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Axonal iron transport in the brain modulates anxiety-related behaviors

Nature Chemical Biology volume 15, pages 1214–1222 (2019)Cite this article

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Abstract

Iron is essential for a broad range of biochemical processes in the brain, but the mechanisms of iron metabolism in the brain remain elusive. Here we show that iron functionally translocates among brain regions along specific axonal projections. We identified two pathways for iron transport in the brain: a pathway from ventral hippocampus (vHip) to medial prefrontal cortex (mPFC) to substantia nigra; and a pathway from thalamus (Tha) to amygdala (AMG) to mPFC. While vHip–mPFC transport modulates anxiety-related behaviors, impairment of Tha–AMG–mPFC transport did not. Moreover, vHip–mPFC iron transport is necessary for the behavioral effects of diazepam, a well-known anxiolytic drug. By contrast, genetic or pharmacological promotion of vHip–mPFC transport produced anxiolytic-like effects and restored anxiety-like behaviors induced by repeated restraint stress. Taken together, these findings provide key insights into iron metabolism in the brain and identify the mechanisms underlying iron transport in the brain as a potential target for development of novel anxiety treatments.

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Fig. 1: Iron transport from the ventral hippocampus to the mPFC.
Fig. 2: Mapping vHip–mPFC iron transport.
Fig. 3: vHip–mPFC iron transport depends on neuronal activity in the vHip.
Fig. 4: Increasing vHip–mPFC iron transport produces anxiolytic-like behaviors.
Fig. 5: Impaired vHip–mPFC iron transport induces anxiety-like behaviors.
Fig. 6: Anxiolytic treatments promote vHip–mPFC iron transport.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request. Source data for Figs. 1–6 are available online.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (81930034 and 81325008 to X.H.Z.), the Natural Science Foundation of Guangdong Province (2016A030308005 to X.H.Z.), the Guangzhou Science and Technology Project (201804020061 to X.H.Z.), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37 to X.H.Z.) and Science and Technology Program of Guangdong (2018B030334001 to X.H.Z.). The authors thank the laboratories of Y.-Y. Fang, S.-J. Li and X.-W. Li for their technical support.

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Author notes

  1. These authors contributed equally: Zhuo Wang, Yuan-Ning Zeng.

Authors and Affiliations

  1. Institute of Mental Health, Southern Medical University, Guangzhou, China

    Zhuo Wang, Yuan-Ning Zeng, Peng Yang, Li-Qiang Jin, Wen-Chao Xiong, Min-Zhen Zhu & Xin-Hong Zhu

  2. Key Laboratory of Mental Health of the Ministry of Education and Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China

    Zhuo Wang, Yuan-Ning Zeng, Peng Yang, Li-Qiang Jin, Wen-Chao Xiong, Min-Zhen Zhu & Xin-Hong Zhu

  3. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China

    Jun-Zhe Zhang & Xiao He

  4. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China

    Xin-Hong Zhu

  5. Guangdong–Hong Kong–Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China

    Xin-Hong Zhu

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Contributions

X.H.Z. designed the research. X.H.Z., Z.W., Y.N.Z. and W.C.X. analyzed the data and wrote the paper. Z.W. performed experiments for stereotaxic microinjections, FFT and immunostaining. Z.W., Y.N.Z., P.Y., M.Z.Z. and L.Q.J. conducted the behavioral tests. Y.N.Z. and P.Y. performed experiments for 56Fe detections, quantitative PCR with reverse transcription and immunoblots. Z.W., J.Z.Z. and X.H. performed experiments for 59Fe and 57Fe detections L.Q.J. performed Perl’s staining. M.Z.Z., P.Y. and L.Q.J. performed genotyping.

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Correspondence to Xin-Hong Zhu.

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Wang, Z., Zeng, YN., Yang, P. et al. Axonal iron transport in the brain modulates anxiety-related behaviors. Nat Chem Biol 15, 1214–1222 (2019). https://doi.org/10.1038/s41589-019-0371-x

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