Long-term memory (LTM) storage requires remodeling of pre-existing synapses and formation of new ones. While the necessity of transcription in the temporal phases of LTM such as formation and persistence has been described, we lack comprehensive information on how gene expression changes in a neural circuitry mediate the formation and persistence of LTM. In any of the animal models of learning, we do not know what components of the transcriptomes are recruited specifically in pre- or post-synaptic neurons for mediating the formation and persistence of LTM. Particularly we know very little about the gene expression changes required for the persistence of LTM. Lack of this knowledge is a critical barrier for deciphering the molecular underpinnings of synapse specificity and LTM. The central hypothesis of this proposal is that coordinated regulation of the pre- and the post-synaptic neuronal transcriptome mediate the formation and persistence of synapse specific LTM. We propose to test this hypothesis using the well-characterized neural circuitry of gill-withdrawal reflex (GWR) of the marine snail, Aplysia californica. Specifically, using a modified bifurcated sensory neuron-motor neuron culture, we will assess the changes in the subcellular transcriptome of pre-synaptic sensory neurons and post-synaptic motor neurons during the formation and persistence of the synapse specific LTM. Furthermore, the role of molecular motor kinesin mediated transport of RNAs from the cell body to synapses in synapse specific LTM will be determined. We anticipate that these experiments will facilitate the decoding of the gene expression program for the formation and persistence of LTM in components of a defined neural circuitry. Furthermore, our studies are expected to produce a ground- breaking impact on the basic biology of synapse specific LTM as well as to facilitate identification of novel candidates for the development of therapeutics for memory disorders.
Despite the advances in our understanding of molecular and cellular basis of learning and long-term memory storage (LTM), we do not know whether and how the composition of transcriptome is modified in specific components of a circuitry for the formation and persistence of synapse specific LTM. Exploring the advantages of identified pre- and post-synaptic neurons of gill withdrawal reflex of sea slug Aplysia, we now propose a multidisciplinary approach to unravel the regulation of subcellular transcriptome for the formation and persistence of LTM. Successful completion of these studies will provide novel insights into the regulation of memory storage and thus facilitate better understanding of dysfunction in memory disorders.
