日本神経化学会-国際神経化学会ジョイントシンポジウム
Neurogenesis and its role in brain development and repair
ニューロン新生：脳の発達・修復における役割 |
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| 3E-JSN/ISN-1
Migration of new neurons for maintenance and repair of adult brain
澤本 和延1,2
1名古屋市立大学大学院医学研究科再生医学分野，2自然科学研究機構生理学研究所神経発達・再生機構研究部門
Neuronal migration is an important process in brain development and homeostasis, which occurs in the adult brain, not only in the embryonic brain. In fact, throughout life, new neurons are continuously generated by adult neural stem cells in the ventricular-subventricular zone（V-SVZ）and migrate towards the olfactory bulb through the rostral migratory stream. The neural stem cells in the V-SVZ have the capacity to partially regenerate neurons after various insults. After ischemic stroke in rodents, the V-SVZ-derived new neurons migrate from the V-SVZ towards the injured sites along blood vessels wrapped by astrocytes. Neuron-astrocyte interaction mediated by Slit-Robo signaling is critical for efficient neuronal migration in both physiological and pathological conditions. Laminin-integrin signaling facilitates the chain migration of new neurons along the blood vessel scaffold. Transplantation of laminin-rich porous sponge promotes the migration of new neurons towards the injured brain tissue, suggesting that artificial blood vessel-like scaffold may enhance neuronal regeneration. | | 3E-JSN/ISN-2
Conserved serotonergic projections govern postnatal neuroblast migration in vertebrates
Khodosevich Konstantin
Biotech Research ＆ Innovation Centre（BRIC）, University of Copenhagen
The ventricular（VZ）and subventricular zones（SVZ）are the major neurogenic niches in the brain that continue to generate new neurons after birth not only in mammals, but also in non-mammalian vertebrates. Postnatally-generated neurons often migrate long distance from the VZ/SVZ to reach their final destination where they help shape local circuit activity. For instance, in rodents postnatally-generated neurons regulate olfactory information processing that animals receive from environment, whereas in birds postnatally-generated neurons are required for vocal learning. Such long-distance migration（up to several cm）requires precise coordination by extracellular guiding cues that should provide both trophic support and directionality of migration. Here we show that all studied streams of postnatally generated neuroblasts in vertebrate brains are innervated by serotonergic projections. We found serotonergic fibers projecting along the streams of migrating neuroblasts not only in mammalian brains（mouse, rhesus monkey and human）, but also in bird（zebra finch）and fish（zebrafish）brains. Using mouse as a model organism to study involvement of serotonin in postnatal neuroblast migration, we showed that in vivo gene ablation or overexpression of serotonin receptor 3A modulated directionality and speed of migrating neuroblasts. Furthermore, 5HT3A receptors were absolutely necessary to trigger large calcium spikes in migrating neuroblasts, and calcium transients promoted neuroblast migration. Finally, stimulating serotonergic axons from the raphe nucleus by optogenetics, we showed that serotonin release enhances speed of neuroblast migration and this enhancement was abolished by knockout of 5HT3A receptors in neuroblasts. | | 3E-JSN/ISN-3
Zebrafish as a model of analysis of regulatory mechanism of adult neurogenesis
大島 登志男
早稲田大学先進理工生命医科
Adult neurogenesis is a phenomenon that neural stem cells（NSCs）produce new neurons and glia in the adult brain. In zebrafish have 16 NSCs niches and can continue to produce new neurons through life. In the optic tectum where optic nerves project, neuroepithelial-like cells in the dorsomedial margin of the perventricular gray zone（PGZ）have the property of NSCs. Radial glia cells（RGCs）in the deeper layer of PGZ expressing several stem cell markers are quiescent, while RGCs in the telencephalon are proliferative and work as NSCs. Our pharmacological experiments revealed that several signaling pathways regulate proliferation of neuroepithelial-like NSC in optic tectum of adult zebrafish. Our recent experimental data suggest inflammation activates quiescent RGCs to produce new neurons in optic tectum as reported in telencephalon. Since inflammation suppresses proliferation of NSCs in mouse brain, opposite reaction of NSC proliferation is unique in adult zebrafish brain. Understanding of this uniqueness will be useful to provide a new insight to contribute neural regenerative medicine. | | 3E-JSN/ISN-4
Exercise-induced hippocampal neurogenesis and antidepressant effects：Essential role of the 5-HT3 receptor
近藤 誠
大阪大学大学院医学系研究科 神経細胞生物学講座
Exercise causes a variety of effects on the animal brain at many levels. At the cellular level, exercise enhances hippocampal neurogenesis. At behavioral level, exercise induces antidepressant effects and improves learning behavior. Brain serotonin（5-hydroxytryptamine, 5-HT）levels increase following exercise, and the serotonin system has been suggested to play an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient（htr3a-/-）mice revealed that lack of the 5-HT type 3（5-HT3）receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. Our findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is essential for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that plays a fundamental role in exercise-induced morphological changes and psychological effects. | | 3E-JSN/ISN-5
Remodeling the adult hippocampal neurogenic niche：coupling between newborn cell apoptosis and microglial phagocytosis
Sierra Amanda
Achucarro Basque Center for Neuroscience
In the adult hippocampus, the vast majority of newborn cells naturally undergo apoptosis in two critical periods of survival, which are maintained across adulthood from 1mo to 12mo. Up to 40-50% of the newborn cells are lost in the main critical period, in the first 2-4 days of cell life. However, apoptotic newborn cells are rarely detected because they are rapidly and efficiently phagocytosed by“resting”or“unchallenged”microglia that is present in the niche. Microglial phagocytosis is tightly coupled to apoptosis in physiological conditions as well as during inflammation and excitotoxicity. In contrast, the hyperactivity of the hippocampal network in a mouse model of temporal lobe epilepsy induced by intrahippocampal administration of kainic acid disturbs the microgradients of the apoptotic cell“find-me”signal ATP, and impairs microglial phagocytosis. As a result, the number of apoptotic newborn cells increases without altering the number of surviving newborn cells, suggesting that seizures do not induce de novo apoptosis of newborn cells but rather that the impairment of microglial phagocytosis leads to an increased clearance time and the accumulation of non-phagocytosed apoptotic cells. In summary, our data shows that microglial phagocytosis efficiency is essential to determine the dynamics of newborn cell apoptosis in the adult neurogenic niche in health and disease. | | | |
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