The influence of sex and chronic restraint stress on transcriptional and post-transcriptional regulations on the rat dorsal and ventral hippocampus

Abstract

Our increasing understanding of sex has unveiled its relevance for health and disease. Importantly, the search of the molecular bases that act as the foundations for sex differences in health and disease may provide novel insights to improve clinical outcomes in females and males. In neuropsychiatric disorders, sex biases are quite robust. Specially, stress-related disorders are at least twice as prevalent in females than males. A growing amount of evidence support that alterations in the hippocampus –a limbic brain area in the temporal lobe– may contribute to cognitive and affective symptoms in stressrelated disorders. Importantly, considering the sex biases in stress-related neuropsychiatric disorders and the role of the hippocampus in these disorders, it is mandatory to understand the effects of sex on hippocampal physiology and pathology. Basal sex differences in hippocampal behavior, morphology and plasticity suggest that the molecular architecture must also differ by sex. While this has been studied considering the hippocampus as a homogeneous structure, there are circuitry and molecular gradients along the hippocampal longitudinal axis that differentiates its poles: dorsal-ventral in rodents and posterioranterior in primates. However, no study has investigated the inFluence of sex on the molecular proFiles of the dorsal and ventral hippocampus, nor how they may be regulated. Chronic stress constitutes a risk factor for the majority of neuropsychiatric disorders. We have learned that chronic restraint stress triggers sex-speciFic behavioral and transcriptomic outcomes in the dorsal and ventral rat hippocampus. Nonetheless, we do not know which transcriptional and post-transcriptional regulators may produce such differences. In light of these antecedents, we propose: “Sex and chronic restraint stress inFluence the transcriptional and post-transcriptional regulators in the dorsal and ventral rat hippocampus”. To prove this hypothesis, we First characterized the sex differences in gene expression in the dorsal and ventral hippocampus of adult rats by RNA-seq. We found a larger effect size of sex on the dorsal than ventral hippocampus, and that sex and the hippocampal pole may interact to drive unique expression signatures of a subset of genes. Furthermore, the sex-biased genes were mostly enriched in distinct biological processes and cell-type clusters. Moreover, we also described the sex-biased mature miRNAs in each hippocampal pole. By employing a network-based analysis, we unveiled both known and novel putative transcriptional regulators and miRNAs that may drive the sex-biased gene expression in the adult hippocampus. Similarly, we also describe the putative master regulators for the sex-speciFic effects of chronic restraint stress on the transcriptome. These results may guide future studies to dissect the role of these transcriptional regulators and miRNAs in the study of susceptibility and resilience of each sex against an insult