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Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats

Abstract

Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.

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Fig. 1: Overview of study design.
Fig. 2: Brain region- and sex-specific effects of perinatal fluoxetine and maternal adversity on gene expression.
Fig. 3: Gene expression related to “Myelin sheath” is associated with perinatal fluoxetine and maternal adversity in a brain region- and sex-specific manner.
Fig. 4: Maternal adversity and perinatal fluoxetine exposure interact to affect myelin-related gene expression in the BLA.
Fig. 5: DNA methylation of Mag and Mbp correlates to gene expression.

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Acknowledgements

We thank Judith Swart, Wanda Douwenga, and Christa Reitzema-Klein for their assistance with the early life stress procedure and drug administration. In addition, we thank Wanda Douwenga for performing the qPCR work.

Funding

JDAO was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska Curie Individual Fellowship under Grant 660152-DEPREG; and a NARSAD young investigator grant under Grant 25206.

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Study conception and design: JDAO, TP. Acquisition of data: ASR, RNVS, and DJH. Analysis and interpretation of data: ASR, JDAO. Drafting of paper: ASR, JDAO. Critical revision: RNVS, DJH, and TP.

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Correspondence to Jocelien D. A. Olivier.

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Ramsteijn, A.S., Verkaik-Schakel, R.N., Houwing, D.J. et al. Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats. Neuropsychopharmacol. 47, 1620–1632 (2022). https://doi.org/10.1038/s41386-022-01270-z

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