Xiong Rui, Hu Yinyin, Wang Menghan, Han Ting, Hu Yuying, Ma Chaolin, Li Baoming
Institute of Life Science and School of Life Science, Nanchang University, Nanchang 330031, China.
Institute of Brain Science, School of Basic Medical Science, Hangzhou Normal University, Hangzhou 311121, China.
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2412995122. doi: 10.1073/pnas.2412995122. Epub 2025 Apr 16.
Maternal separation (MS), a chronic stress event in early life, impairs myelination in the prefrontal cortex (PFC) and leads to PFC cognitive disorders. It remains largely unclear how such deficits are mediated. Here, we show that peripheral CD4 T cells play an essential role in mediating the destructive effects of MS on medial prefrontal cortical (mPFC) myelination and cognitive functions in mice. Offspring mice with MS experience (MS mice) exhibited an increase in CD4 T cells and xanthine levels in peripheral blood and a severe deficit in mPFC-dependent cognitive functions such as working memory, social interaction, and anxiety/depression emotion regulation, along with a decrease in oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) in the mPFC. These phenotypes were rescued upon treatment with the antibody neutralizing peripheral CD4 T cells. Rag1 immunodeficient mice receiving transplantation of CD4 T cells isolated from the peripheral blood of MS mice showed similar phenotypes as observed in MS mice. Immunofluorescence staining revealed a rich expression of adenosine receptor A1 (A1) in OPCs in the mPFC, and the A1-expressing OPCs decreased in the Rag1 mice receiving CD4 T cell transplantation. The present study demonstrates a causal link between peripheral CD4 T cells and MS-induced prefrontal cortical hypomyelination and cognitive dysfunction, and such a link is probably mediated via xanthine-adenosine receptor A1 signaling in OPCs.
母婴分离（MS）是早期生活中的一种慢性应激事件，会损害前额叶皮质（PFC）的髓鞘形成并导致PFC认知障碍。目前尚不清楚这些缺陷是如何介导的。在这里，我们表明外周CD4 T细胞在介导MS对小鼠内侧前额叶皮质（mPFC）髓鞘形成和认知功能的破坏作用中起重要作用。有MS经历的子代小鼠（MS小鼠）外周血中CD4 T细胞和黄嘌呤水平升高，mPFC依赖的认知功能严重缺陷，如工作记忆、社交互动和焦虑/抑郁情绪调节，同时mPFC中的少突胶质前体细胞（OPC）和少突胶质细胞（OL）减少。用中和外周CD4 T细胞的抗体治疗后，这些表型得到挽救。接受从MS小鼠外周血分离的CD4 T细胞移植的Rag1免疫缺陷小鼠表现出与MS小鼠相似的表型。免疫荧光染色显示mPFC中OPC中有丰富的腺苷受体A1（A1）表达，接受CD4 T细胞移植的Rag1小鼠中表达A1的OPC减少。本研究证明了外周CD4 T细胞与MS诱导的前额叶皮质髓鞘形成不足和认知功能障碍之间的因果关系，这种关系可能是通过OPC中的黄嘌呤 - 腺苷受体A1信号介导的。
