Pre-reproductive stress (PRS) to adolescent female rats alters anxiogenic behavior in first (F1)- and second-generation (F2) offspring and increases mRNA expression of corticotropin-releasing factor receptor type 1 (Crhr1) in oocytes and in neonate offspring brain. Here, we ask whether the expression of Crhr1 and Crhr1-targeting microRNA is altered in brain, blood, and oocytes of exposed females and in the brain of their neonate and adult F1 and F2 offspring. In addition, we inquire whether maternal post-stress drug treatment reverses PRS-induced abnormalities in offspring. We find that PRS induces a selective increase in Crhr1-targeting mir-34a and mir-34c in blood and oocytes, while non-Crhr1 microRNA molecules remain unaltered. PRS induces similar microRNA changes in prefrontal cortex of F1 and F2 neonates. In adult animals, cortical Crhr1, but not mir-34, expression is affected by both maternal and direct stress exposure. Post-PRS fluoxetine (FLX) treatment increases pup mortality, and both FLX and the Crhr1 antagonist NBI 27914 reverse some of the effects of PRS and also have independent effects on F1 behavior and gene expression. PRS also alters behavior as well as gene and miRNA expression patterns in paternally derived F2 offspring, producing effects that are different from those previously found in maternally derived F2 offspring. These findings extend current knowledge on inter- and trans-generational transfer of stress effects, point to microRNA changes in stress-exposed oocytes as a potential mechanism, and highlight the consequences of post-stress pharmacological interventions in adolescence.
Bibliographical noteFunding Information:
We thank Donna Linder, Reut Donner, Shahar Afek, Samma Zaidan, and Aysha Agbarya for assistance in behavioral procedures. Natalie Gindi and Ruth Shalgi for help with miRNA protocols. Osnat Hadad-Ophir and Lior Ariel for help with CORT quantification. Sigalit Mangut and Nitza Barkan for statistical advice. We also thank Prof. Micah Leshem, Brenda Sbarski, Guy Nahardiya, Hagar Bauminger, and Anna Portugalov for help with extraction of brain and blood samples. This work was made possible by grant support from U.S.-Israel Binational Science Foundation (IGS, 2015036) and from the Israel Science Foundation (IGS, 1481/20). H.Z. was also supported by the President of Israel Scholarship for Excellence and Innovation in Science and the Werner Otto Scholarships, the Jewish Arab Center, University of Haifa; and the Ministry of Science, Technology and Space PhD scholarship competitive doctoral scholarship for minorities in Israel.
© 2021, The Author(s).
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Biological Psychiatry