| Consolidation of nascent memory into long lasting forms involves synaptic plasticity. Even in the relatively simple brain of Drosophila , memory evolves in neural location and temporal stability. While distinct biochemical mechanisms likely act on the neural pathways that acquire and stabilize memories, the sequence and identity of these activities and their locales within neural circuits remain unclear. MicroRNAs (miRNAs) have been shown to act as modulators of synaptic plasticity. I have observed that the expression of several miRNA genes is similarly regulated by neural activity or the US component of the spaced training paradigm that leads to Long Term Memory (LTM) formation in flies. I focused on miRNAs encoded by the let-7-Complex (let-7-C). Let-7-C is a polycistronic locus encoding three heterochronic miRNAs (let-7 , miR-100, and miR-125). I have shown that let-7-C is expressed in the Mushroom Body in the adult fly brain and is upregulated by neural activity and after LTM formation. This induction requires dopaminergic output, which is both necessary and sufficient. This also requires the ecdysone-inducible gene Broad Complex (BR-C). BR-C is highly expressed in the MB Kenyon cell bodies and, surprisingly, strongly localized to the MB neuropil. BR-C levels in the MB neuropil were down-regulated following an induction in let-7-C and are under genetic control of let-7-C. This auto-regulation is likely due to let-7-C activity on a novel long 3'UTR associated with the Z3 isoform. Thus, let-7 and BR-C may form an autoregulatory loop in the MB of the fly brain under basal conditions and during the formation of consolidated memory. let-7-C miRNAs target the abrupt (ab) gene, which encodes a BTB/POZ domain transcription factor. Ab is normally expressed in a subset of Kenyon Cells and was downregulated by induced let-7-C expression. The level of let-7 and Ab expression was found to regulate the number and/or size of sites detected by a pre-synaptic zone marker on the axons of the alpha'/beta' and gamma in adult Kenyon Cells. This molecular circuitry was shown to be required for LTM formation (consolidation). Thus, let-7 appears to regulate ab to bring about synaptic structural plasticity, which is required for LTM formation. |
