| Abstract | dc.description.abstract | The primary findings from our research group suggest that control female Sprague Dawley rats show poor cognitive performance in tests involving the dorsal hippocampus, but their performance significantly improves under chronic restraint stress. Conversely, males exhibit the opposite pattern, with control males demonstrating better cognitive performance, which declines under stress.
This thesis delves deeper into the basal and stress-induced differences in various molecular aspects, including the morphology of hippocampal neurons, specifically in the CA1 stratum, as well as the evaluation of transcriptomic and epitranscriptomic signatures in the dorsal hippocampus of rats. Our findings indicate that CA1 neurons in female rats at estrus exhibit more Sholl intersections in apical dendrites at 60 μm from the soma compared to males. After chronic stress, females lose their dendritic complexity, resembling the profile of control males. In contrast, stressed males display greater dendritic complexity, similar to that of control females. On the other hand, basal dendrites showed a higher number of crossings in the Sholl analysis at 330-340 μm, without showing any influence of sex or stress. These morphological differences clearly highlight their sex-specific neuronal connectivity, which may not only shape hippocampal functioning in males and females but also play a role in their vulnerability to chronic stress conditions.
Furthermore, activity-dependent gene expression and mRNA translation confer neurons the ability to dynamically modify their synaptic strength in response to stimuli and during learning and memory processes. The most abundant and reversible RNA modification in the brain is m6A, which regulates RNA stability, splicing, export, localization, and translation, positioning the m6A tag as a versatile regulator of nervous system functions, including neuronal plasticity, learning, and memory. In this thesis, we report for the first time that biological sex impacts the levels of some components of the m6A machinery at basal levels and under chronic restraint stress. ALKBH5 in females showed a higher dendritic/somatic ratio in CA1, with levels insensitive to stress, suggesting a demethylase activity in CA1 dendrites of females. Interestingly, the YTHDF2 m6A reader —linked to axonal growth of DG granular neurons— was reduced in the CA1 of stressed females, with a similar but not significant profile in DG. In contrast, the YTHDF3 reader has been reported to have a dual effect. In synergy with YTHDF1, it promotes mRNA translation, but combined with YTHDF2, it favors methylated mRNA decay. YTHDF3 immunoreactivity increased in the DG of females under chronic stress, showing a similar pattern in CA1, although not significant.
Finally, using Nanopore direct RNA sequencing technology, we described for the first time that stressed females exhibited a higher number of both m6A sites and modified transcripts in the dorsal hippocampus compared to stressed males. Additionally, we detected that approximately 41.6% of m6A sites and 88.8% of modified genes were common across all groups (both control and stress in either sex). | es_ES |
