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Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain

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Abstract

Major depressive disorder and alcoholism are significant health burdens that can affect executive functioning, cognitive ability, job responsibilities, and personal relationships. Studies in animal models related to depression or alcoholism reveal that the expression of Krüppel-like factor 11 (KLF11, also called TIEG2) is elevated in frontal cortex, which suggests that KLF11 may play a role in stress- or ethanol-induced psychiatric conditions. KLF11 is a transcriptional activator of monoamine oxidase A and B, but also serves other functions in cell cycle regulation and apoptotic cell death. In the present study, immunohistochemistry was used to quantify intensity of nuclear KLF11, combined with an unbiased stereological approach to assess nuclei in fronto-limbic, limbic, and other brain regions of rats exposed chronically to social defeat or ethanol. KLF11 immunoreactivity was increased significantly in the medial prefrontal cortex, frontal cortex, and hippocampus of both stressed rats and rats fed ethanol. However, expression of KLF11 protein was not significantly affected in the thalamus, hypothalamus, or amygdala in either treatment group compared to respective control rats. Triple-label immunofluorescence revealed that KLF11 protein was localized in nuclei of neurons and astrocytes. KLF11 was also co-localized with the immunoreactivity of cleaved caspase-3. In addition, Western blot analysis revealed a significant reduction in anti-apoptotic protein, Bcl-xL, but an increase of caspase-3 expression in the frontal cortex of ethanol-treated rats compared to ethanol-preferring controls. Thus, KLF11 protein is up-regulated following chronic exposure to stress or ethanol in a region-specific manner and may contribute to pro-apoptotic signaling in ethanol-treated rats. Further investigation into the KLF11 signaling cascade as a mechanism for neurotoxicity and cell death in depression and alcoholism may provide novel pharmacological targets to lessen brain damage and maximize neuroprotection in these disorders.

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Acknowledgments

The authors appreciate the support provided by the Animal Behavior Core (Directed by Dr. Ian Paul) of the Center for Psychiatric Neuroscience. This study was supported by Public Health Service Grants R01 AA020103, P30 GM103328, The Brain & Behavior Research Foundation (NARSAD), an Alcohol Research Resource Award Grant (R24 AA015512-02) and an Intramural Research Support grant from the University of Mississippi Medical Center.

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Authors and Affiliations

  1. Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA

    Jeremy Duncan & Jun Ming Wang

  2. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS, 39216, USA

    Jeremy Duncan, Niping Wang, Xiao Zhang, Shakevia Johnson, Sharonda Harris, Grazyna Rajkowska, Jose Javier Miguel-Hidalgo, Xiao-Ming Ou, Craig A. Stockmeier & Jun Ming Wang

  3. Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA

    Baoying Zheng, Qinli Zhang & Jun Ming Wang

  4. Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA

    Donald Sittman

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  1. Jeremy Duncan
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  2. Niping Wang
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Correspondence to Jun Ming Wang.

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Duncan, J., Wang, N., Zhang, X. et al. Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain. Neurotox Res 28, 18–31 (2015). https://doi.org/10.1007/s12640-015-9524-1

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  • DOI: https://doi.org/10.1007/s12640-015-9524-1

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