MDD is one of the most severe and debilitating illnesses that affects millions of individuals worldwide. Despite considerable advances over the past decades, a clear understanding of the etiology of MDD is still lacking. Accumulating evidence suggests that MDD may arise from impairments in cellular cascades, which lead to aberrant information processing in the circuits that regulate mood, cognition, and neurovegetative functions. Recently, microRNAs (miRNAs) have emerged as an important class of small non-coding RNAs that by binding to 3' UTR of mRNAs, suppress the translation and/or stability of specific mRNA targets. Since miRNAs show a highly regulated expression, they contribute in the development and maintenance of a specific transcriptome and thus have the unique ability to influence physiological and disease phenotypes. Our recent studies show that the expression of a group of miRNAs is altered in PFC of MDD subjects and that they are involved in coping response to stress. In addition, accumulative evidence points to the involvement of miRNAs in neural plasticity. These studies suggest a strong possibility that miRNAs may contribute significantly to the etiopathogenesis of MDD. We hypothesize that subsets of miRNAs and their variants, regulated in a coordinated fashion, will show differential co-expression in MDD brain, which by affecting specific neural/synaptic mRNA targets and cellular pathways, will participate in MDD pathogenesis. In well characterized postmortem brain samples obtained from MDD and control subjects, we propose to: 1) profile miRNA expression by small RNA sequencing, identify novel miRNAs, and analyze differentially expressed miRNAs; 2) profile mRNA expression by RNA sequencing and identify regulatory relationships between mRNA and miRNA by mapping co-expression network modules; 3) analyze miRNA-mRNA pairs, validate altered miRNAs and specific target genes experimentally, and localize these changes at the cellular level; 4) analyze pathway associated with differentially co-expressed modules in MDD; 5) examine miRNA biogenesis by determining pri-/pre-miRNAs, RISC complexes, and components of biogenesis machinery; and 6) examine the role of synaptic miRNAs in MDD pathogenesis by determining miRNA enrichment via small RNA sequencing in synaptosomes, analyzing target genes and co-expression modules of miRNA-mRNA specifically altered in the synaptic fraction, and examining pri-/pre-miRNAs and components of miRNA biogenesis machinery at synaptic level. By using a combination of the state-of-the-art high throughput small RNA and RNA sequencing, analyzing data by novel bioinformatics tools and validation, identifying changes in miRNAs and their targets in specific cell type(s), and examining the role of miRNAs at the synaptic level in brain regions implicated in mood and cognition, our proposed study is uniquely positioned to advance the field of MDD research at the molecular level. These investigations will provide novel avenues for the development of miRNAs as ''molecular tools'' with the potential to generate new molecular-based therapies to treat this devastating disorder.

Public Health Relevance

microRNAs are the best-known and best-understood class of small non-coding RNAs that have emerged as major regulators of gene expression. In recent studies, we have found that microRNAs are altered in the brain of depressed subjects and are involved in coping response to stress. These studies, along with studies showing that microRNAs are involved in biological functions including synaptic plasticity, suggest that microRNAs may play a crucial role in the etiopathogenesis of major depression. Our proposed study is aimed at delineating how microRNA can contribute to the pathogenesis of major depression. Since microRNAs are ideally positioned to play a central role in regulating complex gene network, diagnostic and therapeutic strategies based on modulation of microRNA activity hold great promise. By using a combination of the state- of-the-art high throughput small RNA and RNA sequencing, analyzing data by novel bioinformatics tools and validation, identifying changes in microRNAs and their targets in specific cell type(s), and examining the role of microRNAs at the synaptic level in brain regions implicated in mood and cognition, our proposed study is uniquely positioned to advance the field of depression research at the molecular level. These investigations will provide novel avenues for the development of microRNAs as ''molecular tools'' with the potential to generate new molecular-based therapies to treat this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH100616-02
Application #
8816137
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2014-03-05
Project End
2019-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
2
Fiscal Year
2015
Total Cost
$351,050
Indirect Cost
$101,050
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Ludwig, Birgit; Dwivedi, Yogesh (2018) The concept of violent suicide, its underlying trait and neurobiology: A critical perspective. Eur Neuropsychopharmacol 28:243-251
Wang, Qingzhong; Roy, Bhaskar; Turecki, Gustavo et al. (2018) Role of Complex Epigenetic Switching in Tumor Necrosis Factor-? Upregulation in the Prefrontal Cortex of Suicide Subjects. Am J Psychiatry 175:262-274
Ludwig, Birgit; Roy, Bhaskar; Dwivedi, Yogesh (2018) Role of HPA and the HPG Axis Interaction in Testosterone-Mediated Learned Helpless Behavior. Mol Neurobiol :
Dwivedi, Yogesh (2018) MicroRNAs in depression and suicide: Recent insights and future perspectives. J Affect Disord 240:146-154
Roy, Bhaskar; Wang, Qingzhong; Dwivedi, Yogesh (2018) Long Noncoding RNA-Associated Transcriptomic Changes in Resiliency or Susceptibility to Depression and Response to Antidepressant Treatment. Int J Neuropsychopharmacol 21:461-472
Ii Timberlake, Matthew; Dwivedi, Yogesh (2018) Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications. Mol Psychiatry :
Timberlake 2nd, Matthew; Prall, Kevin; Roy, Bhaskar et al. (2018) Unfolded protein response and associated alterations in toll-like receptor expression and interaction in the hippocampus of restraint rats. Psychoneuroendocrinology 89:185-193
Wang, Qingzhong; Shelton, Richard C; Dwivedi, Yogesh (2018) Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. J Affect Disord 225:422-428
Roy, Bhaskar; Wang, Qingzhong; Palkovits, Miklos et al. (2017) Altered miRNA expression network in locus coeruleus of depressed suicide subjects. Sci Rep 7:4387
Wang, Qingzhong; Dwivedi, Yogesh (2017) Transcriptional profiling of mitochondria associated genes in prefrontal cortex of subjects with major depressive disorder. World J Biol Psychiatry 18:592-603

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