公募シンポジウム

公募シンポジウム5【脳の体積変化を考えるー疾患から分子までー】

2021/9/30　14:00～16:00　ZOOM B会場 S5-1 淡蒼球の機能と病態生理 Physiology and pathophysiology of the globus pallidus ^○南部篤自然科学研究機構生理学研究所生体システム研究部門 ^○Atsushi Nambu National Institute for Physiological Sciences, Division of System Neurophysiology The globus pallidus (GP) is composed of the internal (GPi) and external (GPe) segments (the entopeduncular nucleus and GP, respectively, in rodents), and they have different neural connections and functions. The GPi, together with substantia nigra pars reticulata (SNr), receives signals from the input nuclei of the basal ganglia (BG), the striatum and subthalamic nucleus (STN), and projects to the thalamus as the output nucleus, while the GPe is a relay nucleus that relays signals from the input nuclei to the GPi/SNr through the STN. Both GPi and GPe neurons change their activity during voluntary movements and are considered to play important roles in controlling movements, while the GPe has cognitive functions, as well. In normal states, cortical stimulation induces early excitation, inhibition, and late excitation in the both GPi and GPe, but this response pattern is modulated differently between the two nuclei in movement disorders. In Parkinson’s disease, cortically induced inhibition is greatly reduced in the GPi, which causes the loss of disinhibitory signals to the thalamus, resulting in akinesia, while cortically induced late excitation is enhanced in the GPe. In L-DOPA induced dyskinesia, cortically induced inhibition is greatly enhanced, and late excitation is lost in the GPi, which cause enhanced disinhibitory signals to the thalamus, resulting in involuntary movements, while cortically induced late excitation is reduced in the GPe. Lesions or high frequency stimulation in the GPi blocks these abnormal signals to the thalamus and ameliorates motor symptoms, while the GPe is not the target of stereotactic surgery. Therefore, we have to differentiate the role of the GPi from that of the GPe when we discuss the functions of the BG.		2021/9/30　14:00～16:00　ZOOM B会場 S5-2 L-DOPA 誘発性ジスキネジアで何故淡蒼球体積が増加するのか A mechanism of an increase in globus pallidus volume in L-DOPA-induced dyskinesia ^○阿部欣史¹,福村麻里子²,安達瑠花¹,田中謙二¹ 1.慶應義塾大学医学部精神神経科学教室,2.慶應義塾大学医学部脳神経外科学教室 ^○Yoshifumi Abe¹,Mariko Fukumura²,Ruka Adachi¹,Kenji F Tanaka¹ 1.Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan,2.Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan It is known that a volume of the external segment of globus pallidus (GPe) increases in a mouse model of L-DOPA-induced dyskinesia (LID). However, it has not been clear which cell type or cellular component volume changes engage in the net GPe volume increase. In this study, we conducted a histological evaluation to comprehensively address above questions. A super-resolution microscopy revealed significant volume increases of VGAT⁺ axon terminals of striatal medium spiny neurons (MSNs), GPe neuronal soma and dendrites, and myelin surrounding passing cortical neuron axons. An electron microscopic analysis confirmed these structural changes. Other cell types including astrocytes, microglia, oligodendrocyte progenitor cells, and vasculature cells did not be involved in the net GPe volume change. Among cellular level volume changes, we focused on the enlargement of VGAT⁺ MSN axon terminals for the further analysis because it was reported that the mRNA expression levels of GABA-related genes (VGAT, GAD65, and GAD67) and the GABA content were elevated in MSNs in a LID model. We therefore hypothesized that the artificial GABA content increase in MSNs lead to the increased GPe volume. To test this hypothesis, we overexpressed VGAT, GAD65 and GAD67 genes in MSNs by an AAV-mediated gene delivery. Single gene induction was enough to enlarge VGAT+ terminal and triple gene induction maximized the volume increase. This is the first to demonstrate molecular mechanism underlying the volume increase in LID. The next theme will be the pathophysiological and therapeutic impacts of these gene inductions on dyskinesia.

2021/9/30　14:00～16:00　ZOOM B会場 S5-3 淡蒼球におけるアストロサイトの多様性と運動刺激に対する形態変化について Diversity of astrocytes in the globus pallidus and their morphological changes ^○辰巳晃子¹,絹川薫²,石西綾美¹,奥田洋明³,竹村晶子¹^,⁴,田中達英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.奈良県立医科大学医学部脳神経内科学講座,3.金沢大学医薬保健研究域医学系機能解剖学分野,4.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 ^○Kouko Tatsumi¹,Kaoru Kinugawa²,Ayami Isonishi¹,Hiroaki Okuda³,Shoko Takemura¹^,⁴,Tatsuhide Tanaka¹,Akio Wanaka¹ 1.Department of Anatomy and Neuroscience, Nara Medical University 2.Department of Neurology, Nara Medical University 3.Department of Anatomy, Graduate school of Medical Science, Kanazawa University 4.Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences Astrocytic heterogeneity is one of the hot topics in recent glial research. Single cell RNA expression analyses have revealed that there are several subpopulations of astrocytes with different gene expression patterns in the central nervous system including the globus pallidus (Gpe). We have previously identified the Olig2 lineage astrocytes (Olig2-AS) as a subpopulation of astrocytes, and they share mutually exclusive territories with the GFAP-positive astrocytes (GFAP-AS) in the GPe. Olig2-AS tend to be localized primarily in the brain nuclei that strongly express vesicular GABA transporter and the fine processes of Olig2-AS preferentially encapsulate GABAergic synapses in the GPe, suggesting that Olig2-AS is specifically involved in inhibitory transmission. To prove this hypothesis, we dissected out Olig2-AS and GFAP-AS from GPe with laser microdissection and compared gene expression patterns by qPCR. Expressions of GABA transporters (GAT-3 and GAT-1) were significantly higher in Olig2-AS than in GFAP-AS. Consistent with these findings, we found that Olig2-expressing astrocytic clusters in the single-cell RNA-seq datasets of adult mouse GPe. The astrocyte clusters are enriched with an amino acid transporter ASC-1 in addition to the GABA transporters. We confirmed the preferential expression of the ASC-1 in the Olig2-AS in the laser-microdissected samples. The ASC-1 could negatively regulate NMDA receptor functions, which awaits further analyses. Finally, we found that Olig2-AS increased their morphological complexities in response to exercise activities. The complexities reverted to normal levels after a sedentary period. In this symposium, we will discuss possible functional implications of Olig2-AS, which constitutes one subpopulation of GPe astrocytes.		2021/9/30　14:00～16:00　ZOOM B会場 S5-4 統合失調症臨床病期からみた淡蒼球体積特徴 in response to exercise activities ^○小池進介東京大学心の多様性と適応の連携研究機構 ^○Shinsuke Koike The University of Tokyo Institute for Diversity and Adaptation of Human Mind(UTIDAHM) A multi-site volumetric MRI mega study showed that patients with chronic schizophrenia have increased pallidum volume compared to healthy controls. The characteristics was well-replicated in a Japanese multi-site mega study. In addition, the study also found the laterality alteration of the pallidum volumes in patients with schizophrenia. These volumetric and laterality alterations were also found in multi-site studies for different clinical stages of schizophrenia such as first-episode schizophrenia and ultra-high risk for psychosis, suggesting that the pallidum could reflect a pathological progression in schizophrenia. Thus, a question arises that when and how the pallidum volume and function alter through the life course according to the disease progression. Cohort studies are categorized as prospective studies and are able to know the development of the brain and psychopathology, as well as a causal relationship between them. Tokyo TEEN Cohort study project (http://ttcp.umin.jp/) is a cohort targeting adolescence in Tokyo, Japan. More than 3,000 population-representative children received multi-disciplinary assessments every 2 years. Of these, around　400　participants　also　received　multi-modal　brain　image　scans　every　2　years (http://klab.c.u-tokyo.ac.jp/project/cohort/pn-ttc/). Now, the participants reach age at 18 years, and we can start to see the relationship between adolescent brain development and the onset of psychological symptoms using more than 1,000 brain images. In this presentation, we would like to introduce clinical studies in various clinical stages of schizophrenia and then cohort studies of the relationship between sub-clinical psychotic symptoms and brain development.