강수진 (Osaka University)

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Osaka University

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Neuron, Jul 09 2024, S0896-6273(24)00452-5 | https://doi.org/10.1016/j.neuron.2024.06.017 Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs

Yoshimitsu Nakanishi ^1,2,3,4,18, Mayuko Izumi^1,2,3,4,18, Hiroaki Matsushita ^3,5, Yoshihisa Koyama ^4,6,7, Diego Diez ⁸, Hyota Takamatsu ^1,2, Shohei Koyama ^1,2, Masayuki Nishide ^1,2, Maiko Naito ^1,2, Yumiko Mizuno ^1,2, Yuta Yamaguchi ^1,2, Tomoki Mae ¹, Yu Noda ¹, Kamon Nakaya ¹, Satoshi Nojima ⁹, Fuminori Sugihara¹⁰, Daisuke Okuzaki^{4,11,12,15,16}, Masahito Ikawa ^13,15,17, Shoichi Shimada ^6,7, Sujin Kang ^14,15, Atsushi Kumanogoh ^{1,2,4,15,16,17,19}

¹Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

²Department of Immunopathology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka 565-0871, Japan

³Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

⁴Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan

⁵Discovery Pharmacology Department, Research Division, Chugai Pharmaceutical Co. Ltd., Kanagawa 247-8530, Japan

⁶Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

⁷Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Osaka 541-8567, Japan

⁸Quantitative Immunology Research Unit, WPI-IFReC, Osaka University, Osaka 565-0871, Japan

⁹Department of Pathology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

¹⁰Laboratory of Biofunctional Imaging, WPI-IFReC, Osaka University, Osaka 565-0871, Japan

¹¹Laboratory of Human Immunology (Single Cell Genomics), WPI-IFReC, Osaka University, Osaka 565-0871, Japan

¹²Genome Information Research Center, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan

¹³Department of Experimental Genome Research, RIMD, Osaka University, Osaka 565-0871, Japan

¹⁴Laboratory of Immune Regulation, WPI-IFReC, Osaka University, Osaka 565-0871, Japan

¹⁵Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Osaka 565-0871, Japan

¹⁶Japan Agency for Medical Research and Development—Core Research for Evolutional Science and Technology (AMED–CREST), Osaka University, Osaka 565-0871, Japan

¹⁷Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka 565-0871, Japan

¹⁸These authors contributed equally

¹⁹Lead contact

Corresponding authors: Sujin Kang, Atsushi Kumanogoh

Abstract

Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis. Using genome-wide approaches, we identify SEMA6D as a pleiotropic gene for both psychiatric and metabolic traits in human. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d ^-/- mice display attenuated obesity and enhanced myelopoiesis compared with control mice due to higher sympathetic activity via the β3-adrenergic receptor. Genetic manipulation and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdalar interneurons is responsible for regulating anxiogenic and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results demonstrate that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-16)
연구진국외 연구진
분야 의약학 > 면역의학

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