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Dopamine-based mechanism for transient forgetting


Active forgetting is an essential component of the memory management system of the brain1. Forgetting can be permanent, in which prior memory is lost completely, or transient, in which memory exists in a temporary state of impaired retrieval. Temporary blocks on memory seem to be universal, and can disrupt an individual’s plans, social interactions and ability to make rapid, flexible and appropriate choices. However, the neurobiological mechanisms that cause transient forgetting are unknown. Here we identify a single dopamine neuron in Drosophila that mediates the memory suppression that results in transient forgetting. Artificially activating this neuron did not abolish the expression of long-term memory. Instead, it briefly suppressed memory retrieval, with the memory becoming accessible again over time. The dopamine neuron modulates memory retrieval by stimulating a unique dopamine receptor that is expressed in a restricted physical compartment of the axons of mushroom body neurons. This mechanism for transient forgetting is triggered by the presentation of interfering stimuli immediately before retrieval.

Fig. 1: External stimuli transiently disrupt retrieval of PSD-LTM.
Fig. 2: Transient suppression of memory engages a single pair of PPL1 DANs and the dopamine receptor DAMB.
Fig. 3: Stimulating PPL1-α2α′2 did not erase the 72-h PSD-LTM trace in MBON-α2sc.
Fig. 4: Airflow, electric shock or blue light require PPL1-α2α′2 and DAMB function to cause transient forgetting.

Data availability

All relevant data are available from the corresponding author upon request.


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This work was supported by NIH grant 5R35NS098224 to R.L.D. and F31MH123022 to J.M.S. We thank Janelia Research for providing split-gal4 lines and all other colleagues who have supplied Drosophila stocks, as well as past and current members of the Davis laboratory for their constructive conversation and criticism.

Author information




J.M.S. planned and performed all behavioural experiments, data analysis and interpretation, and figure design, and wrote the initial draft of the manuscript. J.A.B. helped to plan experiments, performed all in vivo imaging and contributed to data interpretation and manuscript writing. R.L.D. acquired funding, helped with planning experiments, supervised the overall execution of the project, provided feedback on data interpretation and edited the manuscript along with J.M.S. and J.A.B.

Corresponding author

Correspondence to Ronald L. Davis.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Kaoru Inokuchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Dose-dependent suppression of LTM.

ac, Conditioned wild-type (Canton-S) flies were exposed to distracting stimuli of increasing potency: airflow (a), electric shock (b) or blue light (c), terminating 1 min before a 72-h memory retrieval test. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 8 (ac), one-way ANOVA with Dunnett’s test. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 2 PPL1 DAN bidirectionally modulate PSD-LTM expressed at 72 h.

a, Schematic illustrating the PPL1 DAN cluster (TH-D′-gal4) that innervates five subcompartments of the mushroom body neuropil. b, c, Seventy-two-hour PSD-LTM without (b) or with (c) a manipulation of PPL1 DAN activity. Stimulation (TH-D′>TrpA1) decreased, whereas synaptic blockade (TH-D′>Shibire) enhanced, the expression of PSD-LTM. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 9 (b, c), two-way ANOVA with Tukey’s test. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 3 Mapping the phenotype of impaired expression of PSD-LTM to a single DAN.

PPL1 DAN screen using split-gal4 lines and uas-TrpA1 to stimulate discrete DAN subpopulations. Stimulating PPL1-α2α′2 significantly decreased the expression of PSD-LTM when tested at 72 h. Other neurons from the PPL1 cluster did not impair expression of PSD-LTM. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 12, two-way ANOVA with Tukey’s test. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 4 Multiple epochs of TrpA1 stimulation extend the suppression of memory expression.

a, Memory rapidly recovered after a brief bout of TrpA1 stimulation. b, Retention of PSD-LTM across 14 d, after spaced conditioning without PPL1-α2α′2 stimulation. c, Expression of PSD-LTM was significantly dampened at 3 d after a single 6-h bout of TrpA1 stimulation, but resurfaced at 6 d. d, Three 6-h-spaced TrpA1 stimulations prolonged the memory expression deficit to 10 d, but expression of PSD-LTM resurfaced at normal levels at 14 d. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 8 (a), one-way ANOVA with Dunnett’s post hoc test; n = 6 (b), n = 12 (c, d), two-way ANOVA with Tukey’s test. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 5 Enhanced PSD-LTM of DAMB maps to α/β MBN.

a, Loss of DAMB (loss-of-function allele) elevated expression of PSD-LTM up to 14 d. Wild type, Canton-S. b, Pan-neuronal knockdown of DAMB increased 24-h PSD-LTM. The RNAi lines target nonoverlapping sites of DAMB that affect all transcript variants. Coding exons, green; noncoding exons, blue; introns, black line. NSyb-gal4>uas-RNAi, uas-dicer 2. RNAi no. 1: KK line. RNAi no. 2: GD line. RNAi no. 3: TRiP line. c, DAMB knockdown in α/β MBN enhanced 24-h LTM. Gal4>uas-RNAi(KK), uas-dicer 2. d, DAMB knockdown in the α/β MBN elevated PSD-LTM up to 14 d after spaced conditioning. C739-gal4>uas-RNAi(KK), uas-dicer 2. e, Functional reinstatement of DAMB restored PSD-LTM to normal levels. Wild type, Canton-S. f, DAMB RNAi knockdown and normalizing expression of PSD-LTM by differential spaced conditioning. C739-gal4, gal80ts>uas-RNAi, uas-dicer2. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 9 (c), unpaired two-tailed Welch’s t-test; n = 12 (a, b, df), two-way ANOVA with Tukey’s test. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 6 Robust 72-h-old PSD-LTM plasticity is formed in MBON-α2sc.

a, Blocking synaptic output (R34B02-lexA>lexAop-Shibire) from MBON-α2sc impaired retrieval of PSD-LTM. b, Schedule for training and imaging. c, MBON-α2sc dendrites imaged as the region of interest. d, Representative pseudocoloured images (scale bar, 10 μm) showing responses to octanol (OCT) or benzaldehyde (BEN) for naive, OCT+ (OCT as CS+), or BEN+ (BEN as CS+) flies. e, f, Response traces of group data and quantification for OCT+ (e) and BEN+ (f) conditioned flies relative to naive. Left, activity as a function of time with odour stimulation. Right, average response magnitude within the first 5 s of odour onset (duration of odour delivery). Calculations of the activity versus mean responses are provided in the Methods. The differential reflects the difference in odour response between CS+ and CS. Multiple spaced cycles generated increased calcium transients compared to naive flies, with OCT+ generating a more-potent differential than that of BEN+. g, Feeding schedule for cycloheximide before spaced conditioning and representative pseudocoloured images (scale bar, 10 μm) showing the effects of cycloheximide on odour responses. h, i, Cycloheximide+ blunted the OCT+ (h) or BEN+ (i) training-induced calcium transients, indicating that the differential represents a PSD-LTM trace. j, Training schedule and representative pseudocoloured images (scale bar, 10 μm) without (23 °C) or with (30 °C) a 6-h TrpA1 stimulation. Response traces and quantification are in Fig. 3b. Box-and-whisker plots show the range of individual data points, with the interquartile spread as the box and the median as the line bisecting each box. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n = 8 (a), two-way ANOVA with Tukey’s test; n = 20 (e, naive), n = 21 (e, OCT+), n = 20 (f, naive), n = 20 (e, BEN+), n = 20 (h, i), unpaired two-tailed Mann–Whitney test (e, f, h, i). Imaging experiments (dj) were performed three independent times with proper controls present within each set. All activity traces, mean responses and representative images shown were reproducible. Exact P values and comparisons are shown in Supplementary Information.

Extended Data Fig. 7 Working model comparing permanent and transient forgetting.

Two forms of forgetting include permanent (red) and transient (orange) forgetting. Left, Permanent forgetting involves a PPL1 DAN that synapses onto the MBN-γ2α′1 compartment (red). The slow ongoing DAN activity after learning is transduced by the Gq-coupled DAMB receptor. This forgetting signal mobilizes the Scribble scaffolding complex and recruits Rac1, Pak3 and Cofilin to erode labile nonconsolidated memory. The cellular memory traces formed and stored in the following neuron (MBON-γ2α′1) are also eroded. This process can be exacerbated by enhanced sensory stimulation (+) or repressed by sleep or rest (−). Right, Transient forgetting incorporates a different PPL1 DAN (to that in permanent forgetting) that synapses onto the MBN-α2α′2 compartment (orange). This forgetting signal, transduced by DAMB, temporarily impairs the expression of consolidated PSD-LTM. The cellular memory traces stored in MBON-α2sc are not abolished after activating the forgetting pathway. This process can be triggered by interfering or distracting stimuli (+) to transiently block the retrieval of PSD-LTM.

Supplementary information

Reporting Summary

Supplementary Table

This file contains Supplementary Table 1, showing reagents, behavioural control experiments and statistical analyses. Sheet number one lists the fly strains, reagents and equipment used in the study. Sheet number two contains the odour and shock avoidance across various genotypes and conditions. Sheets number three and four list the statistical comparisons for each experiment in the main and extended figures, respectively. Sheet number five details additional statistical comparisons (two-way ANOVA with repeated measures) to determine spontaneous recovery of memory.

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Sabandal, J.M., Berry, J.A. & Davis, R.L. Dopamine-based mechanism for transient forgetting. Nature (2021).

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