Anterior Cingulate MicroRNA Expression Differences in Mood Disorder Patients: Contrasts with Transcriptomic Analyses in an Animal Model of Depression.

Psychiatric illness;microRNA;Genetics;Neurosciences;Health Sciences;Neuroscience

Azevedo, Joshua A.Uhler, Michael D ;

University of Michigan

关键词: Psychiatric illness;    microRNA;    Genetics;    Neurosciences;    Health Sciences;    Neuroscience;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/120860/jazevedo_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Mood disorders were initially recognized as a legitimate illness in Hippocrates’ Aphorisms. Two of the most prevalent and debilitating mood disorders are major depressive disorder (MDD) and bipolar disorder (BP). While a number of studies have established a genetic component to these illnesses, the genomic architecture remains less than clear. Recently, microRNAs—small, non-coding RNAs that act as posttranscriptional regulators of gene expression—have demonstrated dysregulation in psychiatric disease state. Given these data, we hypothesized that miRNAs may exhibit mood-disorder-dependent differential expression in the anterior cingulate cortex (AnCg), a brain region heavily involved in the regulation of mood. In our first set of studies we employed qPCR analyses of 29 miRNAs implicated in psychiatric illness in AnCg of patients with MDD and BP versus controls. We validated a number of miRNAs as dysregulated in these illnesses and subsequently identified (and validated) several mRNA targets of miRNAs dysregulated in disease. Finally, we demonstrated alterations in the steady-state levels of two of these mRNA targets. In a second set of studies we examined the impact of chronic stress on the transcriptomic network in medial prefrontal cortex (mPFC). Chronic stress is a major precipitant of neuropsychiatric illness and induces a number of physiological and genetic changes in a highly brain-region-dependent fashion. Due to this, we hypothesized that chronic stress would have a significant impact on gene expression in mPFC, a brain region centrally involved in stress responses and regulating HPA axis activity. Furthermore, given that mPFC hypofunction is one of the most commonly observed stress-induced deficits, we hypothesized these gene changes would be consistent with mPFC hypofunction. By employing RNA sequencing and high throughput qPCR analyses, we validated a number of mRNA and miRNA transcripts as stress-regulated. We finally constructed a biochemical ;;interactome” of stress-regulated mRNAs using bioinformatics tools and literature screens that is consistent with chronic stress- induced glutamatergic hypofunction in mPFC. The work outlined in this thesis sheds light on transcriptomic events that occur in in human mood disorders or in animal models of chronic stress, which could be of clinical relevance in understanding the molecular architecture of mood disorders.