シンポジウム（Symposium）

Symposium Brain diversity induced by glial heterogeneity シンポジウムグリアの不均一性により表出する脳の多様性 Sponsored by IBRO-APRC Lecturer Exchange Program

7月25日（木）9:00～9:30　第4会場（朱鷺メッセ　3F　301） 1S04m-1 脳機能回復へ貢献するグリアheterogeneity Rieko Muramatsu（村松里衣子）国立精神・神経医療研究センター神経研究所 Central nervous system (CNS) injury is associated with severe neurological deficits in motor, sensory, cognitive, and other functions. One of the reasons of neurological deficits is due to the disruption of neuronal network following injury. Recent studies have been shown that injured neuronal network can regenerate spontaneously with time, but the mechanism of spontaneous regeneration of neuronal network is not fully clarified. Remyelination is an essential process of functional regeneration of myelinated neuronal network, and it is supported by the development of oligodendrocyte, one of the glial cells. Oligodendrocyte is developed from their precursor, oligodendrocyte precursor cell (OPC), which is distributed throughout the CNS. In the response to injury, OPC promotes their proliferation and differentiation, resulting in repair myelin around the injured site. Regarding the mechanism of remyelination, we previously reported that OPC proliferation was enhanced by the circulating factor, such as fibroblast growth factors 21 derived from pancreas. In this talk, I will show the update of the circulating factor-mediated remyelination, especially focused on the molecular mechanism of OPC differentiation.		7月25日（木）9:30～10:00　第4会場（朱鷺メッセ　3F　301） 1S04m-2 グリコーゲン分布に見られるアストロサイトの多様性 Hajime Hirase（平瀬肇）^1,2，Yuki Oe（大江佑樹）¹ ¹理研CBS 神経グリア回路 ²CTN, Univ of Copenhagen, Copenhagen, Denmark Amongst major glia cell types, astrocytes have been investigated for their heterogeneity in recent years. Glycogen metabolism has been implied in synaptic plasticity and learning, yet the distribution of this molecule has not been fully described. We investigated the distribution of glycogen in the mouse brain by immunohistochemistry (IHC) using two monoclonal antibodies that have different affinities depending on the glycogen size. The use of focused microwave irradiation yielded well-defined glycogen immunoreactive signals compared with the conventional periodic acid-Schiff method. The IHC signals displayed a punctate distribution localized predominantly in astrocytic processes. Glycogen immunoreactivity was high in the hippocampus, striatum, cortex, and cerebellar molecular layer, whereas it was relatively low in the white matter and most of subcortical structures. Additionally, glycogen distribution in the hippocampal CA3-CA1 and striatum had a "patchy" appearance with glycogen-rich and glycogen-poor astrocytes appearing in alternation. The glycogen patches were more evident with large-molecule glycogen in young adult mice but they were hardly observable in aged mice (1-2 years old). Our results reveal brain region-dependent glycogen accumulation and a possible metabolic heterogeneity of astrocytes. Glycogen metabolism is known to be activated by G protein-coupled receptors (GPCR). Currently, we are investigating the organization of GCR-driven Ca2+ activities in cortical astrocytes in vivo.

7月25日（木）10:00～10:30　第4会場（朱鷺メッセ　3F　301） 1S04m-3 Astrocytic heterogeneity in modulating sensory signal processing Sun Kwang Kim（Kim Sun Kwang）¹，Sang Jeong Kim（Kim Sang Jeong）²，Schuichi Koizumi（Koizumi Schuichi）³，Junichi Nabekura（Nabekura Junichi）⁴ ¹Kyung Hee University College of Korean Medicine ²Seoul National University School of Medicine ³Yamanashi University Faculty of Medicine ⁴National Institute for Physiological Sciences Although the pain modulating roles of astrocytes within the spinal cord have been well documented, it is still unclear whether and how astrocytes in the brain are involved in pain sensation. Using in vivo two-photon microscopy imaging with genetic and pharmacological manipulations, we investigated the calcium signaling in either of S1 cortical astrocytes or cerebellar Bergmann glia (BG) during pain processing in mice. (1) Partial sciatic nerve ligation (PSL) injury induces an early re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astrocytes, which elicits spontaneous somatic calcium transients, thrombospondin-1 release and synapse formation. Such activation of S1 astrocytes was evident only during a critical period (~1w post-injury), correlating with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover following PSL injury. Blocking this astrocytic signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of injury induced long-lasting allodynia. (2) The calcium activity of BG in intact cerebellar cortex lobule IV/V was monitored in anesthetized mice. Various noxious electrical stimuli were delivered to the mouse hind paw during calcium imaging and pharmacological manipulation. Capsaicin was also injected to the hind paw to monitor BG calcium responses under an acute spontaneous pain condition. We found that i) noxious electrical stimulation (ES) in anesthetized mice results in calcium activation of BG network in the cerebellum, ii) the ES-induced BG calcium response was completely blocked by a microinjection of prazosin, an alpha1-adrenergic receptor blocker, into the cerebellar cortex, iii) capsaicin injection induces strong BG calcium responses during the first 5 min of the capsaicin test, and iv) the capsaicin-induced BG calcium response and pain behavior (paw licking) were significantly blocked by a microinjection of prazosin. Taken together, we suggest that glutamatergic signaling through mGluR5 and noradrenergic signaling through alpha1-adrenergic receptor mediate the calcium activation of the S1 cortical astrocytes and cerebellar BG network, respectively, during pain processing in mice.		7月25日（木）10:30～11:00　第4会場（朱鷺メッセ　3F　301） 1S04m-4 アストロサイトの不均一性とシナプスリモデリング Schuichi Koizumi（小泉修一）山梨大学・院・医・薬理 When pathological condition, astrocytes become "reactive astrocytes°; and contribute to both beneficial and hazardous brain functions. Here, I show reactive astrocyte-mediated synapse remodeling in the somatosensory cortex (S1) and the striatum. (1) Mechanical allodynia: We previously showed that when partial sciatic nerves are ligated (PSL), S1 astrocytes became synaptogenic and re-wired S1 neuronal networks, thereby leading to cross-talk between nocuous and innocuous circuits and mechanical allodynia. For this, upregulation of mGluR5 in S1 astrocytes has a pivotal role. When mGluR5 is selectively deleted in astrocytes, both uncontrolled synapse formation and mechanical allodynia were abolished. Thus, mGluR5 could be a key molecule that control astrocyte-mediated synapse formation and mechanical allodynia. (2) Brain ischemia: After transient brain ischemia, phagocytic astrocytes were observed within ischemic penumbra region in the later stage of ischemia. Phagocytic astrocytes upregulated ABCA1 and its pathway molecules, MEGF10 and GULP1, which were required for their phagocytosis. In addition, upregulation of ABCA1 was sufficient for the phagocytosis. Together, these findings suggest that astrocytes should be transformed into phagocytic phenotype via increasing ABCA1 and its related molecules. Judging from the spatiotemporal pattern of the phagocytic astrocytes, they have distinct roles from microglia, and would contribute to remodeling of the penumbra networks.