Cellular mechanisms of forgetting a long-term memory

PROJECT SUMMARY/ABSTRACT: This project will investigate the neurobiology of forgetting in a model of memory conserved across the animal kingdom. Through study of long-term sensitization memory in Aplysia californica we have found that forgetting is due in part to an active, intrinsically regulated process that works to oppose the expression of long-term memory. Specifically, we have found that acquiring a sensitization memory activates not only encoding mechanisms but also a persistent up-regulation of the expression of an inhibitory transmitter (FMRF-amide) in a population of inhibitory interneurons that opposes the expression of sensitization memory (Patel et al., 2018; Perez et al., 2018). We have now confirmed in a registered report that blocking FMRF-amide signaling after learning slows forgetting of sensitization (Rosiles et al., 2024), demonstrating that forgetting is, in part, an active process that can be regulated. We now propose characterizing the active-forgetting component of sensitization, addressing three fundamental questions:  What is the nature of forgetting? Our research suggests that learning produces an increase in FMRF-amide signaling that contributes to forgetting. We propose a stringent test of this hypothesis at the physiological level. We will manipulate FMRF-amide signaling while tracking the synaptic and cellular changes that encode sensitization memory. We predict that FMRF-amide will diminish sensitization-induced plasticity, demonstrating a cellular mechanism of active forgetting.  Why are some memories not forgotten? Although most long-term memories are forgotten, extensive training can produce memories that resist forgetting. We have confirmed this in Aplysia, showing that 1 day of sensitization training produces a memory forgotten within 1 week (recall fades to baseline) while 4 days of training produces an unforgettable memory. This stark contrast in forgettability is likely related to differential induction of neuronal transcriptional states, as extensive training produces synaptic outgrowth and increases gene expression of a key neuromodulator. We propose comparing the transcriptional states accompanying forgettable and unforgettable forms of sensitization to shed new light on the selectivity of active forgetting.  How does forgetting persist? Our research shows that learning produces transcriptional changes that encode memory as well as opposing transcriptional changes in inhibitory neurons that persist for weeks, perhaps mediating the long timespan over which forgetting occurs. We propose isolating the inhibitory transcriptional program induced by sensitization by conducting microarray and qPCR on the large, identifiable FMRF-amide-expressing neurons that seem to contribute to forgetting. The research proposed in this renewal will further advance a generative line of inquiry into the fundamental mechanisms of forgetting while providing exceptional opportunities for undergraduate involvement.