Periodic Reporting for period 1 - EstroGen (Reciprocal interactions between hypogonadism and epigenetic modifications: A path for the development of personalized treatments for depression)
Période du rapport: 2022-03-14 au 2024-03-13
This project examines the relationship between hormonal changes, particularly hypogonadism (insufficient sex hormone production), and depression. Depression is a prevalent mental health disorder affecting millions, resulting in significant personal, social, and economic burdens. A critical factor contributing to depression, especially in aging populations or individuals undergoing procedures that lower hormone levels (e.g. gonadectomy), is the deficiency of sex hormones like estrogen or testosterone. However, the precise biological mechanisms linking hormonal imbalances to mood disorders are still unclear.
Understanding these connections is vital for enhancing mental health treatments, especially for vulnerable groups like the elderly. Depression is a leading cause of disability, affecting quality of life, productivity, and healthcare costs while contributing to societal issues like suicide risk. Additionally, exploring how hormonal changes affect brain function can lead to targeted therapies. This project investigates potential biomarkers for earlier detection and personalized treatment of depression, improving therapeutic effectiveness and reducing the burden of mental health disorders.
The project has two main objectives: 1) To characterize the effects of combined hypogonadism and mild stress on the brain and its epigenetic landscape (changes in gene expression without altering the DNA sequence). 2) To identify biomarkers of hypogonadism-induced epigenetic changes that predict vulnerability to depression, paving the way for earlier and more personalized interventions.
Understanding these connections is vital for enhancing mental health treatments, especially for vulnerable groups like the elderly. Depression is a leading cause of disability, affecting quality of life, productivity, and healthcare costs while contributing to societal issues like suicide risk. Additionally, exploring how hormonal changes affect brain function can lead to targeted therapies. This project investigates potential biomarkers for earlier detection and personalized treatment of depression, improving therapeutic effectiveness and reducing the burden of mental health disorders.
The project has two main objectives: 1) To characterize the effects of combined hypogonadism and mild stress on the brain and its epigenetic landscape (changes in gene expression without altering the DNA sequence). 2) To identify biomarkers of hypogonadism-induced epigenetic changes that predict vulnerability to depression, paving the way for earlier and more personalized interventions.
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.
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.
Our project enhances the understanding of mood disorders by integrating systems bioinformatics with hormonal and epigenetic studies. We found that ERβ knockout mice had significant REM sleep and behavioral changes after stress. These results underscore the importance of hormonal regulation in mood and sleep. Hormonal changes due to hypogonadism significantly impact mood and sleep, indicating a need for hormonal therapies in age-related mood disorders. Changes in H3K27me3 suggest that epigenetic modifications contribute to mood regulation through the silencing of ERβ. In our study of adolescent depression, stress-induced behavioral deficits in adolescent mice could be reversed by HDAC inhibitors like Trichostatin A, indicating that targeting epigenetic mechanisms may offer a novel treatment approach. Our RNAseq analysis revealed downregulation of cholesterol biosynthesis pathways, linking hormonal dysregulation to mood disorders across life stages. These findings suggest that increased deacetylation during adolescence reduces steroid biosynthesis, heightening stress susceptibility and depression risk. We examined the comorbidity of MDD and SUDs with aging-related conditions like Alzheimer’s disease. We identified aging signatures in MDD and SUDs, showing that inhibiting the FOS gene family may mitigate premature aging. Additionally, targeting Histone 4 could effectively treat both progeria syndrome and MDD, while some rapid-acting antidepressants may accelerate aging in patients with comorbid conditions. Notably, estradiol administration may reverse depression in aging populations. Analysis of postmortem hippocampal samples from Alzheimer’s patients showed upregulation of estrogen signaling pathways, indicating a compensatory neuroprotective response. We identified key susceptibility genes interacting with ERβ that may serve as potential biomarkers for early Alzheimer’s detection. Looking ahead, we aim to validate our findings by focusing on ERβ and epigenetic regulation in mood disorders. Identifying novel strategies, such as ERβ agonists or HDAC inhibitors, could lead to effective treatments for adolescent depression and aging-related mood disorders. The socio-economic impact is significant, as effective therapies for MDD, SUDs, and age-related disorders could lower healthcare costs and improve quality of life. Early detection of Alzheimer’s through identified biomarkers could slow disease progression, easing the burden on families and healthcare systems. Ultimately, our research seeks to enhance mental health outcomes and promote healthy aging by addressing the hormonal and epigenetic roots of mood disorders, paving the way for personalized and effective treatments. Importantly, the Marie Curie had a significant impact the researcher career. She was able to secure 2 job offers for the position of the Assistant Professor. This would have not been possible without the skills earned and publications and funding gained due to the Marie Curie project.