シンポジウム
09 精神科医が推進する精神医学研究の最前線
09 Cutting-edge research led by clinical psychiatrists
座長：牧之段 学（奈良県立医科大学医学部精神医学講座）・田中 謙二（慶應義塾大学医学部 先端医科学研究所 脳科学研究部門） |
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| 2022年7月3日 14:00～14:24 沖縄コンベンションセンター 会議場B1 第3会場
4S03a-01
幼若期逆境体験による前頭前野神経回路の再編成
Reorganization of the prefrontal cortex neural circuit due to childhood adversity experience
*山室 和彦(1)
1. 奈良県立医科大学精神医学講座
*Kazuhiko Yamamuro(1)
1. Dep of Psychiatry, Univ of Nara Medical, Nara, Japan
Keyword: social isolation, prefrontal cortex, paraventricular nucleus of thalamus, E/I balance
COVID-19 has quickly spread around the world, and many countries have imposed travel and curfew restrictions to control the infection. Isolation is increasingly recognized as a serious threat to mental health. Social isolation, especially in childhood, has adverse effects on adult brain function and social behavior in rodents as well as humans. Children who are placed in foster care at an early age and are able to leave the socially disadvantaged institutional care environment are known to have improved functional outcomes compared to children who have never been placed in foster care or who are placed in foster care at a later age. In mice, juvenile social isolation (jSI; juvenile social isolation) during the first two weeks after weaning (21 to 35 days of age) is known to lead to reduced social behavior in adulthood, suggesting that this is a sensitive period for establishing social behavior. A number of studies in humans as well as rodents have shown that the medial prefrontal cortex (mPFC; medial prefrontal cortex) is an important region of the brain network that regulates social behavior. In our previous study, we found that L5/6 pyramidal cells projecting to the subcortical area of the mPFC are vulnerable to social isolation in juveniles and that adult pyramidal cell activity is attenuated in jSI. In addition, previous genetics and transcriptome studies have shown that many risk genes for autism spectrum disorders and schizophrenia are highly expressed in mPFC L5/6 pyramidal cells, and mouse studies have shown that the function of subcortical projecting mPFC pyramidal cells (L5/6) is impaired in mouse models of autism spectrum disorders. In our study, we found that mPFC projecting pyramidal cells (L5/6), which project to the subcortical region, are functionally abnormal in a mouse model of autism spectrum disorder. In our study, we found that the paraventricular nucleus of the thalamus (PVT) is a candidate subcortical region that projects from mPFC pyramidal cells (L5/6) and is related to social behavior. Considering that this region projects to various reward-related areas such as the nucleus accumbens, striatum internus, and central nucleus of the amygdala, the mPFC→PVT neural circuit is suitable for top-down control of brain networks. We have identified a neural circuit (mPFC→PVT) that requires juvenile social experience for appropriate social behavior in adulthood. In this talk, I will focus on the functional and behavioral roles of the mPFC→PVT neural circuit and its development in juvenile social experience. | | 2022年7月3日 14:24～14:48 沖縄コンベンションセンター 会議場B1 第3会場
4S03a-02
前頭側頭葉変性症におけるRNA-翻訳研究
RNA-translation research in frontotemporal lobar degeneration
*森 康治(1)
1. 大阪大学大学院医学系研究科精神医学
*Kohji Mori(1)
1. Psychiatry, Osaka University Graduate School of Medicine
Keyword: repeat expansion, RAN translation, FTLD, C9orf72
Frontotemporal lobar degeneration (FTLD), clinically referred to as frontotemporal dementia, is characterized with behavioral disturbance and progressive aphasia typically accompanied with frontal and/or temporal lobar atrophy. 40-50% of FTLD cases show TDP-43 pathology (FTLD-TDP). An aberrant intronic GGGGCC repeat expansion in C9orf72 (chromosome 9 open reading frame 72) is a leading genetic cause of familial forms of both FTLD-TDP and amyotrophic lateral sclerosis (ALS). The expanded DNA repeat is bidirectionally transcribed into sense and antisense repeat RNA. These repeat RNA transcripts sequestrate a subset of RNA binding proteins and accumulate as RNA foci. Part of the repeat RNA transcripts are even translated into dipeptide repeat protein (DPR)s in the absence of the canonical initiation codon (AUG). DPRs form disease-characterizing inclusions in the brain of C9orf72-FTLD/ALS patients and are considered potentially neurotoxic. We have focused on revealing how these repeat RNAs accumulate in cells and how they are translated. Modulation of these processes would be an indispensable theme when considering development of novel therapeutics against C9orf72-FTLD/ALS and the other neuropsychiatric repeat expansion disorders. | | 2022年7月3日 14:48～15:12 沖縄コンベンションセンター 会議場B1 第3会場
4S03a-03
精神疾患における神経オシレーション異常に注目したトランスレーショナル・アプローチ
Translational approach focusing on abnormal neural oscillation in psychiatric disorders
*多田 真理子(1,2)、切原 賢治(2,3)、國井 尚人(4)、宇賀 貴紀(5)、越山 太輔(2)、藤岡 真生(2)、臼井 香(2)、西村 亮一(2)、荒木 剛(2,6)、笠井 清登(2)
1. 東京大学相談支援研究開発センター、2. 東京大学医学部附属病院精神神経科、3. 東京大学バリアフリー支援室、4. 東京大学医学部附属病院脳神経外科、5. 山梨大学総合研究部医学域統合生理学、6. 帝京大学医学部附属溝口病院精神科
*Mariko Tada(1,2), Kenji Kirihara(2,3), Naoto Kunii(4), Takanori Uka(5), Daisuke Koshiyama(2), Mao Fujioka(2), Kaori Usui(2), Ryoichi Nishimura(2), Tsuyoshi Araki(2,6), Kiyoto Kasai(2)
1. Center for Research on Counseling and Support Services, Univ of Tokyo, Tokyo, Japan, 2. Dept Neuropsychiatry, Univ of Tokyo Hospital, Tokyo, Japan, 3. Disability Services Office, Univ of Tokyo, Tokyo, Japan, 4. Dept Neurosurgeon, Univ of Tokyo Hospital, Tokyo, Japan, 5. Dept Integrative Physiology, Grad Sch Med, Univ of Yamanashi, Yamanashi, Japan, 6. Dept Psychiatry, Teikyo University Hospital, Kanagawa, Japan
Keyword: Translational approach, neural oscillation, psychiatric disorders, EEG/ECoG
Translational approaches are useful for elucidating the pathophysiology of psychiatric disorders by conducting both patient-based clinical research and basic research. For this purpose, a strategy that focuses on neuroscientific findings in patients with psychiatric disorders and investigates their generating mechanisms may be effective. In this presentation, we will report on a translational approach focusing on gamma oscillation, a neurophysiological finding known to be abnormal in psychiatric disorders. Gamma oscillation is thought to be involved in the basis of information processing in the brain. In particular, the auditory steady-state response (ASSR), one of the auditory oscillations observed when listening to auditory stimuli, is known to be decreased in psychiatric disorders such as schizophrenia. In schizophrenia, ASSR is known to be decreased not only in chronic patients with advanced disease but also in young patients in the early stages of the disease (Tada et al., 2016), and recently, its relationship with GABAergic dysfunction has been discussed. To clarify the pathophysiology behind the ASSR abnormalities observed in patients, we have been conducting electrocorticogram (ECoG) measurements for preoperative recording of patients with intractable epilepsy and measurements in pharmacological models using experimental animals. Comprehensive ECoG measurements from multiple patients revealed that the source of ASSR is not limited to the auditory cortex, as previously assumed, but originates from a complex network throughout the brain that extends to the frontal and parietal lobes (Tada et al., 2021). This may correspond to the fact that the symptoms exhibited by patients with psychiatric disorders are not abnormal auditory information processing but rather various cognitive dysfunctions. As our understanding for the pathophysiology of psychiatric disorders progresses at the molecular and circuit levels, the current phenomenological diagnostic system could be expected to evolve into a neuroscientific system that is directly related to therapeutic approaches. | | 2022年7月3日 15:12～15:36 沖縄コンベンションセンター 会議場B1 第3会場
4S03a-04
ゲノム医科学は臨床精神医学の補助になりうるか？
Can genomic medicine help clinical psychiatry?
*池田 匡志(1)
1. 藤田医科大学医学部精神神経科学
*Masashi Ikeda(1)
1. Department of Psychiatry, Fujita Health University School of Medicine
Keyword: Precision medicine
Progress of genomic medicine have provided clues for detecting pathophysiology of complex disorders including psychiatric disorders, and have identified a large number of susceptibility genes for these conditions. Also, Pharmacogenetic/Pharmacogenomic (PGt/PGx) studies progressed substantially, resulting in establishing precision medicine. However, in the real clinical psychiatric field, the evidence from PGt/PGx has been limited so far, except that of risk HLA variants for Carbamazepine-induced cutaneous adverse drug reaction, therefore we feel the “gap between bench and bedside”. In this symposium, I will introduce the current status of genomic medicine for complex disorders. Also, I will discuss about the best approach to apply the results from genomic research, where many significant genes have been detected, into the clinical psychiatry. | | 2022年7月3日 15:36～16:00 沖縄コンベンションセンター 会議場B1 第3会場
4S03a-05
治療抵抗性うつ病に対するケタミン治療：AMPA受容体PET研究
Ketamine for treatment-resistant depression: AMPA receptor PET study
*内田 裕之(1)
1. 慶應義塾大学医学部
*Hiroyuki Uchida(1)
1. Keio University School of Medicine
Keyword: depression, ketamine, AMPA, positron emission tomography
While conventional pharmacotherapy for depression is ineffective in approximately 30% of patients, robust therapeutic effects of ketamine on such treatment-resistant depression have consistently been demonstrated. The mechanism of action of ketamine has been reported to involve alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in animal studies; however, human data are lacking. A novel positron emission tomography (PET) ligand, [11C]K-2, that specifically attaches to AMPA receptors in the living brain, was recently developed (Miyazaki et al. Nat Med 2000). We have currently been conducting a placebo-controlled, double-blind, randomized controlled trial to examine the efficacy of ketamine and elucidate its mechanisms of antidepressant action, using this brand-new PET ligand (jRCT (jRCTs031210124; https://jrct.niph.go.jp/en-latest-detail/jRCTs031210124). Thirty-four patients with depression according to Structured Clinical Interviews for DSM-5: Research Version who did not respond to at least two antidepressants for at least four weeks will be included. The participants receive either ketamine (0.5 mg/kg twice weekly for 2 weeks: 4 times in total) or a placebo (saline). Pre- and post-treatment assessments include the Montgomery-Aberg Depression Rating Scale (MADRS), AMPA receptor density and distribution, using PET with [11C]K-2, Glx and Glu in the anterior cingulate cortex, using magnetic resonance spectroscopy (MRS), tractography using diffusion tensor imaging (DTI), and functional connectivity, using resting-state functional magnetic resonance imaging (rs-fMRI). This study aims to elucidate the dynamics of neural circuits with a special focus on AMPA receptors during the antidepressant action of ketamine as well as the recovery process among patients with treatment-resistant depression. Still, as ketamine is designated as a narcotic, its use is highly regulated. Moreover, challenges of ketamine therapy include a lack of long-lasting effectiveness. If this ongoing study is successfully completed, the results regarding its antidepressant mechanism will be utilized for future development of safer and more effective treatment for depression, i.e. next ketamine. | | | |
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