Transcriptional Regulation Underlying Long-Term Sensitization in Aplysia

Abstract The induction of a long-term memory requires both transcriptional change and neural plasticity. Many of the links between transcription and memory have been revealed through the study of long-term sensitization in the Aplysia genus of marine mollusks. Sensitization is a conserved, non-associative form of pain memory in which a painful stimulus produces an increase in arousal and defensive behavior. The neural circuits that help encode sensitization memory are well characterized, and sensitization can be simulated in neuronal cell cultures. One feature of sensitization in Aplysia is that only some training protocols initiate transcription and produce long-term memory; others produce only short-term memories. This occurs because the induction of long-term sensitization requires the activation of two signal-transduction pathways that regulate transcription: (a) a fast but transient activation of the cAMP/PKA pathway that activates the transcription factor CREB1 and (b) a delayed activation of the ERK isoform of MAPK that deactivates the transcriptional repressor CREB2. The effectiveness of different training protocols is based on the synchronization of these pathways. The cAMP/PKA and MAPK pathways are complex, involving extracellular and trans-synaptic signaling, feedback loops, and crosstalk. It has proven possible to model transcriptional activation with enough fidelity to generate in silico predictions for optimized learning, which has been validated in cell cultures and intact animals. Training protocols that successfully activate CREB1 while deactivating CREB2 produce a complex transcriptional cascade that helps encode long-term sensitization memory. The transcriptional cascade involves a focused wave of immediate-early transcriptional activations. This includes the activation of additional transcription factors, such as C/EBP, as well as effectors such as uch, sensorin, and tolloid/BMP-1. These early transcriptional changes close feedback loops that help extend and stabilize the early wave of transcriptional changes, triggering a broader late wave of transcriptional changes likely to alter neural signaling, increase protein production, transport mRNAs, and induce meta-plasticity. A small set of transcripts participate in both the early and late waves, and several of these (CREB1, synataxin, eIF4) play essential roles in completing the induction of long-term sensitization. Most transcriptional changes fade as sensitization memory is forgotten, but some changes persist beyond forgetting, including a long-lasting up-regulation of an inhibitory peptide transmitter that could foster forgetting. The maintenance of long-term sensitization may involve self-sustaining transcriptional feedback loops. In particular, CREB1 binds to its own promoter, producing a long-lasting increase in CREB1 mRNA, protein, and gene activation that is essential for sustaining cellular correlates of sensitization for at least 1 day after induction. Many aspects of the induction, stabilization, and maintenance of sensitization memory in Aplysia are conserved, suggesting that it will continue to be a fruitful, simpler system for understanding the physical basis of lasting memory.