Active Forgetting and Neuropsychiatric Diseases · Jacob A. Berry

2026-06-09 · A faithful, transcript-grounded reading by PodLens

Source paper:https://www.nature.com/articles/s41380-024-02521-9.pdf

What This Paper Is About

In this Expert Review, Jacob A. Berry, Dana C. Guhle, and Ronald L. Davis comprehensively elucidate the neurobiological mechanisms of "active forgetting" and their relationship with neuropsychiatric diseases. The authors argue that forgetting is not a passive consequence of memory consolidation failure, but rather an active process controlled by specific cellular and molecular signaling pathways. The article systematically reviews the forgetting pathways discovered in Drosophila and mammals (including dopamine signal transduction, cytoskeleton remodeling, receptor endocytosis, neurogenesis, and glial phagocytosis), and proposes that the impairment of these mechanisms in disorders such as post-traumatic stress disorder (PTSD), anxiety, addiction, and schizophrenia is the core cause of intrusive memories and pathological cognitive impairments.

Paper Skeleton

• Core Question: To elucidate how the brain clears or shields memories through active biological pathways, and what cognitive consequences arise when these clearance pathways fail in clinical disorders (INTRODUCTION · "Active forgetting increases behavioral flexibility and removes irrelevant information").
• Central Claim: Forgetting is an actively occurring and highly controlled process that regulates the connection strength of memory engram cells at the synaptic level to achieve behavioral flexibility (SUMMARY AND PERSPECTIVES · (paraphrase, non-verbatim quote)).
• Argumentation Path: The paper first elaborates on the association between impaired active forgetting and pathological intrusive memories in various psychiatric disorders, such as PTSD, anxiety, and addiction (FORGETTING AND NEUROPSYCHIATRIC DISEASES · "Intrusive memories, distressing thoughts, and unwanted impulses"). Subsequently, it delves into the Drosophila mushroom body (MB) to dissect in detail the DAMB dopamine receptor-mediated calcium signaling release, Scribble-Rac1-regulated actin cytoskeleton remodeling, and the NO-cGMP molecular cascade pathway. Next, it demonstrates the conserved role of Rac1 in the mammalian hippocampus, the endocytosis mechanism of AMPA receptors (AMPAR), new neuron competition (neurogenesis), and synaptic pruning by microglia.
• Evidentiary Support: Experiments with Drosophila mutants show that blocking DAMB receptors or knocking out the Scribble protein significantly slows memory decay; mammalian studies have found that inhibiting Rac1 activity or knocking out the Syt3 protein (which regulates AMPAR endocytosis) in the hippocampus leads to forgetting deficits; furthermore, microglia depletion experiments directly confirm the necessity of synapse-dependent pruning in natural forgetting.
• Limitations and Boundaries: The authors acknowledge that in patients with neuropsychiatric disorders, it is difficult to completely disentangle forgetting deficits from abnormalities in the memory encoding or retrieval stages, as standardized measurements of encoding strength cannot be achieved in vivo (FORGETTING AND NEUROPSYCHIATRIC DISEASES · "disentangling an impairment in forgetting").

Core Arguments List

1. Biological Essence of Active Forgetting: Forgetting is an energy-consuming, active clearance process regulated by specific molecular cascades, used to maintain the brain's behavioral flexibility. - Anchor: (SUMMARY AND PERSPECTIVES · (paraphrase, non-verbatim quote)) - Type: Claim
2. Active Forgetting Deficit Hypothesis of Neuropsychiatric Diseases: Intrusive memories and distressing thoughts in disorders such as PTSD, addiction, anxiety, and schizophrenia stem from the impairment of active forgetting mechanisms, leaving unwanted memories unable to be erased. - Anchor: (FORGETTING AND NEUROPSYCHIATRIC DISEASES · "Intrusive memories, distressing thoughts, and unwanted impulses") - Type: Claim
3. Experimental Measurement Classification of Forgetting: Forgetting can be classified into "intentional forgetting," which requires active suppression during retrieval, and "incidental forgetting," where unretrieved memories are cleared due to the retrieval of other competing memories. - Anchor: (FORGETTING AND NEUROPSYCHIATRIC DISEASES · (paraphrase, non-verbatim quote)) - Type: Fact
4. Bidirectional Regulation Mechanism of Dopamine Receptors: In Drosophila, dopamine signaling mediates both memory formation and regulates forgetting, where the DAMB receptor, by coupling with Gαq, activates endoplasmic reticulum calcium release to trigger the forgetting-related regulation of synaptic strength. - Anchor: (DA neuron modulation of engram synapses · "utilizes Ca2+ signaling from the ER") - Type: Fact
5. Cytoskeleton Remodeling Controls Forgetting: Active forgetting involves the physical remodeling of the actin cytoskeleton within synapses, where small GTPases such as Rac1 and Cdc42 serve as highly compelling core regulators. - Anchor: (Actin cytoskeleton remodeling and forgetting · (paraphrase, non-verbatim quote)) - Type: Fact
6. Glutamate Receptor Endocytosis Drives Mammalian Forgetting: The trafficking and endocytosis of glutamate AMPA receptors at the postsynaptic membrane is the core molecular mechanism for reducing synaptic strength and achieving active forgetting in mammals. - Anchor: (Glutamatergic receptor endocytosis · (paraphrase, non-verbatim quote)) - Type: Fact
7. New Neuron Competition Mediates Forgetting: The continuous generation of newborn neurons in the hippocampus (neurogenesis) provides a physical mechanism that drives the decay of old memories by competing with existing neurons for synaptic inputs and outputs. - Anchor: (Network level regulation of forgetting · (paraphrase, non-verbatim quote)) - Type: Claim
8. Multiple Regulation of the Extracellular Environment of Engram Cells: Forgetting in the brain does not occur in isolation within a single cell, but is highly controlled by microenvironmental networks including non-engram cells, newborn neurons, and glial cells. - Anchor: (SUMMARY AND PERSPECTIVES · "heavily influenced by non-engram brain cells") - Type: Claim

Plain English Explanation

To put it simply, our brain's memory system is not like a hard drive that only records, but more like a blackboard that automatically erases redundant drafts. Forgetting in the brain doesn't happen because memories naturally "rust" or leak out, but because the brain has a dedicated "cleaning crew" actively wiping away old memories. If this cleaning crew goes on strike, our minds become cluttered with stale, conflicting, and useless information, eventually developing into PTSD or anxiety.

At the microscopic level, this cleanup work is initiated by dopamine. Dopamine is generally thought of as a signal for pleasure and learning, but in forgetting, it acts as an "erase command." When the brain decides to forget something, dopamine binds to a specific receptor called DAMB, activating intracellular calcium release and instructing molecules like Rac1 to dismantle the actin "skeleton" inside the synapse. This is like removing the scaffolding that supports a house; the synaptic structure shrinks, and the physical trace of the memory disappears with it.

In the mammalian brain, there is another ingenious clearing mechanism: pulling away the "antennas" on the synapses. The chemical receptors that synapses use to receive signals are called AMPA receptors. The brain uses specific enzymes (such as Caspase-2 and Syt3 proteins) to drag these receptors from the synaptic surface into the cell interior (endocytosis). When there are fewer antennas on the synaptic surface, the conversation between two neurons becomes quieter, and the memory gradually fades away.

In addition, the brain optimizes cleanup through two network-level methods: 1. The hippocampus continuously generates new brain cells (neurogenesis). This is like new hires joining a department; they actively seize the business lines (synaptic connections) of the veterans, causing the old cells to be marginalized and the old memories to disappear. 2. Microglia act like "gardeners" in the brain. They patrol the brain, and once they find a synaptic connection that has become very weak and is rarely called upon, they trigger immune system signals to directly engulf and clear away this weak synapse.

This multi-layered active cleanup is a core compromise the brain makes to allow us to flexibly adapt to new environments—only by learning to forget can we better move forward.

Glossary

• Active forgetting: The process by which the brain actively recruits specific molecular pathways to degrade or shield existing memories, serving as the core mechanism for maintaining cognitive flexibility and clearing information. (INTRODUCTION · "Active forgetting increases behavioral flexibility and removes irrelevant information")
• Memory engram: The physical and chemical changes left in specific neuronal ensembles after learning, serving as the synaptic foundation of concrete memories. (INTRODUCTION · (paraphrase, non-verbatim quote))
• Intentional forgetting: The phenomenon of suppressing unwanted memories through conscious and volitional effort during the memory retrieval stage, commonly measured clinically using the Think/No-Think paradigm. (FORGETTING AND NEUROPSYCHIATRIC DISEASES · (paraphrase, non-verbatim quote))
• Incidental forgetting: The mechanism by which unretrieved memories decay unintentionally due to the retrieval of specific competing memories. (FORGETTING AND NEUROPSYCHIATRIC DISEASES · (paraphrase, non-verbatim quote))
• Cytoskeleton remodeling: The microscopic physical process in which structural proteins inside the synapse (primarily actin) undergo polymerization or depolymerization under the control of small GTPases like Rac1, thereby altering synaptic size and connection strength. (Actin cytoskeleton remodeling and forgetting · "remodeling the actin cytoskeleton within engram synapses")
• AMPA receptor endocytosis: The biological phenomenon where glutamate receptors on the postsynaptic membrane are trafficked back into the cell interior, leading to decreased receiving capacity and weakened synaptic strength, serving as the dominant molecular means of forgetting in mammals. (Glutamatergic receptor endocytosis · (paraphrase, non-verbatim quote))
• Neurogenesis: The process of continuously generating new neurons in the brain, where new neurons compete for synaptic connections and displace the physical status of old memory engrams, thereby driving forgetting. (Network level regulation of forgetting · (paraphrase, non-verbatim quote))

Before and After This Paper

• Before This Paper: Neuroscience had long viewed forgetting as a "passive decay" or "consolidation failure." The scientific community's attention was almost entirely focused on learning (LTP synaptic potentiation) and memory consolidation (protein synthesis). Forgetting was intuitively equated with information loss or the natural aging of the system, like a piece of paper passively fading in the sun, lacking support from specific molecular-level mechanisms.
• After This Paper: This review established "active forgetting" as a core mechanism of memory management in the brain. The scientific community began to realize that forgetting is an energy-consuming, highly controlled defense mechanism operating through dedicated molecular pathways (such as DAMB, Rac1, and AMPAR endocytosis). This implies that brain disorders such as Alzheimer's disease, PTSD, and anxiety are not merely "impaired memory," but are rather due to the dysregulation or failure of the brain's active forgetting mechanisms. Consequently, clinical drug design can target active forgetting pathways, providing a brand-new dimension of intervention for clearing pathological memories.

Sections Most Worth Reading in the Original

• The part regarding the DAMB-Gαq-endoplasmic reticulum calcium signaling chain in the section "DA neuron modulation of engram synapses".
• Anchor: DA neuron modulation of engram synapses · "utilizes Ca2+ signaling from the ER"
• Reason: This section explains in extremely rich, step-by-step detail the precise mechanism of how dopamine triggers the reversal of synaptic strength via intracellular calcium stores after learning.
• The part regarding the regulatory mechanisms of small GTPases (Rac1 and Cdc42) in the section "Actin cytoskeleton remodeling and forgetting".
• Anchor: Actin cytoskeleton remodeling and forgetting · (paraphrase, non-verbatim quote)
• Reason: This section uses precise genetic evidence to prove that the brain's forgetting is not crude, but rather a fine-tuned design that uses different cytoskeleton remodeling pathways to differentially clear short-term (ASM) and long-term (ARM) memories, respectively.
• The part regarding the patterns of glutamate receptor trafficking in the section "Glutamatergic receptor endocytosis".
• Anchor: Glutamatergic receptor endocytosis · (paraphrase, non-verbatim quote)
• Reason: This section provides the most solid electrophysiological and molecular evidence for mammalian forgetting, vividly revealing how cells "silence" synapses by internalizing receptors.
• The theoretical conception of "layered formation and forgetting" of memory in the section "SUMMARY AND PERSPECTIVES".
• Anchor: SUMMARY AND PERSPECTIVES · (paraphrase, non-verbatim quote)
• Reason: This is the most inspiring summary of the brain's system architecture design in the entire literature, elevating scattered molecular pathways into a macro-picture of brain information management with a hierarchical structure.

Resonances with past episodes

• Corroboration→ Agent Memory: System Characterization and Implications for Long-Horizon Workloads · Yasmine Omri
  The system bottleneck where AI agents experience quadratic growth in computational overhead due to full history accumulation corroborates, from the opposite side, why biological brains must evolve an energy-consuming 'forgetting' mechanism to clear redundant information in order to maintain behavioral flexibility and operational efficiency.
  This(SUMMARY AND PERSPECTIVES · (paraphrase, non-verbatim quote)) Forgetting is an energy-consuming, active clearance process regulated by specific molecular cascades, used to maintain the brain's behavioral flexibility.

  Related1. Introduction · "prefill costs scale" Prefill overhead of the full history context scales quadratically with history accumulation, and carries the risk of losing information in the middle.
• Extension← A New Perspective on Synaptic Pruning · Soyon Hong
  The previous study pointed out that microenvironmental networks such as glial cells play a key regulatory role in mediating brain forgetting and memory elimination. This study extends on the microscopic mechanism, specifically elucidating how microglia specifically engulf and clear weaker synaptic connections by recognizing neuronal electrical activity.
  ThisSUMMARY AND PERSPECTIVES · "heavily influenced by non-engram brain cells" Forgetting in the brain is not something that occurs in isolation within a single cell, but is highly controlled by microenvironmental networks such as non-engram cells, newly generated neurons, and glial cells.

  RelatedDynamic microglia–synapse interactions in the healthy brain · "microglia preferentially phagocytosed less active inputs" Neuronal electrical activity regulates microglial engulfment of synapses, with microglia tending to preferentially clear weaker or inactive synaptic inputs.

A faithful reading and plain-language retelling of the paper, generated by PodLens.

This is one source-grounded reading, not a replacement for the original. Every point is anchored to its source, so you can check it yourself — and corrections are welcome.