. Machizawa(1), Atsuo Yoshino(1), Ayumu Matani(1), Shigeto Yamawaki(1), Go Okada(1), Yasumasa Okamoto(1)
1. Hiroshima University
Keyword: major depressive disorder, interoception, cardiac regulation, brain interoception network
Major depressive disorder (MDD), classically associated with reduced mood control, is also linked with autonomic nervous system disturbances that affect the function of visceral processes important for survival, such as cardiovascular regulation (e.g., heart arrhythmia), and that predict the development of MDD. In the brain, the insula, anterior cingulate, amygdala, and hypothalamus form part of the brain interoception network (BIN) responsible for the regulation of visceral functions. Active inference accounts of interoception suggest that the brain controls visceral processes by predictions of expected interoceptive sensory data. However, it remains unknown whether neuroanatomical abnormalities of BIN structures are linked with the generation of disordered interoceptive predictions and ensuing cardiac disturbances in MDD. Here, we investigated differences in the neuroanatomical representation of cardiac signals between healthy controls [HC, n = 104] and MDD patients [n = 81] from a large-scale clinical study at Hiroshima University. We also used photoplethysmogram (PPG) to acquire resting cardiac signals in order to investigate heart rate variability measures of sympathetic and parasympathetic cardiac functions. Analysis of PPG data revealed increased heart rate and decreased low frequency sympathetic and high frequency parasympathetic signals in MDD patients relative to HC. MDD patients also showed significant reduced volumes of the insula, anterior cingulate, amygdala and hypothalamus. Among the BIN regions, the posterior insula volume showed a significant negative correlation with low-frequency measures of cardiac sympathetic function among HC but not among MDD patients, whereas smaller left hypothalamus volume was linked with lower cardiac parasympathetic function among MDD patients. These findings suggest that cardiac disturbances in MDD may originate from faulty predictive processes in brain structures implicated in interoceptive information processing and may inform the development of novel brain-visceral therapeutical interventions seeking to treat depressive symptoms and cardiovascular disturbances observed in depression. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-031
炎症性サイトカインによる神経活動変調効果のin vitroモデリング
In vitro modeling of neural activity modulation induced by inflammatory cytokines
*酒井原 一守(1,2)、山本 英明(1,2)、佐藤 茂雄(1,2)、平野 愛弓(1,2,3)
1. 東北大学電気通信研究所、2. 東北大学大学院工学研究科、3. 東北大学材料科学高等研究所
*Mamoru Sakaibara(1,2), Hideaki Yamamoto(1,2), Shigeo Sato(1,2), Ayumi Hirano-Iwata(1,2,3)
1. RIEC, Tohoku Univ, Sendai, Japan, 2. Grand Sch Eng, Tohoku Univ, Sendai, Japan, 3. WPI-AIMR, Tohoku Univ, Sendai, Japan
Keyword: NEURONAL NETWORK, MICROFLUIDIC DEVICE, INTERLEUKIN-6, DISEASE MODELING
Neurological dysfunctions such as epilepsy and encephalitis have been reported as one of the typical symptoms in severe patients with SARS-CoV2 infection, which is thought to be partly mediated by the excessive release of inflammatory cytokines. Among several inflammatory cytokines, interleukin-6 (IL-6) has been found to be significantly increased in the blood concentration in severe patients. IL-6 has been reported to decrease GABAergic currents in the medial prefrontal cortex, and thus may underlie dysfunctions caused by network-level hyperexcitability. In vitro neuronal culture systems are widely used in neuroscience as a model system to investigate how chemical and pharmacological environment modulates network function and to develop new therapeutics. However conventional cultured neuronal networks in their mature stage spontaneously generate a strongly coherent burst activity, which limits the observation of hyperexcitation caused by the inflammatory cytokines. Here, we used microfluidic devices to impose modular architecture in cultured neuronal networks and suppress the coherent bursting activity [1, 2] and analyzed the effect of IL-6 administration on spontaneous neural activity. Analysis revealed that 50% of the modular networks (n = 16) were hyper-responsive to IL-6 and increased its burst frequency over two times from DIV 12 to 13 during which IL-6 was administered. In contrast, the fraction of networks hyper-responsive to IL-6 was only 14.3% in the non-modular culture (n = 7). This result indicates that the induction of modular architecture in cultured neuronal networks enhances their sensitivity to IL-6, making it a suitable system to investigate the underlying mechanisms of hyperexcitability and to screen candidate compounds that suppress the pathological effect. The work was supported by MEXT KAKENHI Grant-in-Aid for Transformative Research Areas (B) “Multicellular Neurobiocomputing” (21H05164), JSPS KAKENHI (19H00846, 20H02194), JST-PRESTO (JMPJPR18MB), JST-CREST (JPMJCR19K3), and the Cooperative Research Project Program of the Research Institute of Electrical Communication, Tohoku University. References: [1] Yamamoto et al. Sci Adv 4, eaau4914 (2018). [2] Takemuro et al. Jpn J Appl Phys 59, 117001 (2020). | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-032
クラウドソーシングによる大規模な描画データと疾患横断的精神疾患症状の解析
Large-scale data analysis for goal-directed drawing task with trans-diagnostic psychiatric symptoms in general population
*内田 裕輝(1,2)、村田 真悟(3)、宗田 卓史(1,2)、片平 健太郎(4)、鈴木 真介(5)、山下 祐一(1)
1. 国立精神・神経医療研究センター、2. 東京医科歯科大学大学院医歯学総合研究科、3. 慶應義塾大学理工学部、4. 産業技術総合研究所情報・人間工学領域、5. メルボルン大学
*Yuuki Uchida(1,2), Shingo Murata(3), Takafumi Soda(1,2), Kentaro Katahira(4), Shinsuke Suzuki(5), Yuichi Yamashita(1)
1. Department of Information Medicine, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan, 2. Grad Sch Med and Dent, Tokyo Medical and Dental Univ, Tokyo, Japan, 3. Department of Electronics and Electrical Engineering, Keio Univ, Tokyo, Japan, 4. Mental and Physical Functions Modeling Group, Human Informatics and Interaction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan, 5. Brain, Mind and Markets Laboratory, Department of Finance, Faculty of Business and Economics, The University of Melbourne, Melbourne, Victoria, Australia
Keyword: big data, online experiment
Drawing is an integrative human brain function, containing exteroceptive and proprioceptive information processing, goal-directed control, and planning. Therefore, analysis of drawing performed by various individuals including healthy people and psychiatric patients may bring better understanding about human brain functions. However, collecting such large-scale data of drawing and questionnaires onsite (i.e., at laboratory) is a difficult problem. In order to address this issue, we developed a novel experimental paradigm to collect goal-directed drawing and self-report psychiatric symptom questionnaires performed online (i.e., on the web) with participants in general populations recruited via a crowdsourcing platform. In cooperation with 1152 participants of various psychiatric symptom scores, we collected 193536 trajectory data and answers to seven types of questionnaires consisted of 181 items. We conducted an exploratory factor analysis using bi-factor model on the correlation matrix of the psychiatric symptom questionnaire items, and assessed the relationship between behavioral characteristics in the goal-directed drawing task and psychiatric symptoms from the perspective of trans-diagnostic (i.e. dimensional) approaches. As a result, significant correlations were found between characteristics of drawings of the trajectories and the scores of a general (p-factor) and specific psychopathological factors. For example, the redundancy of the trajectories was significantly correlated with the scores of a general (p-factor) and a specific factor representing reduced social skills. On the other hand, the curvature of the trajectories was significantly correlated only with the scores of a general psychopathological factor, but not with other specific factors. These results suggest that the proposed paradigm of online drawing experiment may benefit for estimating psychiatric symptoms in general populations from the perspective of trans diagnostic approaches. | | 2022年7月1日 11:00～12:00 宜野湾市民体育館 ポスター会場2
2LBA-033
ミトコンドリアホスホリパーゼPNPLA8の両アレル機能喪失変異は外側放射状グリアの数を減少させ、単純脳回型小頭症を引き起こす
Biallelic loss-of-function variants in mitochondrial phospholipase PNPLA8 decrease in the number of basal radial glial cells and lead to microcephaly with simplified gyral pattern
*中村 勇治(1)、嶋田 逸誠(1)、藤本 真徳(1)、佐藤 恵美(1)、宮内 彰彦(2)、宮 冬樹(3)、角田 達彦(4)、大久保 幸宗(5)、萩野谷 和裕(5)、輿水 江里子(6)、宮武 聡子(6)、松本 直通(6)、有岡 祐子(7)、尾崎 紀夫(7)、加藤 洋一(1)、齋藤 伸治(1)
1. 名古屋市立大学大学院医学研究科、2. 自治医科大学医学部、3. 慶應義塾大学医学部、4. 東京医科歯科大学、5. 宮城県立こども病院、6. 横浜市立大学大学院医学研究科、7. 名古屋大学大学院医学系研究科
*Yuji Nakamura(1), Issei S Shimada(1), Masanori Fujimoto(1), Emi Sato(1), Akihiko Miyauchi(2), Fuyuki Miya(3), Tatsuhiko Tsunoda(4), Yukimune Okubo(5), Kazuhiro Haginoya(5), Eriko Koshimizu(6), Satoko Miyatake(6), Naomichi Matsumoto(6), Yuko Arioka(7), Norio Ozaki(7), Yoichi Kato(1), Shinji Saitoh(1)
Keyword: PNPLA8, basal radial glia, brain organoid, gyrification
Evolutionary expansion and gyrification of the cerebral cortex are both linked to an abundance of basal radial glial cells (bRGCs) in the developing cortex. bRGCs, unlike apical RGCs (aRGCs) from which they are derived, possess highly proliferative potential, leading to a pronounced increase in the number of neurons. RGCs are the major neural stem cells (NSCs) that divide into various types of daughter cells depending on cell fate determinants. However, the mechanism which determines RGC fate is not fully understood. Here, we identified biallelic loss-of-function variants in PNPLA8 in two patients with severe neurodevelopmental disability exhibiting congenital microcephaly with simplified gyral pattern. PNPLA8, encoding mitochondrial phospholipase, plays an important role in mitochondrial membrane lipid remodeling. Indeed, enlarged mitochondria and reduced oxygen consumption was identified in patient’s skin fibroblasts, suggestive of mitochondrial-related etiology. PNPLA8 knockout mice reported to date appear to lack neurodevelopmental phenotypes. Therefore, to gain insight into brain development of PNPLA8-deficient patients, we generated cerebral organoids using PNPLA8 gene-edited human induced pluripotent stem cells (hiPSCs) which carried biallelic truncating variants in PNPLA8 as well as control hiPSCs. Immunohistochemical analysis of cerebral organoids revealed that loss of PNPLA8 function specifically reduces the abundance of HOPX+ bRGCs and SATB2+ upper-layer neurons, consistent as the pathogenesis of microcephaly and simplified gyrus. Furthermore, PNPLA8 knockout induced cell-cycle exit in aRGCs, suggesting that PNPLA8-deficient neural stem cells tend to undergo neurogenic division rather than self-renewing division. To further investigate how the NSC fate determinants are altered, we generated PNPLA8 gene-edited hiPSC-induced NSCs in vitro. Mitochondrial staining and transmission electron microscopy revealed that mitochondria in the NSCs were hyperfused and enlarged with obscure cristae shape. Given many links between mitochondria and cell fate decision, loss of PNPLA8 function could alter morphology and function of mitochondria, thereby dysregulate aRGC fate decision. Overall, these findings not only reveal neurodevelopmental pathomechanisms of PNPLA8-deficient patients, but also imply mitochondrial quality control by PNPLA8-dependent lipid remodeling as an upstream regulator of NSC fate decisions in gyrencephalic species. | | | |
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