1 PROJECT SUMMARY 2 3 Long-term memory (LTM) formation is a critical process for the survival of virtually all animals. The 4 ability to acquire, store, and recall information over long periods of time is crucial for even the most basic 5 aspects of life including feeding, defense, mating, as well as more advanced social behaviors. Even more 6 striking is that the cellular and molecular mechanisms underlying LTM formation are remarkably evolutionarily 7 conserved and are shared in some part by every creature on earth. Understanding the infinitely complex 8 choreography of cells and molecules that gives rise to LTM formation is made possible by the study of simple 9 neural systems, such as the central nervous system of the marine mollusk Aplysia californica. In this system, 10 presynaptic facilitation of the sensory neuron – motor neuron (SN-MN) circuit in the pleural-pedal ganglia 11 completely mediates behavioral LTM for sensitization of the animal’s defensive tail-elicited tail withdrawal 12 reflex. Using this system, our laboratory has previously demonstrated that members of a specific family of 13 RNA-binding proteins (ELAVs) are required for the stabilization of apc/ebp mRNA, and this stabilization is 14 required for LTM formation in Aplysia. We have recently discovered that ELAVs shuttle from the SN nucleus to 15 distal neurites and synapses after LTM training, and that the ELAV target mRNA apc/ebp is present in distal 16 SN neurites after training. Since ELAVs bind a large quantity of RNAs, a change in the binding profile of ELAVs 17 by LTM training can have profound effects on the cellular transcriptome including transcript stabilization, 18 alternative splicing, and mRNA shuttling. In fact, differential regulation of ELAV binding has been shown to 19 affect amyloid processing and alternative pre-mRNA splicing in brains of Alzheimer’s Disease patients. In Aim 20 1, I propose a research program to identify the differential RNA binding profile of ELAVs in the SNs of Aplysia 21 resulting from LTM training. I will use the experimentally advantageous organization of the Aplysia nervous 22 system to complete targeted dissections of the SN neurites and determine which of these ELAV target RNAs 23 are shuttled towards the SN-MN synapse during LTM formation. In Aim 2, I will investigate the mode of 24 trafficking and the functional consequence of apc/ebp mRNA at distal SN neurites. Noting the binding of 25 apc/ebp mRNA by ELAVs during LTM formation, I predict that ELAVs are required for distal apc/ebp mRNA 26 localization. I hypothesize that this localization underlies a mechanism for ‘savings’ memory, the reinstatement 27 of a latent, non-expressed memory trace by a later reminder event. The experiments outlined in this proposal 28 will serve to produce data strategically useful for the development of novel drugs and therapies for neurological 29 disorders, as well as to further our understanding of how these molecular mechanisms support ...