Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory

Abstract

Recent studies have identified molecular pathways driving forgetting and supported the notion that forgetting is a biologically active process. The circuit mechanisms of forgetting, however, remain largely unknown. Here we report two sets of Drosophila neurons that account for the rapid forgetting of early olfactory aversive memory. We show that inactivating these neurons inhibits memory decay without altering learning, whereas activating them promotes forgetting. These neurons, including a cluster of dopaminergic neurons (PAM-β′1) and a pair of glutamatergic neurons (MBON-γ4>γ1γ2), terminate in distinct subdomains in the mushroom body and represent parallel neural pathways for regulating forgetting. Interestingly, although activity of these neurons is required for memory decay over time, they are not required for acute forgetting during reversal learning. Our results thus not only establish the presence of multiple neural pathways for forgetting in Drosophila but also suggest the existence of diverse circuit mechanisms of forgetting in different contexts.forgetting | Drosophila melanogaster | associative memory | mushroom body | reversal learning A lthough forgetting commonly has a negative connotation, it is a functional process that shapes memory and cognition (1-4). Recent studies, including work in relatively simple invertebrate models, have started to reveal basic biological mechanisms underlying forgetting (5-15). In Drosophila, single-session Pavlovian conditioning by pairing an odor (conditioned stimulus, CS) with electric shock (unconditioned stimulus, US) induces aversive memories that are short-lasting (16). The memory performance of fruit flies is observed to drop to a negligible level within 24 h, decaying rapidly early after training and slowing down thereafter (17). Memory decay or forgetting requires the activation of the small G protein Rac, a signaling protein involved in actin remodeling, in the mushroom body (MB) intrinsic neurons (6). These so-called Kenyon cells (KCs) are the neurons that integrate CS-US information (18,19) and support aversive memory formation and retrieval (20)(21)(22). In addition to Rac, forgetting also requires the DAMB dopamine receptor (7), which has highly enriched expression in the MB (23). Evidence suggests that the dopamine-mediated forgetting signal is conveyed to the MB by dopamine neurons (DANs) in the protocerebral posterior lateral 1 (PPL1) cluster (7,24). Therefore, forgetting of olfactory aversive memory in Drosophila depends on a particular set of intracellular molecular pathways within KCs, involving Rac, DAMB, and possibly others (25), and also receives modulation from extrinsic neurons. Although important cellular evidence supporting the hypothesis that memory traces are erased under these circumstances is still lacking, these findings lend support to the notion that forgetting is an active, biologically regulated process (17,26).Although existing studies point to the MB circuit as essential for forgetting, several questions remain to be answered. Fir...

Dopamine Neurons Mediate Learning and Forgetting through Bidirectional Modulation of a Memory Trace

“…The segregation of the US through parallel DAn→MBn (compartments) theoretically allows the encoding of independent cellular memory traces, or “memory bits,” in parallel. However, this model is overly simplistic as several MBOns project laterally to provide synaptic input to other MBn:MBOn compartments and probably regulate the expression or stability of memory engrams stored there (Perisse et al, 2016; Shuai et al, 2015). In addition, the axon terminals of some MBOns localize in proximity to the dendrites of DAns modulating different MBn:MBOn compartments (Aso et al, 2014a).…”

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The Biology of Forgetting—A Perspective

“…Two additional small clusters of neurons that promote forgetting were identified by screening for enhanced memory retention after inhibiting neural activity among a diverse set of MB extrinsic neurons that connect the MB lobes with other brain regions (Shuai et al, 2015). These include a small cluster of DAn (PAM-β′1) and a pair of glutamatergic neurons that terminate in distinct subdomains of the MB lobes.…”