Long-term memory (LTM) storage requires remodeling of pre-existing synapses and formation of new
ones. While the roles of transcription and synaptic protein synthesis in these processes are well described,
relatively little is known about how nuclear and synaptic processes are coordinated during LTM storage. We
have previously shown that kinesin, the molecular motor that mediates communication between the nucleus
and synapses through the microtubule-dependent transport of gene products, has a key role in this process.
While these studies established the role of anterograde transport during learning and memory storage, the
contribution of retrograde transport during learning is unknown. Understanding retrograde transport will help
elucidate the molecular communication from the synapse to the cell body and thus provide a deeper
understanding of LTM formation and storage. Based on our genomics, proteomics, gene expression and live
cell-imaging experiments described in the preliminary results section, our central hypothesis is that storage
of LTM requires regulation of components of the retrograde transport machinery in both pre- and post-
synaptic neurons. Here, we focus on the regulation of two protein complexes that are known to mediate
retrograde transport: the dynein motor complex, which contains dynein heavy chain (DHC), intermediate chain
(DIC), light intermediate chain (DLIC), and light chain (DLC); and the dynactin complex which consists of 23
proteins with dynactin 1 (p150glued) acting as a critical mediator of dynactin function. Exploring the advantages
of identified neurons and defined synaptic connections of the sea slug Aplysia californica, we will test our
hypothesis by assessing (1) regulation of expression of components of dynein-dynactin machinery by 5HT
(serotonin), a modulatory neurotransmitter important for learning in Aplysia; (2) quantitative live cell imaging of
cargo and dynein transport machinery; (3) necessity and sufficiency of 5HT regulated components in pre- and
post-synaptic neurons of gill withdrawal reflex; (4) role of local translation in modulating retrograde transport
and (5) elucidate the molecular nature of cargos transported from the synapses by dynein transport machinery.
We anticipate that these studies will be ground breaking because little is known about the role of dynein-
dynactin complexes in LTM. Successful completion of these studies is expected to have a major positive
impact on mechanisms underlying activity regulated retrograde transport and biology of memory.