公募シンポジウム１１：健康な脳機能を支える脳内ロジスティクス
Symposium11 : Logistics in the neuron-glia vascular network |
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| 2020/9/11 15:10～15:33 Zoom B
SY11-01
健康な脳機能を支える脳脊髄液の流れ
Cerebrospinal fluid flow keeping brain ion homeostasis
*毛内 拡1
1. お茶の水女子大学
*Hiromu Monai1
1. Ochanomizu University
Cerebrospinal fluid (CSF) flow plays an essential role in keeping brain homeostasis and maintenance of the extracellular environment. We have investigated the involvement of brain water channel aquaporin 4 (AQP4) in the infiltration of CSF into the brain parenchyma (Mestre et al., 2018, eLife).
Ischemic stroke induces the retention of CSF flow, i.e., brain edema. It has been reported that recurrent propagating waves of abnormal neural excitability, i.e., spreading depolarization (SD) is related to the expansion of the edema during a hyper-acute phase of the incident. Since a sharp increase of extracellular potassium ion concentration ([K+]ext) usually triggers SD, we aim to develop the treatment to normalize [K+]ext as soon as possible.
The dynamics of CSF have been shown to depends on the noradrenaline of the brain, and adrenergic receptor (AdR) antagonism facilitates CSF infiltration into the brain parenchyma (Xie et al., 2013, Science). It is well known that ischemia induces a sharp increase in noradrenaline. Therefore, we hypothesized that the facilitation of CSF dynamics by AdR antagonisms would accelerate the normalization of [K+]ext through the exchange of stagnating ISF with fresh CSF.
Using photothrombotic stroke model mice, we have shown that the AdR blockade accelerates the normalization of [K+]ext, resulting in faster recovery of neural activities and less infarct area. Besides, the AdR blocker treatment preserved AQP4 polarization, although the signals rapidly diminished in untreated control mice in 1-2 hours. Whereas, AQP4 knock-out mice and mice with acute AQP4 blocker did not show any positive effect of AdR antagonisms. Our observation suggests that the facilitation of CSF flow could induce rapid K+ clearance (Monai et al., 2019, PNAS).
| | 2020/9/11 15:34～15:54 Zoom B
SY11-02
MRSでみるLactateの流れの淀みと脳疾患
Impaired Lactate Utilization in brains of Tauopathy observed by Magnetic Resonance Spectroscopy
*高堂 裕平1
1. 量子科学技術研究開発機構
*Yuhei Takado1
1. National Institutes for Quantum and Radiological Science and Technology
Recent evidence has shown that lactate has essential roles in the brain under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Under physiological conditions, lactate is considered to be transferred from astrocytes to neurons to match neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. Despite the importance of lactate for brain function under physiological conditions, the roles of lactate in brain diseases remain largely unknown. In this work, we utilized a non-invasive imaging modality, magnetic resonance spectroscopy (MRS), to clarify the association between lactate concentration changes and brain dysfunction of brain disorders, and especially tauopathy, which is known to have abundant phosphorylated abnormal tau protein accumulation in brain, resulting in cognitive impairment. We performed MRS in progressive supranuclear palsy (PSP) patients and a tauopathy mouse model (rTg4510) to investigate the involvement of lactate metabolism in the disease mechanism. The results demonstrated high lactate concentrations in the brains of PSP patients and rTg4510 mice compared to healthy controls and wild-type mice, respectively, suggesting impaired lactate metabolism in tauopathy. Moreover, the levels of glycogen in rTg4510 mice were altered, suggesting that astrocyte dysfunction could be associated with high lactate concentrations in rTg4510 mice. This presentation demonstrates that lactate has significant roles in diseased brain, and MRS would be a powerful modality to detect such findings noninvasively.
| | 2020/9/11 15:55～16:15 Zoom B
SY11-03
睡眠覚醒に伴う神経細胞内ATP動態とその制御機構
In vivo state-dependent dynamics of cortical neuronal intracellular ATP levels
*夏堀 晃世1
1. 公益財団法人東京都医学総合研究所
*Akiyo Natsubori1
1. Tokyo Metropolitan Institute of Medical Science
The brain is assumed to exert homeostatic functions to keep the cellular energy status constant under physiological conditions, however, this has not been experimentally proven. We conducted in vivo optical recordings of adenosine 5'-triphosphate (ATP), the major cellular energy metabolite, using a genetically-encoded fluorescent probe (ATeam: Imamura et al., 2009, PNAS) in the physiological mouse brain. We demonstrate that intracellular ATP levels in cortical excitatory neurons fluctuate in a cortex-wide manner depending on the sleep-wake states, correlating with arousal in animals. Interestingly, the ATP levels profoundly decreased during rapid eye movement sleep, suggesting a negative energy balance in neurons despite a simultaneous increase in hemodynamics for energy supply. Our preliminary data show that the state-dependent global dynamics of intracellular ATP levels in cortical neurons could be brought about by astrocyte-neuron lactate shuttle, regulated by the brain monoaminergic systems, in terms of brain metabolic activities for ATP production.
| | 2020/9/11 16:16～16:30 Zoom B
SY11-04
グルコースロジスティクス障害を伴う脳毛細血管障害は新たな精神疾患の指標となりうるか
Brain angiopathy and impaired glucose metabolism in model mice with psychiatric-Related phenotypes
*平井 志伸1
1. 東京都医学総合研究所
*Shinobu Hirai1
1. Tokyo Metropolitan Institute of Medical Science
There has been a remarkable increase in intake of simple sugar (sucrose, isomerized sugar (corn syrup)) from beverages and diets in modern society. Doesn't an excessive intake of simple sugar affect higher brain function? The intake of simple sugars in adolescents in which mental disorders frequently occur is higher than any other generations.
In human study, it is difficult to distinguish whether it is one of the symptoms that is a consequence of disease or it may be a causative factor for disease development. Therefore, we attempted to elucidate this causal relationship.
As a susceptibility gene for psychiatric disorder, we selected Glyoxylase-1(GLO1), which has SNP mutations with reduced function and reduced expression in various psychiatric disorder (e.g. schizophrenia or bipolar disorder). By combining the heterozygous mice with environmental factors of excessive sugar intake at the age of puberty, we successfully created a novel mouse model exhibiting various mental disorder-like symptoms. In other words, this demonstrates a possibility that the excessive intake of simple sugar at the age of puberty could be a new environmental risk factor of mental disorders.
Moreover, by analyzing this model mouse, we aimed to identify the new phenotype and mechanism of developing mental disorder. We found “cerebral microvascular angiopathy”. In order to verify the generality of this finding, we used a post-mortem brain from patients with schizophrenia and bipolar disorder, and identified angiopathy similar to the one seen in the model mice. We also found that the angiopathy was accompanied by an impaired glucose logistics to brain parenchyma in our mice model.
The patients used in this study do not necessarily have a record of excessive sucrose intake. They developed psychiatric disorders under various stress circumstances and, which indicates that a variety of environmental stresses could converge to induce angiopathy in these patients.
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