成体ニューロン新生 Adult Neurogenesis
O3-7-2-1 軟髄膜の神経前駆細胞は錐体神経細胞と非錐体神経細胞を生産し成体新皮質の再生に働く Neuron progenitors in the leptomeninges give rise to both pyramidal and nonpyramidal neurons for the adult neocortex ○玉巻伸章1, 晶朕1,2, 二宮省吾1, 福田孝一3, 明石馨4, 崎村建司4, サンドラゴベル5, クラウスアーミンナーベ5, 那須信1, 江角重行1, 富岡良平1 ○Nobuaki Tamamaki1, Jing Chen1,2, Shogo Ninomiya1, Takaichi Fukuda3, Kaori Akashi4, Kenji Sakimura4, Sandra Goebbels5, Klaus-Armin Nave5, Makoto Nasu1, Shigeyuki Esumi1, Ryohei Tomioka1 熊本大院・生命科学・脳回路構造1, 第4軍医大学・解剖学2, 熊本大院・生命科学・形態構築3, 新潟大・脳研・細胞神経生物4, マックスプランク　分子生物5 Dept Morphological Neural Sci, Kumamoto Univ, Kumamoto1, Dept of Anatomy, Fourth Military Medical Uni, Xi'an, China2, Dept of Anatomy and Neurobio, Kumamoto Univ, Kumamoto3, Dept of Cellular Neurobio, Brain Research Inst, Niigata Univ, Niigata4, Molecular bio, Max Planck Inst, Göttingen Germany5 Dentate gyrus and subventricular zone of the telencephalon have been regarded as unique sites where neurogenesis continues even after birth. However, here, we report new progenitors which add new neurons to the adult neocortex. Since various stress seems to initiate phenomena related to neurogenesis in the adult neocortex, we induced kindling, a kind of stress in mice brains by electrical stimulation of the amygdala. Then we examined progenitor markers and neuron markers in the neocortex comprehensively. We found granule cells in the leptomeninges express c-fos in an hour, nestin in a day, GAD67 or NeuroD6/NEX in a few days, and finally Tuj1 in a week. Some of the granule cells express FoxP2 or Brn1. According to the markers, the granule cells seem to originate in the VZ of the ganglionic eminence or in the VZ of the pallium. To reveal their origin, we introduced GFP or Fucci-G Cre-reporter plasmids to GAD67-Cre and NeuroD6/NEX-Cre mice, and found a fraction of the tangentially migrating cells and the radially migrating cells penetrate the pia mater. Then the granule cells remain dormant in the leptomeninges. Since there were no axons penetrating basal lamina, the granule cells would detect stress in the brain by transmitters or growth factors released from the parenchyma of the neocortex. We also traced the fate of the GAD67-positive granule cells and the NeuroD6/NEX-positive granule cells by injecting RCAS-GFP simple retrovirus into the subarachnoid space of GAD67-Cre/tvA mice and NeuroD6/NEX-Cre/tvA mice. Then, we found GFP-positive nonpyramidal neurons or pyramidal neurons in the neocortex. Here, we conclude that the granule cells in the leptomeninges produce new neurons for the adult neocortex after severe stress. The information of the granule cells will be indispensable to establish therapeutic treatment for Alzheimer's disease or mental disorders.	O3-7-2-2 成体マウス脳において移動する新生ニューロンの形態制御による嗅球細胞層の選別メカニズム Morphological regulation of migrating new neurons by Sema3E-PlexinD1 signaling determines the final destination layers within the olfactory bulb ○澤田雅人1, 黄詩恵1, 匹田貴夫1, 植村明嘉2, 澤本和延1 ○Masato Sawada1, Shih-hui Huang1, Takao Hikita1, Akiyoshi Uemura2, Kazunobu Sawamoto1 名古屋市大・医・再生医学1, 神戸大・医・血管生物学2 Dept Dev and Regen Biol, Nagoya City Univ Grad Sch of Med Sci, Nagoya, Japan1, Div. Vascular Biol., Kobe Univ Grad Sch of Med, Kobe, Japan2 In the postnatal brain, new neurons are continuously generated in the ventricular-subventricular zone and migrate toward the olfactory bulbs (OB). After arriving at the OB, each new neuron starts to migrate radially and differentiates into one of two types of olfactory interneurons, granule and periglomerular cells, located in the granule and glomerular layers, respectively. However, the mechanisms that determine the final destination layers of new neurons in the OB remain unclear. Here, we studied the function of Semaphorin3E (Sema3E)-PlexinD1 signaling in the migration of new neurons in the OB. We showed that expression of PlexinD1, the receptor for Sema3E, is downregulated in migrating granule cells but maintained in migrating periglomerular cells. To examine the role of Sema3E-PlexinD1 signaling on the cytoskeletal regulation of migrating neurons, we performed in vitro timelapse imaging. Migrating neurons occasionally formed F-actin-riched lateral processes branched from the leading process. We found that Sema3E suppressed the formation of lateral process without affecting the leading process, thereby supporting the maintenance of bipolar morphology in migrating neurons. FRET imaging using Raichu-Rac1 probe revealed that Rac1 activity is transiently increased at the branching point of lateral processes, which is suppressed after Sema3E addition. Furthermore, the effect of Sema3E on the lateral process formation and Rac1 activation was canceled by plxnd1 knockdown. These results suggest that Sema3E-PlexinD1 signaling determines the final destination layers of new neurons in the OB by regulating their migratory morphology.
O3-7-2-3 活性化アストロサイトとの相互作用による新生ニューロンの移動経路制御機構 New neurons regulate Robo signaling in activated astrocytes to clear the path for their migration in the injured striatum after ischemic stroke ○金子奈穂子1, 澤本和延1 ○Naoko Kaneko1, Kazunobu Sawamoto1 名古屋市大院・医・再生医学1 Dept Developmental and Regenerative Biol, Nagoya City Univ, Nagoya1 New neurons generated in the ventricular-subventricular zone (V-SVZ) migrate rapidly for a long distance in the adult brain. During their migration, the new neurons move inside the astrocytic tunnels toward the olfactory bulb. We have previously demonstrated that new neurons control the morphology of surrounding astrocytes to form and maintain the tunnel structure. This cell-cell interaction mechanism is mediated by Slit1, a diffusible protein secreted by new neurons, and Robo, its receptor expressed by astrocytes. On the other hand, V-SVZ-derived new neurons migrate toward injured area after ischemic stroke through the dense meshwork of activated astrocytes, which is considered to inhibit neuronal regeneration. We found that the new neurons in the injured striatum express Slit1, and that activated astrocytes strongly express Robo receptor. Both Slit1-knockout in new neurons and Robo-knockdown in activated astrocytes inhibited neuronal migration and disrupted intimate association between the new neurons and astrocytes in injured striatum. Using time-lapse recording of new neurons and astrocytes in the brain slices after ischemic stroke, we found that these astrocytes actively changed their morphology when they made contact with migrating new neurons. FRET imaging of cultured cells revealed that new neurons caused activation of Cdc42, a Rho family small G-protein, and actin depolymerization, at the contact site in astrocytes, which was dependent on new neuron-derived Slit1. Moreover, Slit1-overexpression in new neurons promoted their migration in association with astrocytes. Taken together, these observations suggest that the Slit-Robo signaling-mediated interaction of the new neurons with activated astrocytes facilitates their migration toward the injured area.	O3-7-2-4 Reduced adult neurogenesis and neuronal abnormalities in the hippocampus underlie cognitive deficiency following prenatal administration of the antiepileptic drug valproic acid ○Berry Juliandi1, Kentaro Tanemura2, Katsuhide Igarashi2, Yusuke Furukawa2, Maki Otsuka2, Takashi Tominaga3, Masahiko Abematsu1, Tsukasa Sanosaka1, Keita Tsujimura1, Jun Kanno2, Kinichi Nakashima1 Laboratory of Molecular Neuroscience, Nara Institute of Science and Technology1, Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan2 Histone deacetylases (HDACs) are the chromatin modifiers that can epigenetically regulate neural stem cells (NSCs) fate choice. Activity of HDACs can be altered by chemicals such as valproic acid (VPA), a widely used antiepileptic drugs (AED), which recently has been shown to have an HDACs inhibition properties. Prenatal exposure to VPA has been reported to impair postnatal cognitive function of children from epileptic mother. Nevertheless, its pathology and proper treatment to minimize the effects are remain unknown. We have previously reported that VPA promotes neuronal differentiation of several NSC types. Here we report that prenatal exposure of VPA to mouse embryo during prominent neurogenic phase also resulted in an enhancement of embryonic neurogenesis. At their adult stages, VPA-treated mice showed cognitive function impairment which largely attributable to a reduction of adult neurogenesis and neuronal abnormalities in the hippocampus, of which could be ameliorated by voluntary running. Our findings suggest that the impairment of cognitive function in children from epileptic mother is plausibly attributable to a reduction of adult neurogenesis and neuronal abnormalities in hippocampus. Although prenatal exposure to AED such as VPA could have persistent effects until adulthood, however, it could be recovered by simple physical activity such as voluntary running.

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