Symposium 7
Have the research minds of the physician-scientists evolved to promote psychiatric research?
シンポジウム7
基礎研究で活躍する精神科医の魂は進化したのか？ |
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| SY7-1
Multi-hierarchic functional connectomics for the psychiatric model animals
精神疾患の神経回路異常の解明にむけた多階層コネクトミクス法の開発
Hayashi-Takagi Akiko（林（高木） 朗子）
Lab of Medical Neurosci, Gunma Univ, Gunma, Japan
The dysregulation of dendritic spines is thought to be involved in a variety of psychiatric disorders, but the links between spines and disorders have been largely correlational because of lacks of a technique for manipulating individual spine. To overcome this problem, we developed a synaptic optoprobe, AS-PaRac1, which is unique not only because it can specifically label the recently potentiated spine, but can also selectively induce shrinkage in just those spines containing AS-PaRac1 (Hayashi-Takagi et al, 2015, Nature). We here aim at the next-generation of AS-PaRac1 imaging. By simultaneous three color imaging of a synaptic activity-dependent expression of the presynaptic marker Vamp2-mTurquoise2, the postsynaptic neuron markers tdTomato, together with AS-PaRac1-mClover, we aim to visualize the potentiated neuronal circuits. To identify the ideal probe with a proper temporal regulation, candidate fluorescence probes were injected into the unilateral visual cortex, and mice were dark reared for 2 d, being followed by short light stimulation. We then systematically compared each probe by visualize the fluorescence in the injected hemisphere as well as axonal terminals in the contraipsilateral visual cortex so that we characterized the extent of the expression, transport throughout neurites, and protein degradation of each probe. With this tool, the visualization of neuronal circuits with synaptic potentiation (micro imaging) among three brain regions (macro imaging) become feasible. This multi-hierarchic connectomics will lead to a quantitative understanding of how the disease model animals are different from normal control, eventually providing the insight into the pathophysiology of the psychiatric disorders. | | SY7-2
Cytoskeleton-based transport of neurotransmitter receptors and animal models of neuropsychiatric diseases
細胞骨格による神経伝達物質受容体輸送と精神神経疾患動物モデル
Takei Yosuke（武井 陽介）
Dept. Anat. Neurosci. Med. Univ. of Tsukuba
Neurons make a neural network and communicate each other via their synapses. Synaptic accumulation of neurotransmitter receptors is necessary for efficient neurotransmission. A series of molecular motor proteins supports synaptic functions by transporting various receptors on microtubules. A member of kinesin-related protein KIF17 transports NMDA receptor subunit 2B in dendrites. KIF17 is essential for neuronal plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Lack of KIF17 resulted in spatial and fear memory disturbances in mice. Transport of NMDA receptors is regulated by phosphorylation and CREB-mediated upregulation of motor and cargoes in an activity-dependent manner. Another member of kinesin-related protein KIF5A transports GABA(A) receptors to synapse via its specific interaction with GABARAP, and KIF5A deficient mice develop epileptic seizures because of impairment in inhibitory synaptic transmission. Thus, excitatory and inhibitory synaptic transmission is controlled by activity of molecular motors. Recently, several lines of evidence suggest that these molecular motors are involved in the pathogenesis of neuropsychiatric and neurodegenerative diseases. Human Genomic and postmortem studies suggest a relationship of KIF17 with schizophrenia. KIF5A has been shown to be responsible for the pathogenesis of axonal neuropathy. In this presentation, I will discuss about a possible animal model of neuropsychiatric diseases, especially a primate model, which is based on the deficient transport of neurotransmitter receptors. | | SY7-3
Biological Psychiatry in Institute for Protein Research
蛋白質研究所での生物学的精神医学研究
Hikida Takatoshi（疋田 貴俊）
Institute for Protein Research, Osaka University
In the previous “Tamasii” symposium in 2016, I presented my research, entitled “From neuronal circuit to pathology of mental disorders” about translational research at Medical Innovation Center, Kyoto University graduate School of Medicine. In 2017, I moved to Institute for Protein Research, Osaka University and started a new lab as the Laboratory for Advanced Brain Functions in the Division of Integrated Protein Functions. I will present the research of biological psychiatry in this new laboratory with staffs and students who have different academic backgrounds. | | SY7-4
Progress in establishment and analysis of mouse models of neurodevelopmental disorders
マウスにおける神経発達障害モデルの作成と解析における進化
Kubo Ken-ichiro（久保 健一郎）
Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
The neurodevelopmental hypothesis of schizophrenia is one of the dominant paradigms for neuropsychiatric research. Moreover, recent genetic studies have suggested a pathological overlap between schizophrenia and other neurodevelopmental disorders, such as autistic spectrum disorders and intellectual disability. These findings indicate the neurodevelopmental aspects of neuropsychiatric disorders and highlight the importance of basic studies of neurodevelopment. Here, the author presents a series of studies that were performed to clarify the pathophysiology of neuropsychiatric disorders. In these studies, we focused on neuronal migration as a fundamental step of brain development. Genetic and environmental factors that are presumed to cause neuropsychiatric disorders were shown to produce deficits of neuronal migration and abnormal cytological architecture in the neocortex of the brain. Abnormal cytological architecture has been pointed out as one of the microscopic pathological findings in the brains of patients with neuropsychiatric disorders. The pathological mechanisms of the abnormal cytological architectures with ectopic neurons will be discussed. | | SY7-5
Computational psychiatry: understanding psychiatric disorders using computational modeling
計算論的精神医学：脳の数理モデルを用いて精神疾患の病態に迫る
Yamashita Yuichi（山下 祐一）
Department of Functional Brain Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
Computational psychiatry is a new research field which seeks to understand mental disorders as aberrant computation by using mathematical modeling of information processing in the brain. Thanks to some exciting discoveries in computational neuroscience that addressed underlying neurobiology of cognitive function, expectations for the contributions of computational approach to psychiatric disorders have been increasing. In recent years, since use of mathematical models in the scientific research, such as machine learning, artificial intelligence and data science (big-data), has become popular, it has got easier to obtain cooperation for the studies of psychiatry from researchers with mathematical and theoretical backgrounds. However, that is especially, involvements of psychiatrist with clinical experiences and sophisticated expertise of psychiatric symptomatology and psychopathology are vital for the studies of computational psychiatry. In this presentation, in order to encourage involvements of young psychiatrists in computational psychiatry, I will introduce how a clinical psychiatrist without any experiences of basic research and mathematical/theoretical background has struggled with the studies of computational neuroscience/psychiatry, including neural network modeling of cognitive functions and robotic models of psychiatric disorders. | | SY7-6
A thought for dissection of "disease" from "disorder" through genomic studies, resurgence
シン・ゲノム研究でDisorderをDiseaseにする試み
Takata Atsushi（高田 篤）
Department of Human Genetics, Yokohama City University Graduate School of Medicine
2014年、人類はDSMに基づいて統合失調症という「disease（似たような症状と社会機能の障害によって定義される病態不明の疾患単位）」と診断される一群のごく一部が、ヒストンメチル化酵素をコードするSETD1Aの機能喪失変異によって定義される「disorder（既知の病因に基づく疾患単位）」であることを明らかにした（この結果は、より大規模な研究によって2016年に確認された）。この発見を端緒としたシン化戦略として、2年前の魂シンポジウムにおいて演者は、1）ゲノム変異によって定義されるDisorderのさらなる同定と臨床への還元、2）ゲノムデータとMolecular phenotypeの統合的解析、3）構成妥当性が高い疾患モデルの作成と解析、を成長の三本柱として提唱した。それから時が流れ、果たして研究は進化したのか、深化したのか、退化したのか、老化したのか。その成果と困難について、演者が携わらせていただいた研究（Takata et al., Nature Communications 2017、Takata et al., Cell Reports 2018）を交えながら報告したい。 | | SY7-7
What kind of intracellular signals are controlled by the antipsychotics in the brain?
統合失調症治療薬は脳内でどのような細胞内シグナルを制御しているのか？
Kuroda Keisuke（黒田 啓介）
Dept. of Cell Pharmacology, Nagoya Univ. Grad. Sch. of Med.
Antipsychotics, which are known to act as antagonist of dopamine D2 receptor (D2R), are used for the treatment of schizophrenia. However, detailed intracellular signals of antipsychotics are still unknown.Recently we reported dopamine type 1 receptor (D1R) signals (Nagai et al. 2016 Neuron) and dopamine type 2 receptor (D2R) signals (Zhang et al. 2018 in press) in the nucleus accumbens using several unique antibodies that detect protein phosphorylation. Although antipsychotics act on various parts of the brain, it is believed that symptoms such as hallucinations and delusions are ameliorated, especially by suppressing the function of D2R in the nucleus accumbens. Protein kinase A (PKA) and mitogen activated protein kinase (ERK) are thought to exist downstream of the D1R/D2R signal, but the activity change of these kinases accompanying administration of antipsychotic drugs has not been well investigated in cell type specifically.In this symposium, I introduce recent our studies and want to discuss what kind of intracellular signals are controlled by the antipsychotics in the brain. | | SY7-8
Think about what you can do to recruit young people from our experiences
若手をリクルートするためにできることを実体験から考えてみる
Mizutani Shunsuke（水谷 俊介）1,2
1Department of Neuropsychiatry the University of Tokyo
2Department of Cellular Neurobiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo
I underwent psychiatric training and knocked on the gate of the basic laboratory. Currently I am studying schizophrenia as a graduate student. From the standpoint of young people, I would like to concretely talk about what helped me when I was hesitant to jump into basic research, and what the junior strayers are talking to me now. In addition, recent advances in technology have made it possible to observe the neural activity of animals alive at the synaptic level. By introducing actual research content, I would like to also tell you the interestingness of basic research. | | SY7-9
Basic research on brain development conducted by a PhD student trained as a psychiatrist
精神科医でもある大学院生が行っている神経発生研究
Yoshinaga Satoshi（吉永 怜史）
Department of Anatomy, Keio University School of Medicine, Tokyo, Japan
I am a psychiatrist and PhD student studying developing cerebral cortex. I studied it when I was a medical student as well. After two-year general internship and two-year psychiatry residency, I decided to restart my experimental research career to dedicate myself to basic work that addresses the whole picture of cortical development. In the developing cortex, neurons are born in the ventricular zone (VZ) and subventricular zone (SVZ), and migrate toward the pial surface to form the well-organized gray matter. It is proposed that abnormal cytoarchitecture caused by defective neuronal migration is one of the biological substrates of some neuropsychiatric disorders. Given that different cortical areas have distinct pathophysiological significance, I hypothesized that there exist significant areal differences in migratory profile or its vulnerability to disturbance. Here I used the FlashTag technology (FT), in which dyes were injected into the ventricle, to visualize neuronal migration in various cortical areas in parallel. I labeled mouse brains at various embryonic stages and fixed chronologically. I observed clear migratory differences of neurons born at embryonic day 13.5-15.5 between different areas of cortex even where there is underlying ventricular surface. This was not clear in brains labeled earlier and later. Previous studies using thymidine analogues failed to detect such differences, suggesting the strength of FT in labeling migrating cells of different areas. Further preliminary analyses are shedding light to an extracellular environment (for migrating neurons) that is associated with this difference and that itself has psychiatric correlation. I hope that this work metamorphoses into the most basic study with clinical implication some day. | | SY7-10
Can we optimally allocate research and clinical efforts?
研究と臨床へのエフォートは最適配分できるのか
Tamune Hidetaka（田宗 秀隆）1,2
1Dept. of Cellular Neurobiology, Grad. Sch. of Med., The Univ. of Tokyo
2Tokyo Metropolitan Tama Medical Center
For young psychiatrists interested in basic research, optimizing time allocation to address basic science and enhance the clinical experience is challenging. Furthermore, this situation is made more difficult by the need to accommodate the demands of private life.
I entered graduate school after five years of clinical experience including my junior residency. As a result, I was able to obtain board certificate and designated physician of mental health. In other words, I obtained a "specialty" as an external standard.
On the other hand, an expert psychiatrist with 50 years of experience may regard himself as clinically inexperienced. As an internal standard, how we each see our own expertise seems to depend on how much clinical experience we consider adequate or satisfactory.
Since optimizing the allocation of time prospectively is challenging, I believe that psychiatrists need to go through their residency guided by their own values or standards (through generating their own internal criteria). This perspective would be useful for weekly scheduling in graduate school.
Most of the psychiatrists I know are happily walking along the path of "their choice"; I am grateful to be part of this culture that is both diverse but bound by a common aim. | |
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