ABSTRACT The estimated 20–30% of women who develop perimenopausal depression (PMD) are at an increased risk of cardiovascular and all-cause mortality. The therapeutic benefits of estradiol

(E2) and symptom-provoking effects of E2-withdrawal (E2-WD) suggest that a greater sensitivity to changes in E2 at the cellular level contribute to PMD. We developed an in vitro model of PMD

with lymphoblastoid cell lines (LCLs) derived from participants of a prior E2-WD clinical study. LCLs from women with past PMD (_n_ = 8) or control women (_n_ = 9) were cultured in three

experimental conditions: at vehicle baseline, during E2 treatment, and following E2-WD. Transcriptome analysis revealed significant differences in transcript expression in PMD in all

conditions (_F_(1,45) = 19.93, _p_ < 0.0001). These transcripts were further validated via qRT-PCR. Gene networks dysregulated in PMD included inflammatory response, early/late

E2-response, and cholesterol homeostasis. Our results provide evidence that differential behavioral responsivity to E2-WD in PMD reflects intrinsic differences in cellular gene expression.

Genes such as _CXCL10_, _CYP7B1_, and corresponding proinflammatory and steroid biosynthetic gene networks, may represent biomarkers and molecular targets for intervention in PMD. Finally,

this in vitro model allows for future investigations into the mechanisms of genes and gene networks involved in the vulnerability to, and consequences of, PMD. Access through your

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BEING VIEWED BY OTHERS INTRINSICALLY DYSREGULATED CELLULAR STRESS SIGNALING GENES AND GENE NETWORKS IN POSTPARTUM DEPRESSION Article 13 February 2023 ALTERED ESTRADIOL-DEPENDENT CELLULAR

CA2+ HOMEOSTASIS AND ENDOPLASMIC RETICULUM STRESS RESPONSE IN PREMENSTRUAL DYSPHORIC DISORDER Article Open access 25 May 2021 TRANSCRIPTOMIC SIGNALING PATHWAYS INVOLVED IN A NATURALISTIC

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Download references ACKNOWLEDGEMENTS We would like to thank Alan Meyers, Cheryl Marietta, Longina Akhtar, Allison Goff, and Maria Mazzu of NIH/NIAAA for their technical assistance and

expertise in conducting this study. We would also like to thank Karla Thompson, Kai Shi, and Linda Schenkel of NIH/NIMH for their clinical support and data management. This research was

supported by the Intramural Research Program of the NIMH and NIAAA NIH; NIMH Protocols 03-M-0175 (NCT00060736), 88-M-0131 (NCT00001231); NIMH Project ZIA MH002537; NIAAA Project ZIA

AA000301. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Behavioral Endocrinology Branch, NIMH, Bethesda, MD, USA Sarah Rudzinskas, Jessica F. Hoffman, Pedro Martinez & Peter J. Schmidt *

Laboratory of Neurogenetics, NIAAA, Rockville, MD, USA Sarah Rudzinskas, Jessica F. Hoffman & David Goldman * Department of Psychiatry, University of North Carolina, Chapel Hill, NC,

USA David R. Rubinow Authors * Sarah Rudzinskas View author publications You can also search for this author inPubMed Google Scholar * Jessica F. Hoffman View author publications You can

also search for this author inPubMed Google Scholar * Pedro Martinez View author publications You can also search for this author inPubMed Google Scholar * David R. Rubinow View author

publications You can also search for this author inPubMed Google Scholar * Peter J. Schmidt View author publications You can also search for this author inPubMed Google Scholar * David

Goldman View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Peter J. Schmidt. ETHICS DECLARATIONS CONFLICT OF INTEREST

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