Type
Text
Type
Dissertation
Advisor
Gergen, Peter | Canli, Turhan | Furie, Martha | Kritzer, Mary | Hadjiargyrou, Michael | DeWan, Andrew.
Date
2015-08-01
Keywords
Anxiety, miR-133a, miR-218, SV2A, TSST | Genetics
Department
Department of Genetics.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77628
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
In humans and other animals, the amygdala has been shown to play a role in implicit emotional learning and memory, emotional modulation of memory, emotional influences on attention and perception, emotion and social behavior. Amygdala function has also been linked to personality traits and neuropsychiatric conditions, including anxiety disorders. The aim of the present study was to investigate the biological underpinnings of trait anxiety through a study of microRNA-mediated gene regulation, which was accomplished by global profiling of post-mortem human brain tissue from the lateral nucleus of the amygdala (LA). Gene expression in postmortem LA tissue from donors with known antemortem high trait anxiety (n=10) was compared to that in donors with known antemortem low trait anxiety (n=10) through an integration of genome-wide proteomics, mRNA, and microRNA approaches. Gene expression analysis and literature search approaches focused on the synaptic vesicle glycoprotein 2A gene (SV2A) which showed decreased protein expression in trait anxious individuals compared to controls, no difference in mRNA expression between the two groups, and increased expression of three microRNAs predicted to target SV2A, namely miR-133a, miR-138, and miR-218. Reporter-gene assays and microRNA overexpression experiments in human neuroblastoma cells showed that miR-133a and miR-218, (but not miR-138), functionally target SV2A. The subsequent addition of 26 LA samples (total study n=46) demonstrated that SV2A expression is more complex in the anxious phenotype. Both increased and decreased levels of SV2A showed association with an anxious phenotype, supporting prior in vitro and in vivo experiments that have demonstrated the necessity of tight regulation of SV2A levels for optimal synaptic functioning. The impact of psychosocial stress on a variety of negative health outcomes is well documented, with much of the current research efforts directed at possible mechanisms. In an effort to investigate the biological effects of psychosocial stress, we performed gene expression analysis in peripheral blood mononuclear cells. We utilized a validated behavioral social stress paradigm (Trier Social Stress Test) to induce acute psychosocial stress in 36 human participants who completed measures on perceived and chronic stress. Cortisol stress reactivity was measured through continuous saliva collection during the paradigm and subsequent cortisol level analysis. Peripheral blood mononuclear cells were extracted from blood drawn at baseline and at two time points following the stress paradigm. For gene expression analysis, we focused on 12 participants who showed a robust cortisol response to the task, suggesting activation of the Hypothalamic-Pituitary-Adrenal axis. Total RNA was extracted and microRNA microarrays were utilized to assess changes in gene expression between baseline and the two post-stressor time points. Pathway analysis of the predicted target genes of differentially expressed microRNAs revealed a link between stress and inflammation and highlighted a potential role for miR-9. The results of this dissertation suggest that microRNAs contribute to both state and trait anxiety. | 170 pages
Recommended Citation
Jurkiewicz, Magdalena, "The Role of microRNA in Trait and State Anxiety" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 3423.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/3423