シンポジウム

シンポジウム 13 グリア細胞により実現する高次脳機能 13 Control by glia of higher brain functions 座長：小泉修一（山梨大学・院医・薬理）・和氣弘明（名古屋大学　院医・機能形態学）

2022年6月30日　16:10～16:40　沖縄コンベンションセンター会議場B1　第3会場 1S03e-01 Negative feedback control of neuronal activity by microglia Anne Schaefer(1) 1. MPI for Biology of Ageing, Cologne, Icahn School of Medicine at Mount Sinai, New York Keyword:* Microglia, neuronal activity, Adenosine, behavior Differentiated neurons exist as highly specialized neuronal subtypes with distinct activation states and functions. Neuronal fitness is surveyed by microglia, the innate immune cells in the brain, which eliminate non-functional cells and/or synapses. Given the multitude of neuronal states, the notion of functionality is likely to differ between different neurons and hence requires microglia adaption to distinct neuronal states. We found that microglia adapt to the neighboring neurons and that this adaptation relies on epigenetic mechanisms. Our findings show that microglia brain region-specific transcriptional and functional adaptation enables co-regulation of microglia and neurons by common triggers including specific neuromodulators and metabolites. Our data further revealed that regulation of neuronal circuits is not the exclusive prerogative of neurons but is controlled by microglia. We found that microglia can sense changes in local neuronal activity and identified a neuronal activity-induced, microglia-mediated feedback mechanism that suppresses neuronal responses. Our findings suggest that this novel microglia-driven negative feedback mechanism plays an important role in protecting the brain from excessive neuronal activity and controls animal behaviors in health and diseases.		2022年6月30日　16:40～17:10　沖縄コンベンションセンター会議場B1　第3会場 1S03e-02 ミクログリアと感覚モダリティー Microglia and sensory modility 和氣弘明(1,2) 1. 名古屋大学、2. 自然科学研究機構　生理学研究所 Hiroaki WAKE(1,2) 1. Nagoya University, 2. National Institute for Physiological Sciences, National Institute of Natural Sciences Keyword: microglia Microglia are the sole immune responding cells in the central nervous system. Their role as neuro-immune cells in the pathogenesis of various neurodegenerative and infectious diseases of the brain have been extensively studied. In addition to the pathological function of microglia, recent developments in molecular probes and optical imaging in vivo have revealed that microglia are highly motile cell in the healthy brain, extending and retracting their process that extend from a largely stationary cell soma. We used in vivo two photon microscopy to reveal their physiological and pathological function on synapse and vessels. We particularly showed the functional consequence of microglial contact on synapse and vessels to indicate their role in neurological or psychiatric brain. In this session, we will show 1. Microglial regulation of blood brain barrier, 2. Microglial role for cross modal plasticity that indicate their pathological role in schizophrenia. In this presentation, we will introduce the contribution of microglia to neural circuit function, their involvement in pathology. In addition, we have recently developed a holographic microscope that can precisely measure and manipulate neuronal and glial cell activities in a spatiotemporal manner in living mice, and have successfully evaluated the functional connectivity of neuronal circuits in a pain model. In this article, we would like to discuss the biological applications of microscopy.

2022年6月30日　17:10～17:40　沖縄コンベンションセンター会議場B1　第3会場 1S03e-03 行動変容に関連するアストロサイト亜集団の探索 Probing and exploring behaviorally-consequential astrocyte ensembles 長井淳(1) 1. 理化学研究所・脳神経科学研究センター Jun Nagai(1) 1. RIKEN Center for Brain Science Keyword: ASTROCYTE, BEHAVIOR, SYNAPSE, CIRCUITS An open question in brain science concerns how interactions occur among cellular components: neurons, glia and blood vessels. We have previoulsy produced a realization that astrocytes actively regulate synapses, circuits and mouse behavior. A key finding is that astrocyte activation or inactivation in the striatum induced behavioral hyperactivity (shift to exploration) or excessive self-grooming (shift to exploitation), respectively. This led us a hypothesis that astrocytes gate exploration/exploitation decisions, shaping flexible and adaptive behavior. Astrocyte dysfunctions could thus potentially contribute to maladaptive behaviors seen in psychiatric phenotypes. Based on this, a question that currently guide my ongoing research is: In the prefrontal cortex, do astrocytes control microcircuits and adaptive behavior? As the first step of landmark study of prefrontal astrocytes, we assessed if astrocyte can respond to 14 neurotransmitters/ agonists with 2-photon imaging and identified most profound evoked astrocyte Ca2+ signaling by norepinephrine via Gq-coupled alpha1-adrenoceptors. We carefully validated that Gq-DREADD mimicked this signaling ex vivo and in vivo and locally activated prefrontal neurons. We will report how mouse behaviors are altered and not altered upon Gq pathway stimulation of prefrontal astrocytes. In addition, we will show a new approach to investigate astrocyte functional diversity. We validated the approach is astrocyte-specific, activity-dependent, brain-wide and temporally-restricted (during a behavioral paradigm). We anticipate our tools to enable us to identify classically inaccessible astrocyte diversity “behavior-specialized astrocytes” at distinct types of behavioral adaptation.		2022年6月30日　17:40～18:10　沖縄コンベンションセンター会議場B1　第3会場 1S03e-04 アストロサイトとシナプス再編 Synapse remodeling by reactive astrocytes 小泉修一(1,2) 1. 山梨大学・院医・薬理、2. 山梨大学・院医・GLIAセンター Schuichi Koizumi(1,2) 1. Dept Pharmacol, Interdisciplinary Grad Sch Med, Univ Yamanashi, 2. Yamanashi GLIA Center, Univ Yamanashi Keyword: astrocytes, synapse remodeling, network remodeling When astrocytes sense environmental changes, they become reactive and contribute to brain diseases. Here, I show reactive astrocyte-mediated synapse remodeling and its pathophysiological consequences in the primary somatosensory cortex (S1) and the hippocampus. Mechanical allodynia is caused by peripheral nerve ligation (PSL) injury. After PSL, S1 astrocytes become reactive and remodel neuronal circuits by excess synaptogenesis. We show that PSL induces a reemergence of mGluR5 in S1 reactive astrocytes, leading to increased Ca²⁺ signals, production of multiple synaptogenic molecules, and excess uncontrolled synapse formation. Then, S1 astrocytes caused misconnection of tactile- and pain-networks, thereby leading to sustained mechanical allodynia. Similar events occurred during formation of epileptogenesis. After status epilepticus, hippocampal astrocytes become reactive, and increased frequency of Ca²⁺ transient, followed by formation of epileptogenesis. The increased Ca²⁺ signals in the reactive astrocytes is a cause of epileptogenesis because inhibition of the Ca²⁺ abolished epileptogenesis. We termed these astrocytes as epileptogenic astrocytes and analyzed molecular profiles of them. RNAseq analysis showed that epileptogenic astrocytes reemerged mGluR5 and increased several synaptogenic molecules. Therefore, we concluded that inappropriate network connection in the hippocampus by reactive astrocytes cause epileptogenesis. Taken together, reactive astrocytes have a key role in regulation of synaptogenesis in the adult pathological brain, for which mGluR5 and Ca²⁺ signals have pivotal roles.