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.

Grant Number: 2R15MH107892-03
NIH Institute/Center: NIH
Principal Investigator: IRINA CALIN-JAGEMAN