公募シンポジウム

公募シンポジウム3【脳機能を支える動的な血管システム】

2021/9/30　10:00～12:00　ZOOM C会場 S3-1 「脳の窓」脳室周囲器官を介した脳と全身の情報交換機構 Blood-brain communication in the circumventricular organs ^○竹村晶子¹^,²、石西綾美¹、田中達英¹、辰巳晃子¹、和中明生¹ 1.奈良県立医科大学医学部解剖学第二講座,2.名古屋市立大学大学院医学研究科脳神経科学研究所神経発達・再生医学分野 ^○Shoko Takemura¹^,²、Ayami Isonishi¹、Tatsuhide Tanaka¹、Kouko Tatsumi¹、Kouko Tatsumi¹ 1.Department of Anatomy and Neuroscience, Nara Medical University 2.Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences Circumventricular organs (CVOs) are “windows on the brain” that lack the typical blood-brain barrier. One of the CVOs, the subfornical organ (SFO), rapidly secretes proinflammatory cytokines including interleukin-1β (IL-1β) in response to peripherally administered lipopolysaccharides (LPS), and repeated LPS injection attenuates IL-1β production. We found that LPS accumulated in the perivascular space of the SFO and perivascular monocytes/macrophages secreted IL-1β after systemic LPS administration. When tolerance developed to LPS-induced sickness behavior in mice, the SFO perivascular monocytes/macrophages ceased producing IL-1β, although peripherally injected LPS reached the SFO perivascular space. In another CVOs, the median eminence (ME), corticotropin-releasing factor (CRF) is released into circulation to upregulate the hypothalamic-pituitary-adrenal (HPA) axis. Accumulating evidences indicate that juvenile social stress disrupts adult HPA axis activity. However, the biological mechanisms by which juvenile social isolation influences HPA axis-activity in adult are poorly understood. Results showed juvenile social isolation induced attenuated HPA axis-activity in adult mice in response to acute swim stress. We observed expansion of vascular coverage by tanycytic endfeet and augmented CRF content after forced swim test in the ME of socially isolated mice than in the group-housed mice, suggesting a reduced release of CRF to the portal circulation in response to acute swim stress. Our data suggest that an inhibition of CRF release into the portal vasculature in the ME of socially isolated mice would be the cause of HPA axis hyporesponsiveness of mice exposed to acute swim stress. These data highlight the importance of the proper blood-brain communication in the CVOs.		2021/9/30　10:00～12:00　ZOOM C会場 S3-2 成体神経幹細胞を制御する血管性ニッチ因子 Vascular niche signals that control adult neural stem cells ^○佐藤祐哉¹^,², Jingqiong Hu¹^,³, Tracy L Young-Pearse¹, 新倉貴子⁵, 向山洋介¹ 1.Laboratory of Stem Cell and Neuro-Vascular Biology, National Heart, Lung, and Blood Institute, National Institutes of Health,2.神戸大学大学院医学研究科神経分化・再生分野,3.Stem Cell Center, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,4.Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School,5.上智大学理工学部情報理工学科 ^○Yuya Sato¹^,², Jingqiong Hu¹^,³, Tracy L Young-Pearse¹,Takako Niikura⁵,Yoh-Suke Mukouyama¹ 1.Laboratory of Stem Cell and Neuro-Vascular Biology, National Heart, Lung, and Blood Institute, National Institutes of Health 2.Division of Neural Differentiation and Regeneration, Graduate School of Medicine, Kobe University 3.Stem Cell Center, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology 4.Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School 5.Department of Information and Communication Sciences, Faculty of Science and Technology, Sophia University Neurogenesis persists throughout life in two germinal regions of the adult mammalian brain; one is the ventricular-subventricular zone (V-SVZ) of the lateral ventricle, and the other subgranular zone of the hippocampus. In both neurogenic regions, accumulating evidence supports the idea that vascular niche signals regulate neural stem cell (NSC) quiescence and proliferation. However, the molecular mechanisms by which NSC number is controlled in the neurogenic regions of the adult mammalian brain still remain elusive. To identify vascular endothelium-derived factors involved in the regulation of NSC behavior, we cultured NSCs as neurospheres in the presence of bEND.3 (brain endothelial cell line)-derived conditioned media (bEND.3-CM). We found that bEND.3-CM significantly increase the number but reduce the size of neurospheres without affecting NSC multipotency, suggesting that bEND.3-CM suppress the proliferation of NSCs while maintaining their stemness. Fractionation of bEND.3-CM by heparin-affinity chromatography, followed by liquid chromatography-mass spectrometry, revealed 27 secreted proteins in the bEND.3-CM, some of which significantly affect the proliferation of NSCs in culture. Among them, we focused on soluble amyloid-precursor protein (sAPP). Further in vivo studies on the role of APP in regulating NSC number in the SVZ clearly demonstrate that endothelial deletion of App causes a significant increase in the number of BrdU label-retaining NSCs in the SVZ, whereas NSC/astrocyte deletion of App has no detectable effect on the NSC number. Taken together, these results suggest that endothelial APP functions as a vascular niche signal that negatively regulates NSC growth to control the NSC number in the SVZ.

2021/9/30　10:00～12:00　ZOOM C会場 S3-3 生命を司る血液循環の定量生体イメージング解析 Quantitative intravital image analyses for dynamic blood circulation that captured with nonlinear optical microscopy ^○本藏直樹浜松医科大学医学部医学科医生理学講座,JST さきがけ ^○Naoki Honkura 1.Hamamatsu University School of Medicine, Department of Medical Physiology 2.PRESTO, JST Organisms maintain the cells in their body which are supported by properly transportation of the absorbed nutrients via a blood vessel. The network of blood vessels must be responsible for substance transportation as the only way to provide tons of molecules in the living animals. We visualize blood vessels and tissues in the mouse skin surface, and how nutrients and oxygen are transported from the blood vessels to cells in the organ, which visualized variable intravital metabolic activity in single cells using fast spectrum FLIM imaging with phasor quantitative analysis. Here, we would like to introduce and discuss our system to measure these activities and a part of the result in this meeting.		2021/9/30　10:00～12:00　ZOOM C会場 S3-4 脳血管オプトジェネティクス vascular optogenetics ^○田中謙二慶應義塾大学医学部精神神経科学教室 ^○Kenji Tanaka Keio University School of Medicine An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generated vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. Illumination of channelrhodopsin-2 (ChR2)-expressing mice induced a local reduction in CBF. Photoactivated adenylyl cyclase (PAC) is an optical protein that increases intracellular cyclic adenosine monophosphate (cAMP) and illumination of PAC-expressing mice induced a local increase in CBF. We targeted the ventral striatum, determined the temporal kinetics of CBF change, and optimized the illumination intensity to confine the effects to the ventral striatum. We demonstrated the utility of this vascular optogenetic manipulation in freely and adaptively behaving mice and validated the task- and actuator-dependent behavioral readouts. The development of vascular optogenetic animal models will help accelerate research linking vasculature, circuits, and behavior to health and disease.

2021/9/30　10:00～12:00　ZOOM C会場 S3-5 虚血に誘導される脳血管応答とその制御 Cerebrovascular response and regulation in the ischemic brain ^○宝田美佳,堀修金沢大学医薬保健研究域医学系神経解剖学講座 ^○Mika Takarada-Iemata, Osamu Hori Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences Cerebral blood vessels supply oxygen and nutrients and maintain brain homeostasis. Ischemic stroke caused by blockage of cerebral artery leads to brain dysfunction due to neuronal cell death or damage, and changes in vascular function itself, such as blood-brain barrier dysfunction and angiogenesis. Vascular dysfunction is closely related to the progression of lesion formation, and clinical exacerbation, while angiogenesis has been suggested to contribute to the functional recovery after stroke. Vascular function is thought to be regulated by complex signaling along the pathology under multicellular communication involving vascular cells such as endothelial cells and pericytes, glial cells, neurons and immune cells. However, the detail of spatiotemporal vascular response after cerebral ischemia and underlying mechanisms are not fully understood. Among several angiogenic factors, vascular endothelial growth factor (VEGF) is a key factor to regulate vascular function including angiogenesis and permeability after brain ischemia. Here, we investigated vascular response after permanent middle cerebral artery occlusion using vascular reporter mice expressing fluorescence under the promotor of VEGF receptor (VEGFR)-1 and VEGFR-2. We found that VEGFR-2 expression was increased in ischemic region and VEGFR-2 positive cells showed morphological differences after cerebral ischemia. In this talk, we would like to introduce the current findings and discuss the possible roles of VEGF signaling in vascular remodeling after cerebral ischemia.