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Minocycline Ameliorates Chronic Unpredictable Mild Stress-Induced Neuroinflammation and Abnormal mPFC-HIPP Oscillations in Mice

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Abstract

Stress-induced neuroinflammation is a hallmark of modern society and has been linked to various emotional disorders, including anxiety. However, how microglia-associated neuroinflammation under chronic unpredictable mild stress (CUMS) alters mitochondrial function and subsequent medial prefrontal cortex-hippocampus (mPFC-HIPP) connectivity remains obscure. We speculated that CUMS might induce neuroinflammation, which involves altered mitochondrial protein levels, blockade of neuroinflammation by a microglial modulator, minocycline, protects against CUMS-induced alterations. Mice were exposed to CUMS for 3 weeks and received minocycline (50 mg/kg) intraperitoneally for 7 consecutive days during the 3rd week of CUMS. Novelty-suppressed feeding test and contextual anxiety test assessed anxiety-like behavior. Western blotting and immunofluorescent staining were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. In vivo dual-site extracellular recordings of local field potential (LFP) were conducted to evaluate the oscillatory activity and brain connectivity in mPFC-HIPP circuitry. We show that CUMS results in excessive microglial activation accompanied by aberrant levels of mitochondrial proteins, such as ATP-5A and the fission protein, Drp-1, increased oxidative stress indicated by elevated levels of nitrotyrosine, and decreased Nrf-2 levels. Furthermore, CUMS causes downregulation of α1 subunit of GABAAR, vesicular GABA transporter (Vgat), and glutamine synthetase (GS), leading to impaired LFP and connectivity of the mPFC-HIPP circuitry. Strikingly, blockage of microglial activation by minocycline ameliorates CUMS-induced aberrant levels of mitochondrial and GABAergic signaling proteins and prevents CUMS-induced anxiety-like behavior in mice. To the end, the study revealed that microglia is critically involved in stress-induced neuroinflammation, which may underlie the molecular mechanism of CUMS-induced anxiety behavior.

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Data Availability

All data generated or analyzed in this study are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (32170950, 31970915, 31871170, 81804197, 31771219), the Guangdong Natural Science Foundation for Major Cultivation Project (2018B030336001), and the Guangdong Grant 'Key Technologies for Treatment of Brain Disorders’ (2018B030332001).

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Author notes

  1. Sidra Tabassum, Afzal Misrani, and Qingwei Huo contributed equally to this work.

Authors and Affiliations

  1. Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, 510006, China

    Sidra Tabassum, Afzal Misrani & Li Yang

  2. South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou, 511400, China

    Sidra Tabassum, Afzal Misrani & Cheng Long

  3. School of Life Sciences, South China Normal University, Guangzhou, 510631, China

    Sidra Tabassum, Afzal Misrani, Adeel Ahmed & Cheng Long

  4. South China Research Center for Acupuncture-Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Qingwei Huo

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  1. Sidra Tabassum
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  2. Afzal Misrani
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  4. Adeel Ahmed
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  5. Cheng Long
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  6. Li Yang
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Contributions

ST, project initiation, experimental design, western blotting, behavior, statistical analysis, and manuscript writing; AM, western blotting, statistical analysis, and manuscript writing; QH, LFP recording, data analysis, and figure generation; AA, immunostaining and analysis; CL, funding acquisition and supervision; LY guided the experiments and was responsible for funding acquisition and critical revision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cheng Long or Li Yang.

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Ethics Approval

This study was approved by the Guangzhou University and South China Normal University Institutional Review Boards. The use of animals in experiments was approved by the Institutional Animal Care and Use Committee (IACUC) and followed National Institutes of Health (NIH) guidelines.

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Tabassum, S., Misrani, A., Huo, Q. et al. Minocycline Ameliorates Chronic Unpredictable Mild Stress-Induced Neuroinflammation and Abnormal mPFC-HIPP Oscillations in Mice. Mol Neurobiol 59, 6874–6895 (2022). https://doi.org/10.1007/s12035-022-03018-8

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