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Neuron-Microglia Interaction is Involved in Anti-inflammatory Response by Vagus Nerve Stimulation in the Prefrontal Cortex of Rats Injected with Polyinosinic:Polycytidylic Acid

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Abstract

Injection of polyinosinic:polycytidylic acid (poly(I:C)) into experimental animals induces neuroimmunological responses and thus has been used for the study of neurological disorders such as anxiety, depression, and chronic fatigue. Here, we investigated the effects of vagus nerve stimulation (VNS) on poly(I:C)-induced neuroinflammation and associated behavioral consequences in rats. The microglia in the prefrontal cortex (PFC) displayed the activated form of morphology in poly(I:C)-injected rats and changed to a normal shape after acute VNS (aVNS). Production of phospho-NF-κB, phospho-IκB, IL-1β, and cleaved caspase 3 was elevated by poly(I:C) and downregulated by aVNS. In contrast, phospho-Akt levels were decreased by poly(I:C) and increased by aVNS. Neuronal production of fractalkine (CX3CL1) in the PFC was markedly reduced by poly(I:C), but recovered by aVNS. Fractalkine interaction with its receptor CX3CR1 was highly elevated by VNS. We further demonstrated that the pharmacological blockade of CX3CR1 activity counteracted the production of IL-1β, phospho-Akt, and cleaved form of caspase 3 that was modulated by VNS, suggesting the anti-inflammatory effects of fractalkine-CX3CR1 signaling as a mediator of neuron-microglia interaction. Behavioral assessments of pain and temperature sensations by von Frey and hot/cold plate tests showed significant improvement by chronic VNS (cVNS) and forced swimming and marble burying tests revealed that the depressive-like behaviors caused by poly(I:C) injection were rescued by cVNS. We also found that the recognition memory which was impaired by poly(I:C) administration was improved by cVNS. This study suggests that VNS may play a role in regulating neuroinflammation and somatosensory and cognitive functions in poly(I:C)-injected animals.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

aVNS:

Acute vagus nerve stimulation

CFS:

Chronic fatigue syndrome

cVNS:

Chronic vagus nerve stimulation

FST:

Forced swimming test

LPS:

Lipopolysaccharide

PFC:

Prefrontal cortex

poly(I:C):

Polyinosinic:polycytidylic acid

VNS:

Vagus nerve stimulation

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Acknowledgements

We are indebted to the former and present members of the Neurophysiology Laboratory at Daejeon University for their valuable discussions and comments. We are grateful to Eui Namgung (University of California, San Diego) for critically reading the manuscript.

Funding

This work was supported by the Basic Science Research Programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1A6A1A03025221) and the Daejeon University fund (grant number 20220159).

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Authors and Affiliations

  1. Department of Korean Medicine, Institute of Bioscience and Integrative Medicine, Daejeon University, Daehak‑ro 62, Daejeon, 34520, South Korea

    Ki-Joong Kim, Jinyeon Hwang, Kang-Woo Lee, Jieun Kim, Yunha Han & Uk Namgung

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Contributions

All experiments were performed in the Daejeon University. All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ki-Joong Kim, Jinyeon Hwang, Kang-Woo Lee, Jieun Kim, Yunha Han, and Uk Namgung. The first draft of the manuscript was written by Uk Namgung and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Uk Namgung.

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All animal care procedures were approved by the Committee on Use of Live Animals for Teaching and Research at Daejeon University.

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Kim, KJ., Hwang, J., Lee, KW. et al. Neuron-Microglia Interaction is Involved in Anti-inflammatory Response by Vagus Nerve Stimulation in the Prefrontal Cortex of Rats Injected with Polyinosinic:Polycytidylic Acid. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04054-2

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