This project investigates hormonal changes, stress, and epigenetic mechanisms in mental disorders, identifying shared molecular pathways across life stages to inform therapies. Initially, we examined the roles of estrogen receptor beta (ERβ) and estradiol in stress-induced depressive-like behaviors. Gonadectomized mice modeling hormonal decline exhibited significant social interaction deficits and anhedonia post-stress, with RNAseq analysis of the ventral hippocampus revealing downregulation of ERβ (ESR2) and sleep regulation genes (RORA, NR1D1). ERβ knockout mice confirmed the receptor’s critical role, displaying REM sleep disturbances, anhedonia, and altered brainwave activity linked to neurotransmission dysregulation. Epigenetic analyses identified H3K27me3 modifications driving these changes. Adolescence emerged as a critical period, with stressed adolescent mice showing social deficits and RNAseq revealing steroid biosynthetic pathway downregulation in the prefrontal cortex. Screening identified histone deacetylase inhibitors like Trichostatin A (TCA) as potential treatments, with TCA reversing stress-induced maladaptive behaviors. In comorbid disorders such as depression and Alzheimer’s, we explored the regulatory role of ERβ. Bioinformatics analyses linked premature aging "signatures" to major depressive disorder (MDD) and substance use disorders (SUDs), identifying FOS gene family inhibition and Histone 4 targeting as potential interventions. Conversely, antidepressants activating the PI3K/Akt/mTOR pathway may accelerate aging, particularly in dementia comorbidities. Estradiol was identified as a promising anti-aging intervention, and susceptibility genes interacting with ESR1/ESR2 were proposed as biomarkers for early Alzheimer’s detection.
Findings have been presented at international conferences, including symposia at the Mediterranean Neuroscience Society Meeting (2023) and Ketamine and Related Compounds Conference (2022). Invited seminars were delivered at Boehringer Ingelheim and the University of Cyprus in 2022. Poster presentations were given at the American College of Neuropsychopharmacology (2022, 2023) and Neuroscience 2023 conferences. Public engagement efforts included but not limited to the European Researchers’ Night. Updates were regularly shared on social media platforms. Two peer-reviewed publications have been released, with two more in preparation, and results informed successful grant applications, including one from the Brain & Behavior Research Foundation. Dr. Georgiou received extensive training in bioinformatics for RNAseq analysis and epigenetic modification identification, RNA extraction techniques, and advanced knowledge in epigenetics. These skills enabled her to conduct cutting-edge research and develop interventions targeting epigenetic changes to reverse maladaptive behaviors.
