Regulation of Brain Derived Neurotropic Factor by MicroRNA-155 in the Prefrontal Cortex Keywords: Brain Derived Neurotropic Factor (BDNF), miR-155, Prefrontal Cortex (PFC) Introduction: The discovery microRNAs

Introduction: The discovery microRNAs (miRNAs) presents an exciting mechanism by which a cell can regulate the expression of particular proteins. miRNAs are short, non-coding, strand of endogenous RNAs of approximately 22 nucleotides in length that can regulate the activity of mRNAs. As post-transcriptional regulators, miRNAs bind to a complementary 3' untranslated region (UTR) of mRNA resulting in a functional repression or degradation of the target mRNA. miRNA synthesis and mode of action are well understood, as illustrated in Figure 1 [1]. miRNAs are known to be involved in various physiological process, including cellular differentiation and synaptic plasticity, as well as regulate complex behaviors; however, the functional role of many miRNAs remains unknown [2]. I initially became interested in miRNAs through my course work at Emory U., but it was not until my lab rotation with Dr. James Herman at the U. of Cincinnati that I have had a chance to study miRNAs in detail. Recently, Dr. Herman completed a large deep sequencing analysis of miRNAs and 3'UTR regions of mRNAs in the PFC of mice which have undergone a well-established model of chronic variable stress (CVS). Results have identified a number of miRNAs and mRNAs expressed in the PFC, which appear to be either up or down regulated following the CVS paradigm. To our knowledge, this is the first demonstration that the expression of particular miRNAs is regulated by stress and presents a promising avenue for exploring the functional and behavioral consequences of stressed-induced alterations of miRNA expression and/or alternative expression of 3'-UTRs mRNA sequences within the central nervous system (CNS). We are also interested in studying the PFC, as this highly developed brain region controls working memory, decision-making, attention, and impulsivity. The PFC regulates emotionality and specific areas of the PFC play a multi-integrative role in emotional learning, expression and extinction [3, 4]. In generating the hypothesis for this proposal, I analyzed the results of Dr. Herman's deep sequencing study to find links between the expression of one or multiple miRNAs and potential target mRNAs. This analysis revealed a correlation between BDNF mRNA levels and miRNA-155. BDNF is an important and interesting target considering that the BDNF protein is implicated in a number of cellular processes and complex behaviors, including learning and memory, neural plasticity, neuronal homeostasis and neural protection [2]. BDNF is also robustly expressed within the PFC and other limbic brain regions involved in fear consolidation and …