Comprehensive Analysis of circRNA Expression and circRNA-miRNA-mRNA Networks in the Ventral Hippocampus of the Rat: Impact of Chronic Stress and Biological Sex

This study provides new insights into how sex and chronic
stress
influence circRNA expression in the rat ventral hippocampus, a region
critical for emotional processing. We identified 206 sex-biased circRNAs
and 194 stress-responsive circRNAs, highlighting distinct expression
profiles. Parental genes of male circRNAs were primarily enriched
in synaptic transmission pathways, while those of female circRNAs
were associated with axon guidance, emphasizing sex-specific molecular
differences. Chronic stress also triggered miRNA changes unique to
each sex, revealing divergent regulatory mechanisms. The identified
circRNA-miRNA-mRNA axes, modulated under stress, appear to regulate
the translation of numerous potential mRNA targets. In males, stress
positively regulated neuroprotective pathways, suggesting a compensatory
response to mitigate stress-induced damage. In contrast, females exhibited
a broader translational network that favored mRNA expression without
distinct pathway-specific actions. However, the smaller repressed
network in femalescharacterized by a higher circRNA-to-miRNA
and mRNA ratiomay indicate a more selective and targeted regulatory
mechanism, with many interactions linked to anti-inflammatory processes.
Coexpression analysis revealed two male-specific modules with altered
activity under stress. These were associated with processes such as
reticulum stress and actin dynamics, the latter linked to dendritic
spine loss and depressive-like behaviors, extensively documented in
chronically stressed male rats. Conversely, females displayed an activated
stress-responsive module, promoting axon guidance and long-term potentiation,
which may contribute to improved cognitive outcomes. Among the identified
circRNAs, rno-Gabrg3_0001 emerged as stress-sensitive in males. This
circRNA exhibited predicted miRNA binding sites and interactions with
proteins involved in vesicle trafficking, forming part of a highly
active module enriched in genes related to ion transport and membrane
protein localization. Overall, these findings uncover sex-dependent
regulatory mechanisms driving transcriptomic changes under chronic
stress, deepening our understanding of ventral hippocampal molecular
functions. Investigating these regulatory networks, which differentially
affect the male and female ventral hippocampus, could inform the development
of sex-specific therapeutic strategies for stress-related disorders.