Sex-Dependent Changes of miRNA Levels in the Hippocampus of Adrenalectomized Rats Following Acute Corticosterone Administration

We
explored sex-biased effects of the primary stress glucocorticoid
hormone corticosterone on the miRNA expression profile in the rat
hippocampus. Adult adrenalectomized (ADX) female and male rats received
a single corticosterone (10 mg/kg) or vehicle injection, and after
6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses.
miRNA profiling microarrays showed a basal sex-biased miRNA profile
in ADX rat hippocampi. Additionally, acute corticosterone administration
triggered a sex-biased differential expression of miRNAs derived from
genes located in several chromosomes and clusters on the X and 6 chromosomes.
Putative promoter analysis unveiled that most corticosterone-responsive
miRNA genes contained motifs for either direct or indirect glucocorticoid
actions in both sexes. The evaluation of transcription factors indicated
that almost 50% of miRNA genes sensitive to corticosterone in both
sexes was under glucocorticoid receptor regulation. Transcription
factor-miRNA regulatory network analyses identified several transcription
factors that regulate, activate, or repress miRNA expression. Validated
target mRNA analysis of corticosterone-responsive miRNAs showed a
more complex miRNA–mRNA interaction network in males compared
to females. Enrichment analysis revealed that several hippocampal-relevant
pathways were affected in both sexes, such as neurogenesis and neurotrophin
signaling. The evaluation of selected miRNA targets from these pathways
displayed a strong sex difference in the hippocampus of ADX-vehicle
rats. Corticosterone treatment did not change the levels of the miRNA
targets and their corresponding tested proteins. Our data indicate
that corticosterone exerts a sex-biased effect on hippocampal miRNA
expression, which may engage in sculpting the basal sex differences
observed at higher levels of hippocampal functioning.