Maternal stress programs a demasculinization in stress-related brain regions of aged rats

Published: 05-26-2021 In Publication

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Maternal stress programs a demasculinizationof glutamatergic transmission in stress-related brainregions of aged rats



Brain aging may be programmed by early-life stress. Aging affects males and females differently,but how perinatal stress (PRS) affects brain aging be-tween sexes is unknown. We showed behavioral andneurobiological sex differences in non-stressed controlrats that were strongly reduced or inverted in PRS rats.In particular, PRS decreased risk-taking behavior, spa-tial memory, exploratory behavior, and fine motor be-havior in male aged rats. In contrast, female aged PRSrats displayed only increased risk-taking behavior andreduced exploratory behavior. PRS induced large reduc-tions in the expression of glutamate receptors in theventral and dorsal hippocampus and prefrontal cortexonly in male rats. PRS also reduced the expression ofsynaptic vesicle-associated proteins, glucocorticoid re-ceptors (GR), and mineralocorticoid receptors (MR) inthe ventral hippocampus of aged male rats. In contrast,in female aged rats, PRS enhanced the expression ofMRs and brain-derived neurotrophic factor (BDNF) inthe ventral hippocampus and the expression of glialfibrillary acidic protein (GFAP) and BDNF in the pre-frontal cortex. A common PRS effect in both sexes wasa reduction in exploratory behavior and metabotropicglutamate (mGlu2/3) receptors in the ventralhippocampus and prefrontal cortex. A multidimensionalanalysis revealed that PRS induced a demasculinizationprofile in glutamate-related proteins in the ventral anddorsal hippocampus and prefrontal cortex, as well as ademasculinization profile of stress markers only in thedorsal hippocampus. In contrast, defeminization wasobserved only in the ventral hippocampus. Measure-ments of testosterone and 17-β-estradiol in the plasmaand aromatase in the dorsal hippocampus were consis-tent with a demasculinizing action of PRS. These find-ings confirm that the brains of males and females dif-ferentially respond to PRS and aging suggesting thatfemales might be more protected against early stress andage-related inflammation and neurodegeneration. Takentogether, these results may contribute to understandinghow early environmental factors shape vulnerability tobrain aging in both sexes and may lay the groundworkfor future studies aimed at identifying new treatmentstrategies to improve the quality of life of older individ-uals, which is of particular interest given that there is ahigh growth of aging in populations around the world.


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