Registered Report: Transcriptional Analysis of Savings Memory Suggests Forgetting is Due to Retrieval Failure

Rosiles, Tania; Nguyen, Melissa; Duron, Monica; Garcia, Annette; Garcia, George; Gordon, Hannah; Juarez, Lorena; Calin‐Jageman, Irina; Calin-Jageman, Robert

doi:10.1523/eneuro.0313-19.2020

Cited by 5 publications

(5 citation statements)

References 69 publications

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“…These findings raise an important question regarding the interpretation of forgetting (85, 86). Previous work has emphasized retrieval deficits as a key characteristic of memory impairment, supporting the idea that memory recall or accessibility may be driven by learning through perceptual feedback from the environment (7, 8, 14–18).…”

Section: Discussionmentioning

confidence: 99%

Natural forgetting reversibly modulates engram expression

O’Leary

Bruckner

Autore

et al. 2023

Preprint

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Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. While progress has been made in understanding the biology of engrams, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we examine whether forgetting is governed by changes in engram plasticity and suggest that it helps animals prioritize relevant memory representations for adaptive behavior. We utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. The results indicate that engram activity correlated with the rate of forgetting. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, the modulation of engram activity was able to prevent forgetting itself. Moreover, through pharmacological and behavioral interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we show that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting is an adaptive form of engram plasticity that involves circuit remodeling, which allows engrams to switch from an accessible state to an inaccessible state.

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Section: Discussionmentioning

confidence: 99%

Natural forgetting reversibly modulates engram expression

O’Leary

Bruckner

Autore

et al. 2023

Preprint

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“…Our study is reminiscent of memory saving 7,10,78 . However, we think our study is more advanced in many ways.…”

Section: Discussionmentioning

confidence: 99%

Forgotten memory storage and retrieval in Drosophila

Wang,

Wu,

Lin

et al. 2023

Nat Commun

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Inaccessibility of stored memory in ensemble cells through the forgetting process causes animals to be unable to respond to natural recalling cues. While accumulating evidence has demonstrated that reactivating memory-stored cells can switch cells from an inaccessible state to an accessible form and lead to recall of previously learned information, the underlying cellular and molecular mechanisms remain elusive. The current study used Drosophila as a model to demonstrate that the memory of one-trial aversive olfactory conditioning, although inaccessible within a few hours after learning, is stored in KCαβ and retrievable after mild retraining. One-trial aversive conditioning triggers protein synthesis to form a long-lasting cellular memory trace, approximately 20 days, via creb in KCαβ, and a transient cellular memory trace, approximately one day, via orb in MBON-α3. PPL1-α3 negatively regulates forgotten one-trial conditioning memory retrieval. The current study demonstrated that KCαβ, PPL1-α3, and MBON-α3 collaboratively regulate the formation of forgotten one-cycle aversive conditioning memory formation and retrieval.

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“…To date, few analyses have extended more than 1 day after induction, a timepoint that may be more associated with memory stabilization than memory maintenance (Miniaci et al 2008). Moreover, microarray analysis suggests that the late wave of transcription almost fully collapses before forgetting (Rosiles et al 2019), and that reminders can produce a long-term reinstatement of sensitization without re-activating the late wave of transcription (Rosiles et al 2020). These analyses might lack sensitivity, but they raise the intriguing possibility that sensitization memory can be expressed in the absence of ongoing transcriptional changes.…”

Section: Transcriptional Loops Could Also Support Memory Maintenance ...mentioning

confidence: 99%

Transcriptional Regulation Underlying Long-Term Sensitization in Aplysia

Calin-Jageman,

Wilsterman,

Calin-Jageman

2024

Oxford Research Encyclopedia of Neuroscience

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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.

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Registered Report: Transcriptional Analysis of Savings Memory Suggests Forgetting is Due to Retrieval Failure

Cited by 5 publications

References 69 publications

Natural forgetting reversibly modulates engram expression

Natural forgetting reversibly modulates engram expression

Forgotten memory storage and retrieval in Drosophila

Transcriptional Regulation Underlying Long-Term Sensitization in Aplysia

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