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Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression

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Abstract

Now astrocytes appear to be the key contributors to the pathophysiology of major depression. Evidence in rodents shows that chronic stress is associated with a decreased expression of astrocytic GFAP-immunoreactivity within the cortex in addition to changes in the complexity and length of astrocyte processes. Furthermore, postmortem brains of individuals with depression have revealed a decrease in astrocyte density. Notably, astrocytes are extensively coupled to one another through gap junctions to form a network, or syncytium, and we have previously demonstrated that syncytial isopotentiality is a mechanism by which astrocytes function as an efficient system with respect to brain homeostasis. Interestingly, the question of how astrocyte network function changes following chronic stress is yet to be elucidated. Here, we sought to examine the effects of chronic stress on network-level astrocyte (dys)function. Using a transgenic aldh1l1-eGFP astrocyte reporter mouse, a six-week unpredictable chronic mild stress (UCMS) paradigm as a rodent model of major depression, and immunohistochemical approaches, we show that the morphology of individual astrocytes is altered by chronic stress exposure. Additionally, in astrocyte syncytial isopotentiality measurement, we found that UCMS impairs the syncytial coupling strength of astrocytes within the hippocampus and prefrontal cortex—two brain regions that have been implicated in the regulation of mood. Together, these findings reveal that chronic stress leads to astrocyte atrophy and impaired gap junction coupling, raising the prospect that both individual and network-level astrocyte functionality are important in the etiology of major depression and other neuropsychiatric disorders.

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All data generated or analyzed for this study are included in this article. Please contact the corresponding author with questions or requests.

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Acknowledgements

The authors thank Michaela Witt for technical assistance.

Funding

This work was sponsored by a grant from National Institute of Neurological Disorders and Stroke; Grant code: RO1NS116059 (MZ), and an Alumni Grants for Graduate Research and Scholarship (AGGRS) and Distinguished University Fellowship, Ohio State University (to SA).

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  1. Sydney Aten

    Present address: Department of Neurology, Division of Sleep Medicine, and Program in Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA

  2. Conrad Kiyoshi

    Present address: Northern Marianas College, Saipan, MP, USA

Authors and Affiliations

  1. Department of Neuroscience, Ohio State University Wexner Medical Center, Graves Hall, Rm 4066C, 333 W. 10th Ave, Columbus, OH, 43210, USA

    Sydney Aten, Yixing Du, Olivia Taylor, Courtney Dye, Kelsey Collins, Matthew Thomas, Conrad Kiyoshi & Min Zhou

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Contributions

All authors contributed to the study conception and design. Conceptualization, data acquisition, data analysis/interpretation, drafting of original manuscript, and manuscript revisions were performed by SA. Conceptualization, data acquisition, data analysis/interpretation, and manuscript revisions were performed by YD. OT, CD, and KC performed data analysis and assisted in manuscript revision. MT assisted with data acquisition and manuscript revision. CK assisted with project conceptualization and manuscript revision. MZ participated in project conceptualization, data interpretation and manuscript revision. All authors read and approved the final manuscript.

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Correspondence to Min Zhou.

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Animal care protocols and methods were approved by the Ohio State University's Institutional Animal Care and Use Committee (IACUC). Mice were exposed to 2–3 stressors each day for a period of six consecutive weeks. Of note, to prevent animals from habituating to the daily stressors, these stressors were performed at different times throughout the day (i.e., in the morning, afternoon, evening, and overnight).

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Aten, S., Du, Y., Taylor, O. et al. Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression. Neurochem Res 48, 1191–1210 (2023). https://doi.org/10.1007/s11064-022-03663-4

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