The role of synaptic microRNA in chronic alcohol consumption and its effects on synaptic composition
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Drug dependence is the process by which the brain learns to depend on a drug and crave for it in its absence. This learning takes place through modifications of synaptic connections between neurons, changing synaptic structure and function, and causing long-lasting neuroadaptations. Over the past decade, several microRNAs have been proposed as playing a key role in regulating local mRNA translation into protein, specifically in the synaptic compartments of the cell (pre-synaptic terminals and post-synaptic densities). There is limited evidence, however, regarding how synaptic microRNAs control local mRNA translation during chronic drug exposure and how this contributes to the development of dependence. Can alcohol-responsive synaptic mRNAs and microRNA be identified? Do synaptic microRNAs regulate the synaptic mRNA expression changes in response to alcohol? Can changes in synaptic microRNA composition affect alcohol consumption? In this thesis, I present research supporting microRNA regulation of local mRNA translation and how drugs of abuse target this process. In the first section, I focus on the identification of alcohol-responsive synaptic mRNAs. In the second section, I focus on identifying alcohol-responsive synaptic microRNAs and predict key mRNA-microRNA interactions. Identifying the primary regulatory elements in the synapse is imperative for an accurate model of the synaptic interactions that lead to mRNA translation underlying plasticity. Since the neuroadaptations associated with response to alcohol rely on many mRNAs, therapy with microRNAs provides a potential treatment for alcohol dependence. In the third section, I focus on manipulating key microRNAs in-vivo to reverse and prevent alcohol consumption and alcohol-induced-neuroadaptations. The ability of synaptic microRNAs to rapidly regulate mRNAs provides a discrete, localized system that could potentially be used as diagnostic and treatment tools for alcohol and other addiction disorders.