Geramiah Drew, “The Impact of Histone Acetylation on Adolescent Stress”
Mentor: Polymnia Georgiou, Psychology, Letters & Science (College of)
Poster #48
Major depressive disorder affects approximately 13% of adolescents in the United States. Although traditional antidepressant treatments can help relieve depressive symptoms in adolescents, they often result in low remission rates and carry potential adverse effects, such as suicidal thoughts, highlighting the need for novel pharmacotherapies for adolescent depression. To address this, we conducted extensive bioinformatics analyses and drug repurposing screenings to identify drugs and compounds capable of reversing or mimicking the molecular signatures of adolescent depression by using RNAseq data from the human dorsolateral prefrontal cortex. To validate these results, we performed behavioral testing to assess the reversal of stress-induced maladaptive behaviors in adolescent male and female mice. Our study demonstrated that histone deacetylase inhibitors can reverse the molecular changes observed in adolescents with depression, indicating that increased histone acetylation affects gene expression. Notably, gene ontology analysis revealed significant downregulation of cholesterol metabolic and biosynthetic processes in adolescent patients compared to adults. Since cholesterol is a precursor for most steroid gonadal hormones, pathway enrichment analysis also showed downregulation in steroid biosynthesis. Drug repurposing screening revealed that histone deacetylase (HDAC) inhibitors can reverse the molecular changes in depressed adolescents suggests that decreased histone acetylation may lead to decreased synthesis of steroid gonadal hormones during adolescence, potentially increasing the risk of developing depression. To validate our findings, we subjected adolescent male and female mice to acute foot-shock stress, and followed with an assessment of the development of anhedonia, social preference deficits, and anxiety-like behavior using the sucrose preference, social interaction, and open field tests. Stressed adolescent mice exhibited social interaction deficits and anxiety-like behaviors, which were reversed by administering an HDAC inhibitor before the acute stress. These same stressors induced no effect on the adult mice. Thus, our findings suggest that targeting histone acetylation could provide novel strategies for treating adolescent depression.