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Microglia shape AgRP neuron postnatal development via regulating perineuronal net plasticity

Molecular Psychiatry (2023)Cite this article

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Abstract

The hypothalamus plays a crucial role in controlling metabolism and energy balance, with Agouti-related protein (AgRP) neurons and proopiomelanocortin (POMC) neurons being essential components of this process. The proper development of these neurons is important for metabolic regulation in later life. Microglia, the resident immune cells in the brain, have been shown to significantly influence neurodevelopment. However, their role in shaping the postnatal development of hypothalamic neural circuits remains underexplored. In this study, we investigated the dynamic changes of microglia in the hypothalamic arcuate nucleus (ARC) during lactation and their impact on the maturation of AgRP and POMC neurons. We demonstrated that microglial depletion during a critical period of ARC neuron maturation increases the number of AgRP neurons and fiber density, with less effect on POMC neurons. This depletion also resulted in increased neonatal feeding behavior. Mechanistically, microglia can engulf perineuronal net (PNN) components surrounding AgRP neurons both in vivo and ex vivo. The absence of microglia leads to increased PNN formation and enhanced leptin sensitivity in ARC. Our findings suggest that microglia participate in the postnatal development of AgRP neurons by regulating the plasticity of PNN formation. This study contributes to a better understanding of microglia’s role in shaping hypothalamic neural circuits during postnatal development and their impact on metabolism regulation.

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Fig. 1: Hypothalamic microglia are highly dynamic during the postnatal period with close affinity to adjacent AgRP/NPY neurons.
Fig. 2: Microglia depletion at a critical time window increases NPY/AgRP neuron growth in ARC.
Fig. 3: RNA-Seq data from the hypothalamus after microglia depletion by PLX3397.
Fig. 4: Postnatal microglia depletion increases PNN formation mainly wrapping AgRP/NPY neurons.
Fig. 5: Postnatal microglia depletion increases leptin sensitivity in ARC.
Fig. 6: Postnatal microglia depletion leads to increased ingestive behavior in neonates.

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Data availability

All the data supporting the findings of this study are available within the article and the Supplementary Material. Additional data related to this paper will be available upon request.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant no.81873654 to YG, 82201579 to YP).

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  1. These authors contributed equally: Jia Sun, Xinyuan Wang.

Authors and Affiliations

  1. Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, P. R. China

    Jia Sun, Xinyuan Wang, Rui Sun, Xiaoao Xiao, Yu Wang, Yu Peng & Yuanqing Gao

  2. Geriatric Hospital of Nanjing Medical University, Nanjing, 210009, P. R. China

    Xinyuan Wang

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Contributions

JS and YG designed the experiments. JS, XW, and RS performed the experiments and analyzed the data. YW and XX contributed to the behavior experiment and animal caring. YP contributed to the data analysis. YG supervised the work. JS, XW, RS and YG wrote the manuscript. All authors discussed the results and contributed to the manuscript.

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Correspondence to Yuanqing Gao.

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Sun, J., Wang, X., Sun, R. et al. Microglia shape AgRP neuron postnatal development via regulating perineuronal net plasticity. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02326-2

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