Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Adolescent binge ethanol (EtOH) abuse induces long-term changes in gene expression, resulting in an increased risk for the development of adult mood disorders. microRNAs (microRNAs) are small, noncoding RNAs that regulate gene expression by translational repression. microRNA altered in response to EtOH and puberty in the developing brain. The biogenesis of mature 22-24 nucleotide (nt), single-stranded microRNAs involves Drosha and Dicer enzymatic processing of microRNA precursors. A mature microRNA imperfectly base pairs with messenger RNA (mRNA) target genes,which leads to mRNA cleavage or translational repression. Our lab has found that repeated binge EtOH exposure alters gene expression in the hypothalamus and dysregulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis in a sexually dimorphic, long-term and gonadal hormone-dependent manner in Wistar rats, and that a subset of microRNAs targeting brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) are differentially expressed in the ventral hippocampus dependent on age and 17β-estradiol (E2). We examine whether microRNA expression, microRNA biogenesis enzymes Drosha and Dicer, and microRNA target genes BDNF and SIRT1 are altered by peripubertal binge EtOH in the ventral and dorsal hippocampus. We also document sex differences in the expression of microRNAs sensitive to EtOH and E2 during pubertal development. Overall, we demonstrate : 1) peripubertal binge EtOH exposure induces long-term alterations in mature microRNA expression levels in the male rat hippocampus, and has the potential to modulate the expression of their downstream target genes, 2) expression profiles of EtOH-sensitive microRNAs (miR-10a-5p, miR-26a, miR-32, miR-103 and miR-495), E2-responsive microRNAs (miR-7a, miR-9, miR-125a and miR-181a), BDNF, SIRT1, Drosha and Dicer are differentially dependent on sex and age throughout pubertal development. This research increases our understanding of how pubertal binge EtOH exposure affects microRNA expression, provides evidence that microRNA are expressed in sexually dimorphic patterns throughout pubertal development, and suggest that microRNAs play a role in normal pubertal hippocampus development as well as hippocampus dysfunction following adolescent alcohol abuse.

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Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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