Symposium
The Confluence of Multi-modal/Multi-scale Imaging and Brain Science
シンポジウム
マルチモーダル・マルチスケールイメージングと脳科学 |
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| 7月28日（日）10:55～11:25 第6会場（朱鷺メッセ 2F 201A）
4S06a-1
神経変性のマルチスケール・マルチモーダル生体イメージング
Makoto Higuchi（樋口 真人）
量子科学技術研究開発機構
A large subset of neurodegenerative disorders are pathologically characterized by depositions of fibrillar protein assemblies in the brain, as exemplified by neuronal and/or glial inclusions composed of tau and alpha-synuclein. These fibrils contain a beta-pleated sheet as a major secondary structure, which can be captured by small-molecule ligands. Such chemicals capable of binding to tau and alpha-synuclein and amyloid-beta aggregates have been developed initially as fluorescent dyes for neuropathological examinations and recently as imaging agents for visualization of proteinopathies in the brains of living individuals. The fact that most of these compounds exhibit selectivity for a beta-sheet of one molecule versus others (e. g. tau-selective ligands) indicate minor variabilities of beta-sheet structures among pathological fibrils, which can be recognized by specific compounds. Even more subtle structural diversities may also exist among assemblies of tau or alpha-synuclein, leading to different neuropathological and clinical phenotypes of tauopathies and alpha-synucleinopathies. To analyze in-vivo behaviors of the pathological fibril strains, we have recently utilized mice and marmosets modeling accumulations of specific tau and alpha-synuclein species, and have performed intravital two-photon laser microscopic examinations of characteristic aggregates in these animals with a self-fluorescent ligand. Notably, a variety of tau and alpha-synuclein fibril strains differentially present subcellular, cellular and regional localizations, propensity for prion-like cell-to-cell disseminations and neurotoxicity. Along with protein inclusions, neurons, astrocytes and microglia can be separately illuminated with fluorescent proteins in the living brains, revealing microglia-mediated primary phagocytosis of aggregate-bearing but viable neurons and non-phagocytic, cell-autonomous death of neurons. The mode of neuronal loss in each animal model appears to be dependent on the fibril strain. Tau and alpha-synuclein ligands have also been radiolabeled and applied to in-vivo macroscopic positron emission tomography (PET) of the animal brains, demonstrating intimate relationships among protein aggregation, neuroinflammation and regional atrophy. The tau PET radioligands have also been employed for human studies, providing clinical evidence for associations between symptomatic manifestations and disease-specific topology defined by a strain of tau fibrils. | | 7月28日（日）11:25～11:55 第6会場（朱鷺メッセ 2F 201A）
4S06a-2
グリア前駆細胞のマルチモダルイメージング
Yosuke Kataoka（片岡 洋祐）1，Yasuhisa Tamura（田村 泰久）1,2，Satoshi Kume（久米 慧嗣）1,2，Mitsuyo Maeda（前田 光代）1,2，Asami Eguchi（江口 麻美）1,2，Mitsuo Suga（須賀 三雄）2
1理研BDR 細胞機能評価研究チーム
2理研ーJEOL連携センター マルチモダル微細構造解析連携ユニット
We are investigating the physiological and pathological roles of stem cells and progenitor cells in living tissues by using multi-modal imaging methods, including positron emission tomography (PET), in vivo optical imaging, and light and electron microscopy. We produced transgenic rats for PET, bioluminescence and fluorescence imaging of progenitor cells which are expressing chondroitin sulfate proteoglycan 4 (NG2), and clarified whole body-distribution of the cells. Further, we generated transgenic rats for selective ablation of the progenitor cells. Using these techniques, we have established a concept for the first time that glial progenitor cells regulate the neuro-immune system in the central nervous system, in addition to a role as germinal cells giving rise to mature glial cells.
Recently, we have developed a technology to obtain the large-scale microstructural imaging data of biological tissue using a scanning electron microscopy (SEM). The technology brings about imaging big data and realizes comprehensive morphological analyses called ""Micro-morphomics"", one of omics analyses of phenotype. Automatic or semiautomatic analysis of the big data will allow us to discover novel biological events that occur under pathophysiological conditions including aging. Using this new imaging technology, we obtained large-scale SEM images covering all cortical layers (layers I-VI comparable to 1.5-2.0 mm) in the rodent sensory cortex. In the large-scale images, glial progenitor cells were often observed to be closely apposed on neuronal somata. The approximal plasma membrane of glial progenitor cells showed membrane dynamics such as caveolae-like structure with electron-dense membrane, and partial fusion with plasma membrane of neurons, indicating the direct functional interaction between these cells. Further, the large-scale electron microscopic technique revealed the increase in area of heterochromatin in nuclei of glial progenitor cells in aging. These observations might be involved in lower proliferating activity in the progenitor cells and in deterioration of neuro-immune regulation in aged brain. Multi-modal imaging study will bring about comprehensive understandings in neuroscience. | | 7月28日（日）11:55～12:20 第6会場（朱鷺メッセ 2F 201A）
4S06a-3
Translational PET Neuroimaging
Christer Halldin（Halldin Christer）
Karolinska Institutet
PET provides a new way to image the function of a target in a translational way from mouse to man, and by elevating the mass, to pharmacologically modify the function of the target. The main applications of PET radioligands in brain research concern human neuropsychopharmacology and the discovery and development of novel drugs to be used in the therapy of psychiatric and neurological disorders. A basic problem in PET brain receptor studies is the lack of useful radioligands with ideal binding characteristics. Prerequisite criteria need to be satisfied for a radioligand to reveal target binding sites in vivo. Molecular biological techniques have now revealed the existence of hundreds of novel targets for which little or no prior pharmacological or functional data existed. Most of the currently used drugs for the treatment of psychiatric and neurological disorders interact with central neurotransmission. Several receptor subtypes, transmitter carriers, and enzymes have proven to be useful targets for drug treatment. Due to the lack of data on the functional significance of these sites, pharmacologists are now challenged to find the physiological roles of these receptors and identify selective agents and possible therapeutic indications. This presentation will review recent examples in translational PET neuroimaging from rodent to humans including radioligand development but also for drug development with focus on the collaboration between academia and pharma. Drug research now benefits from the fast development of functional imaging techniques such as PET or PET-MR. | | 7月28日（日）12:20～12:50 第6会場（朱鷺メッセ 2F 201A）
4S06a-4
統合的マルチモーダルイメージングによる疲労・慢性疲労の分子神経メカニズム
Yasuyoshi Watanabe（渡辺 恭良）
理研RCH+BDR健康病態科学
Integrated multi-modal imaging technologies with Omics analyses and precise biomarker analyses give us the chance to create Precision Medicine and Precision Health. Especially, PET technologies open up a new era of 4-dimentional analyses of molecular events in human body. PET molecular imaging technologies in combination with functional and anatomical imaging with MRI and MEG make a breakthrough in total understanding of human dysfunction such as fatigue and chronic fatigue (Ref. 1). We focused on the multi-modal imaging studies on fatigue and chronic fatigue, even on the patho-physiology of the patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), those of which could promote the correlation studies among morphological changes in the lateral prefrontal cortex, deactivation of task-dependent and task-independent sensory system, neuro-inflammation and serotonergic deterioration. Such pathophysiological changes maybe intermediated through biological oxidation, less repair energy from oxidation, and local inflammation/immune responses, those of which might be resulted in autonomic nerve dysfunction (2, 3), caused through the molecular changes in neurotransmitter systems and cytokine systems, and then functional deterioration in the brain.
Ref.
1.Watanabe Y, Evengard B, Natelson BH, Jason LA, Kuratsune H. eds. Fatigue Science for Human Health, Springer, 2008.
2.Watanabe, Y., Kajimoto, O., Kuratsune, H.: Biochemical indices of fatigue for anti-fatigue strategies and products. In: Matthews G, et al. (eds), The Handbook of Operator Fatigue. Ashgate Publishing Limited, Great Britain, pp. 209-224, 2012.
3.Tanaka M, Tajima S, Mizuno K, Ishii A, Konishi Y, Miike T, Watanabe Y. Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder. J Physiol Sci., 65:483-98, 2015. | |
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