​Adv Sci Niu Jianqin/Xiao Lan's collaborative team reveals the mechanism of the development of astrocyte network regulated by oligodendrocytes in early stress mental behavior

Responsible Editor | Enzyme Beauty As the global urbanization process continues to accelerate, the urban migration of a large number of laborers has caused the problem of left-behind children in rural areas to become increasingly prominent
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Children suffering from early stress such as lack of care during their growth are prone to mental illnesses such as depression and anxiety, and have a higher suicidal tendency [1]
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The mechanisms of related mental disorders are mostly analyzed from the perspective of neurons, but in recent years, the role of glial cells in the occurrence of diseases has gradually gained attention
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The Astrocytic network, which is mediated by connexin, coordinates the functions of astrocytes in the region through calcium wave transmission, and through functions such as energy metabolism supply, neurotransmitter and ion homeostasis regulation, etc.
Participate in synaptic transmission and plasticity regulation, and play an important role in the establishment of neural circuits and animal learning and memory behavior [2, 3]
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The abnormality of the star glue network has been found in both depression patients and early life stress model animals [4, 5], but the mechanism is still unclear
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The team of Professors Niu Jianqin and Xiao Lan of the Army Military Medical University (formerly the Third Military Medical University) has focused on the development of oligodendrocytes and mental diseases for more than ten years
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Starting from the interaction between oligodendrocytes and astrocytes, on June 22, 2021, in collaboration with researcher Yi Chenju’s team from the Seventh Affiliated Hospital of Sun Yat-sen University, an online publication entitled Reduced oligodendrocyte precursor cell impairs astrocytic development in Advanced Science A research paper on early life stress
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This thesis uses a variety of conditions to knock out mice, combined with techniques such as behavior, immunofluorescence staining, and fluorescence bleaching recovery, and found that the reduction of oligodendrocyte progenitor cells (OPC) in the early isolation of the mouse brain can inhibit astrocytes The development of plasma cells and astrocyte network affects the activation of neurons
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Further studies through in vitro experiments, sequencing analysis and in vivo functional loss have found that OPC can release Wnt 7b and regulate the development and network formation of astrocytes in a paracrine form, while the supplementation of exogenous Wnt 7b can effectively alleviate isolation.
The development and network formation of astrocytes in the mouse brain are impeded
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This paper clarified the mechanism of abnormal mental behavior caused by early stress from the perspective of glial cells, and provided a new theoretical basis for the prevention and treatment of related diseases
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The author simulated early stress through an improved mouse parental isolation model, eliminating the interference of the difference in nutritional supply between the isolation group and the control group in the traditional model
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It was found that isolated mice showed depression, anxiety and impulse-like behavioral changes; and from the age of seven days (P7), in the cortex and hippocampus of isolated mice, astrocytes showed reduced protruding branches and down-regulated expression of connexin Cx43 And other developmental abnormalities
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It was confirmed by gap-FRAP, calcium imaging and other technologies that the star glue network of isolated model mice had functional defects
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In order to explore the factors affecting the development of the star gum network, the author further traced the model to establish other pathological changes in the early brain, and found that the number of OPC began as early as P4, and decreased due to the slowing of proliferation, suggesting the potential regulation of OPC on the development of the star gum network
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Using PdgfraCreER:DTA mice to remove OPC in the early stages of development, the authors discovered that OPC has an important role in promoting the development of the star gum network
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In vitro experiments have found that OPC affects the development of astrocytes through secretion rather than direct contact
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So, how does OPC regulate the development of astrocytes? The authors performed RNA sequencing on astrocytes in the isolation model and found that compared with the control group, the Wnt/β-catenin signaling pathway was down-regulated in astrocytes in the isolation group
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OPC is an important source of Wnt ligands in the brain
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The author found through in vitro experiments that the development of astrocytes is most sensitive to OPC-derived Wnt7a and Wnt7b ligands
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In order to verify the important role of OPC-derived Wnt7a/b on the development of astrocyte network, the authors constructed Wnt7a-flox and Wnt7b-flox mice, and crossed them with Pdgfra CreER mice to knock out Wnt7a/b in OPC
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It was found that Wnt7b derived from OPC is necessary for the normal development of the star gum network
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More interestingly, conditional knockout of Wnt7b in OPC can further lead to the depressive phenotype of mice
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In view of the important role of Wnt7a/b in the development of astrocyte network, the authors further explored whether supplementing Wnt7a/b can save the development of astrocyte network in isolated mice
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Through the method of micro-injection pump implantation, the author continuously injected Wnt7a and Wnt7b factors into the hippocampus of mice in the early stage of the isolation model, and found that compared with the control (injection of saline only), the astrocytes protruded after the Wnt7a/b injection group Increasing, the expression of gap junction protein increased, suggesting that Wnt7a/b supplementation can rescue the abnormal development of the star glue network in the isolated mouse model
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To sum up the working model, this study found that in addition to differentiation to form myelin sheath, OPC can activate the Wnt pathway of astrocytes through paracrine, promote cell maturation and new functions of glial network development; at the same time, it also reveals the new function of glial The role of cells in mental disorders caused by early stress provides a new theoretical basis and experimental basis for the prevention and treatment of related mental disorders
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The first author of this article is Wang Yuxin, a 2018 PhD student in Histology and Embryology of the Army Military Medical University, and Su Yixun, a postdoctoral fellow at the Seventh Affiliated Hospital of Sun Yat-Sen University
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Researcher Yi Chenju from the Seventh Affiliated Hospital of Sun Yat-sen University, Professor Xiao Lan of the Army Military Medical University, and Professor Niu Jianqin (lead contact) are the corresponding authors of this article
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Original link: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
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