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Mol Psychiatry
Mol Psychiatry
Molecular Psychiatry
1359-4184
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Nature Publishing Group UK London

38532011
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10.1038/s41380-024-02521-9
Expert Review
Active forgetting and neuropsychiatric diseases
http://orcid.org/0000-0002-5241-1720
Berry Jacob A. jaberry@ualberta.ca

1
http://orcid.org/0009-0004-1640-0954
Guhle Dana C. 1
http://orcid.org/0000-0002-5986-7608
Davis Ronald L. ronalddavis@ufl.edu

2
1 https://ror.org/0160cpw27 grid.17089.37 Department of Biological Sciences, University of Alberta, Edmonton, AL T6G 2E9 Canada
2 https://ror.org/056pdzs28 Department of Neuroscience, UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, FL 33458 USA
26 3 2024
26 3 2024
2024
29 9 28102820
26 9 2023
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6 3 2024
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2024
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Recent and pioneering animal research has revealed the brain utilizes a variety of molecular, cellular, and network-level mechanisms used to forget memories in a process referred to as “active forgetting”. Active forgetting increases behavioral flexibility and removes irrelevant information. Individuals with impaired active forgetting mechanisms can experience intrusive memories, distressing thoughts, and unwanted impulses that occur in neuropsychiatric diseases. The current evidence indicates that active forgetting mechanisms degrade, or mask, molecular and cellular memory traces created in synaptic connections of “engram cells” that are specific for a given memory. Combined molecular genetic/behavioral studies using Drosophila have uncovered a complex system of cellular active-forgetting pathways within engram cells that is regulated by dopamine neurons and involves dopamine-nitric oxide co-transmission and reception, endoplasmic reticulum Ca2+ signaling, and cytoskeletal remodeling machinery regulated by small GTPases. Some of these molecular cellular mechanisms have already been found to be conserved in mammals. Interestingly, some pathways independently regulate forgetting of distinct memory types and temporal phases, suggesting a multi-layering organization of forgetting systems. In mammals, active forgetting also involves modulation of memory trace synaptic strength by altering AMPA receptor trafficking. Furthermore, active-forgetting employs network level mechanisms wherein non-engram neurons, newly born-engram neurons, and glial cells regulate engram synapses in a state and experience dependent manner. Remarkably, there is evidence for potential coordination between the network and cellular level forgetting mechanisms. Finally, subjects with several neuropsychiatric diseases have been tested and shown to be impaired in active forgetting. Insights obtained from research on active forgetting in animal models will continue to enrich our understanding of the brain dysfunctions that occur in neuropsychiatric diseases.

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Neuroscience
Psychiatric disorders
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pmcIntroduction

A normally functioning human brain has the extraordinary ability to acquire and store a countless number of memories that form each day. This is accomplished by the network of ~86 billion neurons and at least as many nonneuronal cells that make up the human brain [1]. The broad process of memory formation, storage, and use occurs through at least four operations: acquisition (or learning), consolidation, retrieval, and forgetting (Fig. 1a). Memory acquisition alters the physiological state of selected and sparse neurons in ways that generate a neural code for each memory (Fig. 1a,b). The alterations in physiological state, which are broadly termed as molecular and cellular memory traces, can include any change in the cellular activity of the cell induced by learning that becomes part of its neural code. Such memory traces include altered expression or function of ion channels that change the excitable state of neurons so that electrical signaling is increased or decreased. They include altered intracellular signaling pathways that influence the neuron’s overall ability to integrate inputs from different types of cues, and synaptic changes that influence the neuron’s ability to stimulate synaptic partners. They include neuronal growth processes that establish new connections, or neurite retraction to remove existing connections. Some of the molecular and cellular memory traces support only short-term memory (STM), and others are further processed by protein-synthesis dependent consolidation mechanisms leading to persistent and resilient long-term memory (LTM). Collectively, the molecular and cellular memory traces induced by learning across all neurons engaged by the learning event together comprise the memory engram (Fig. 1b) that can guide behavior upon subsequent retrieval [2–5].Fig. 1 Principal memory operations and cellular events.

a The nervous system uses four operations for short- and long-term memory formation: Acquisition, Consolidation, Forgetting, and Retrieval. Acquisition is synonymous with “learning,” and represents the initial encoding of information. Consolidation refers to the processes involved in stabilizing memory over time. Forgetting involves mechanisms whereby memories can be erased or hidden from retrieval. Retrieval is simply the recollection, or recall, of existing memories. b Cartoon illustrating the broad cellular and network events of memory formation. During acquisition, selected cells in the nervous system undergo molecular or biochemical changes that alter their physiological state. These selected cells are known as engram cells, and the molecular or biochemical changes within the engram cells are termed molecular or cellular memory traces. Consolidation mechanisms stabilize the cellular memory traces and the selected engram cells. The engram cells and their corresponding memory traces, together, represent the overall “engram” for a given memory. The activity of forgetting cells can erode the memory traces and cause memory failure.

The fate of the engram depends on the fate of these molecular and cellular memory traces formed at acquisition. One fate leads to consolidation, the processes that stabilize a memory so that it is long-lived and resistant to insults like electroconvulsive shock and inhibition of protein synthesis (Fig. 1a, b). Past neuroscience research has focused nearly entirely on this operation and on acquisition [2, 6–15]. Indeed, one might point to the discovery of long-term potentiation by Bliss and Lomo in 1973 [16] as the start of research on acquisition, and the discovery in the 1960s by Flexner and Flexner, Agranoff, and others, that inhibitors of protein synthesis block memory consolidation as the start of research on consolidation [17]. Although much has been learned about acquisition and consolidation across the last 5-6 decades, the neuroscience understanding of retrieval remains largely theoretical [18], but with some mechanistic studies suggesting that retrieval occurs from internal or external stimuli that activate the same engram cells that are selected during acquisition (Fig. 1). Mechanistic studies of forgetting began only about one decade ago, so there remains much more to be discovered. Nevertheless, the mechanisms underlying forgetting are integral to many different brain disorders, including those in neuropsychiatry.

Forgetting and neuropsychiatric diseases

Broad memory dysfunction occurs in many different psychiatric diseases [19, 20]. This indicates that the neurobiological mechanisms serving one or more of the four operations underlying memory formation (Fig. 1a) are disrupted at the cellular and/or network level, perhaps in different ways and degrees in the different diseases. And it may be that operations underlying forgetting are particularly vulnerable in some psychiatric diseases and not others. But disentangling an impairment in forgetting from the other operations underlying memory (Fig. 1a) is not a trivial task. For instance, the impairment in the ability to hold information “on-line” across a short period of time to accomplish a working memory task in individuals with schizophrenia [21] could be due to ineffective encoding of the information or overactive forgetting. An air-tight assignment to processes underlying forgetting in this case would require knowing that all cellular memory traces in all engram neurons are formed to the same strength and that retrieval mechanisms are identical between diseased and control individuals. This, of course, is currently impossible. Nevertheless, experimental psychologists have devised memory tasks that provide relatively pure measurements for the operation of forgetting [22]. In addition, the nature of memory impairments observed in some neuropsychiatric diseases fits rather precisely with problems in the operation of forgetting, rather than acquisition, consolidation, or retrieval.

Intrusive memories, distressing thoughts, and unwanted impulses are common in many neuropsychiatric disorders. These may occur from the involuntary recall of unwanted thoughts and memories, due to the failure to diminish or erase the memories through forgetting processes [23]. For instance, post-traumatic stress disorder (PTSD) occurs from traumatic and often life-threatening events, with the persistent and reoccurring memory of these events disrupting the lives of individuals with the disorder [24]. This can be explained as due to impaired forgetting. Such enhanced memory is also a feature of addiction, where addiction-associated cues take on enhanced salience compared to more pedestrian cues [25]. Furthermore, it may be that impaired forgetting plays a part in other psychiatric disturbances, including the unwanted maintenance of a misperception that could lead to a distorted interpretation of reality, that is, the generation of a delusion [26].

Tests of individuals with such disorders have revealed impairments in two classes of experimentally measurable forgetting, intentional and incidental forgetting (Table 1). Intentional forgetting occurs through effortful suppression of an unwanted memory at the time of retrieval [27]. One method for measuring intentional forgetting involves the Think/No-Think (TNT) paradigm [22]. Subjects are first presented with cue-target pairs, such as word pairs, until they can recall the targets upon presentation of the cue. In a second phase, the subjects are repeatedly presented with the cues and specific instructions to think about the target for some of the cues, or to repress thoughts about the target for other cues. The final test then measures forgetting for all cue-target pairs, with normal subjects recalling No-Think targets less frequently than Think targets. Incidental forgetting occurs when the selective retrieval of some memory items reduces the recall of unretrieved competing items [22]. This can be measured by having subjects learn multiple items within a category, such as Sports/Basketball, Sports/Soccer, Sports/Tennis, Sports/Swimming, etc., followed by practice in retrieving a subset of the items within the category. The retrieval of practiced items promotes the unintentional forgetting of the non-practiced items. Thus, a reduced potency of intentional or incidental forgetting mechanisms, or other mechanisms for forgetting, can account for the unwanted and intrusive thoughts and memories in the psychiatric diseases listed in Table 1.Table 1 Deficits in two broad classes of active forgetting measured in subjects with neuropsychiatric disorders.

Disorder	Impairment	References	
Addiction	Incidental forgetting	[148]	
Anxiety	Intentional and incidental forgetting	[28, 148–150]	
Attention-Deficit/Hyperactivity Disorder (ADHD)	Incidental forgetting	[151, 152]	
Depression	Intentional and incidental forgetting	[28, 148, 153]	
Obsessive-Compulsive Disorder (OCD)	Intentional forgetting	[28]	
Post-Traumatic Stress Disorder (PTSD)	Intentional and incidental forgetting	[28]	
Schizophrenia	Intentional and incidental forgetting	[28, 154–156]	

Accumulating evidence indicates that intentional and incidental forgetting occurs partly at the network level, with selective memory retrieval or retrieval suppression activating the lateral prefrontal cortex which promotes inhibition in other brain regions that contain the engram cells of memories to be diminished [22, 28]. However, model organism research into forgetting processes shows that forgetting also involves cellular and molecular mechanisms. These mechanisms are the focus of the remainder of this review.

Neurobiology of active forgetting

To accelerate and deepen our understanding of forgetting in humans, researchers are using genetically tractable model organisms to understand the underlying genes, circuits, and cellular processes. While model research into forgetting remains in early stages, in little over a decade, researchers have already utilized a variety of model organisms from mammals to invertebrates, including Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (worms), to ask fundamental questions about forgetting. Currently, Drosophila has been exceptionally successful, relying on its superb balance of a simple nervous system, complex behaviors, and genetic expediency.

Rapid progress in understanding the genetic and cellular mechanisms of forgetting in Drosophila can, in part, be attributed to large scale memory suppressor screens. These screens identify genes that, when disrupted, improve memory performance, and thus normally “suppress” memory. Recent screens involving thousands of genes have identified many memory suppressor genes, some of which specifically disrupt forgetting but leave learning intact [29–31]. These studies have utilized the most well-studied type of Drosophila memory, wherein the flies learn to associate a specific odor with either rewarding or punishing stimuli. This type of associative learning relies on responses of the olfactory system to the odor (the conditioned stimuli, CS) integrated with signaling from dopaminergic neurons (DAn) responding to the reinforcing stimuli (the unconditioned stimulus, US). Importantly, findings using this associative memory paradigm have uncovered many similarities to mammalian memory systems including conserved roles for cAMP, CREB and dopamine [32].

Forgetting research in model systems is expanding quickly and many significant findings have already been made that give insight into how our brains forget, discussed below. In this section, we will first discuss the cellular mechanisms that underlie how engrams are altered by forgetting, including dopamine neuron regulation of engram cell synapses, actin cytoskeletal remodeling, and glutamatergic receptor endocytosis. We will subsequently discuss how forgetting is regulated at the network level by neural and glial cells, and how this allows external and internal factors to tune forgetting.

DA neuron modulation of engram synapses

To understand forgetting, it is helpful to know how memories are formed in the first place. Memories are acquired in the brain as changes in the synaptic input or output of memory specific “engram cells” [5]. In Drosophila, memory engrams are thought to be primarily encoded within the mushroom body (MB) brain structure as it is central to acquiring, storing, and retrieving visual and olfactory memories [32, 33]. The foundation of the MB is a network of ~2000 MB intrinsic neurons per hemisphere (or MBn) wherein sparse and specific sets of these neurons respond to and encode information about different sensory stimuli including olfactory, visual, and gustatory [34, 35]. MBn axons synapse heavily onto an array of output neurons (MBOn) and these synaptic connections have been shown to be critical sites for memory storage [36, 37]. Thus, the MBn and MBOn function as “engram cells” as their shared synaptic connections are modified to encode memories as a “synaptic engram”.

What modifies MBn:MBOn synapses to encode memories? A variety of neurons whose axons project and connect heavily with MBn:MBOn synapses [38] express Tyrosine Hydroxylase, the rate-limiting enzyme in dopamine (DA) production and thus they are referred to as dopamine neurons (DAn). Blocking broad DAn synaptic output or DA receptor expression in the MBn completely blocks learning [39, 40], whereas artificial stimulation of DAn in the presence of odor is sufficient to form olfactory memory [41, 42]. Therefore, the DAn transmit the US information during learning. In fact, distinct DAn are activated by specific stimuli that have value to the animal, including sugar rewards or punishments like electric shock and noxious temperature [38, 43]. During learning, US driven DAn release converges with the activation of a sparse set of MBn:MBOn synapses specific to the odor. This drives specific synaptic changes that alter the connectivity between odor specific MBn and distinct MBOn and allow altered behavioral responses to the odor after learning [33, 36, 37, 44–46]. These DAn mediated memory traces can take the form of synaptic depression [36, 37] or potentiation [46, 47] of odor specific MBn:MBOn synapses, resembling long-term depression (LTD) and potentiation (LTP) in mammals, and can last from hours [36, 37] or days [46, 47]. Therefore, in Drosophila, DA neurons are critical for encoding memory engrams by altering synaptic strength of engram cells.

As it turns out, the same DAn that encode memories are also active after learning and are central regulators of forgetting (Fig. 2) [48–50]. Reactivation of DAn after the flies are trained is sufficient to cause forgetting, whereas blocking synaptic output prolongs memory retention [48, 49, 51]. During learning DA release drives acquisition through one DA receptor (dDA1), but after learning DA signals through another receptor DAMB for forgetting [40, 48]. For example, flies mutant for DAMB have relatively normal learning but memory decay is significantly reduced, whereas overexpression of DAMB in the MBn accelerates forgetting [48, 52]. At a physiological level, dDA1 receptor signaling during learning drives synaptic depression between odor specific MBn:MBOn synapses, whereas DAMB signaling is required for potentiating these connections [53]. Therefore, these results indicate that DA based forgetting occurs by re-potentiating previously depressed engram synapses caused by learning [37]. However, it remains to be seen if the re-potentiation occurs through reversing the specific mechanism of depression or if the depression is masked by independent potentiation mechanisms in the same synapses.Fig. 2 Dopamine neuron mediated active forgetting pathways in Drosophila.

Dopamine neurons (DAn) modulate forgetting by driving independent active forgetting pathways within engram synapses (MBn:MBOn) using co-transmitters NO and DA. DA signaling through the MBn expressed DAMB receptor drives forgetting through two fundamental pathways: 1) coupling to Gαq to drive ER Ca2+ release in MBn synapses, or 2) signaling through Scribble/Rac1 complex to regulate actin remodeling. In parallel, DAn terminals synthesize NO gas that diffuses into MBn and binds the Guanylyl Cyclase (GC, or GycB100) and generates cGMP. NO mediated effects require Scribble. DAn->NO->cGMP signaling also drives gene-expression based forgetting through co-localization of Kdm4B/Bur to genomic sites. Kdm4B/Bur activity drives expression of many genes and enlargement of MBn synapses, possibly through Kek2 expression.

Several different cellular signaling mechanisms have been identified that transmit DA mediated forgetting signals downstream in MBn to affect synaptic engrams (Fig. 2). Interestingly, unlike the learning DA receptor dDA1, the DAMB receptor couples strongly and uniquely to Gαq, causing IP3-dependent calcium efflux from the endoplasmic reticulum (ER) [53, 54]. This DAMB→Gαq coupling is likely an important driver of forgetting as reduction of Gαq in MBn reduces forgetting of STM [54]. Furthermore, physiological studies indicate that DAMB signaling through Gαq robustly drives ER Ca2+ release in MBn resulting in MBn:MBOn synaptic potentiation required for memory flexibility [53]. Thus, current data suggest that DAMB receptor signaling utilizes Ca2+ signaling from the ER to modulate engram synapse strength and cause forgetting. It remains unclear what connects Ca2+ release from the ER to synaptic potentiation in the MBn. However, it is notable that the ER in mammals stores Ca2+ in recently activated neurons and regulates synaptic Ca2+ and neural transmission [55]. For example, ER Ca2+ release at the presynaptic terminal is a major driver of evoked neurotransmission and regulator of synaptic plasticity in hippocampal synapses [56, 57]. Therefore, one interesting possibility is that learning leads to Ca2+ storage within the ER of odor activated MBn synapses and DA→DAMB→Gαq signaling then leads to release of this Ca2+ to potentiate synaptic release and cause forgetting.

Another important component of DA→DAMB mediated active forgetting involves the scaffolding protein Scribble, which was discovered in a large memory suppressor screen [30, 52]. Scribble is expressed in MBn and while dispensable for learning, is critical for both memory decay and retroactive interference-based forgetting [52]. Scaffolding proteins, like Scribble, function to assemble different components in a signaling cascade. Interestingly, Scribble was shown to function downstream of DA→DAMB signaling and to interact with the small GTPase Rac1 to mediate cytoskeleton remodeling-based forgetting, which we will discuss in more detail in the next section. At the physiological level, Rac1 activity is required for the decay of MBn:MBOn synaptic depression underlying STM [58]. Therefore, Scribble connects DA→DAMB mediated signaling at the plasma membrane with downstream cytoskeleton remodeling to drive forgetting through re-potentiation of depressed engram synapses (Fig. 2). The mechanism by which Scribble facilitates this intracellular communication and whether it also scaffolds Gαq and DAMB remains unknown, but it clearly functions as an important signaling nexus for forgetting. Future studies to uncover other signaling components it scaffolds will be revealing.

While DA is central to modulating forgetting of MBn:MBOn engrams, it was recently discovered that DAn also release nitric oxide (NO) gas as a co-transmitter that strongly modulates forgetting [50]. Remarkably, this study demonstrated that during learning the DA neurons release two signals: 1) DA that acts through dDA1 to immediately depress MBn:MBOn engram synapses and encode memory, and 2) NO which binds to the NO receptor Guanylyl Cyclase GycB100 (GC) expressed in the MBn to stimulate cGMP production. A role of GycB100 in memory enhancement, reported by an earlier memory suppressor screen, supports this model [30]. Interestingly, learning induced NO signaling does not affect the acquisition of STM but instead leads to a delayed process that accelerates forgetting over time. This forgetting allows better memory flexibility so that flies can adapt to new associations. Mechanistically, the data suggest NO signaling promotes forgetting by re-potentiating MBn:MBOn engram synapses and interfering with DA mediated synaptic depression, similar to DA→DAMB mediated forgetting. Additionally, NO mediated effects require Scribble in the MBn. Future experiments are needed to confirm the physiological effects of NO on synaptic plasticity and investigate the relationship between NO and DAMB and actin remodeling-based forgetting. Regardless, a single learning event can drive opposing cellular traces in the same synapses, one that supports the memory and one that suppresses it later and allows future memory flexibility.

Forgetting STM also depends on gene expression driven by the above DAn→NO→cGMP pathway [59] (Fig. 2). cGMP drives the co-localization of histone demethylase Kdm4B and GMP synthetase Bur at genomic sites to influence the expression of many genes including the cell adhesion protein Kek2, previously shown to regulate synaptic size [60]. Interestingly, gene expression-based forgetting was specific to 3–6 hours after learning, a timepoint following Rac1’s actions in forgetting (Fig. 3), suggestive of sequential forgetting systems working at different times after acquisition. These results corroborate NO based forgetting and link it to the expression of forgetting specific transcriptional programs.Fig. 3 Distinct signaling regulates forgetting of different memory phases and types in Drosophila.

A single trial of aversive olfactory conditioning yields a short-lived memory that is labile and anesthesia-sensitive (ASM) and a consolidated form of memory that is longer-lasting and anesthesia-resistant (ARM). Retention of STM (black line) and its ASM (red) and ARM (blue) components over time require distinct and sequentially engaged cellular pathways. Upon learning, labile ASM is formed and within 1 hour a consolidated ARM component forms. The forgetting of ASM proceeds rapidly through the activation of the Rac1 within the first 3 hours. Raf is also activated during this period and blocks forgetting of a Rac1 independent form of ASM. Gene expression-based forgetting from Kdm4B/Bur activity regulates forgetting of ASM between 3–6 hours. The forgetting of consolidated ARM proceeds through the activation of Cdc42 between 3–6 hours after learning. After 6 hr memory slowly decays, but the forgetting pathways responsible are unknown (??).

Does forgetting of STM and LTM involve similar or different mechanisms? Interestingly, in flies, LTM, formed by repeated and spaced conditioning of odor and electric shock, is forgotten via DA→DAMB signaling but with some key differences [46]. First, unlike STM, the effect of DAn modulation on LTM is transient, as memory performance returns to normal over time. In fact, acute activation of DAn by distracting or interfering stimuli, just prior to testing, robustly and transiently suppresses LTM retrieval. Furthermore, if the DAMB receptor function is removed from MBn after LTM memory has formed, retrieval is still enhanced. The second difference is that transient forgetting involves a different DAn circuit and MBn:MBOn synapses than those involved in forgetting STM. Interestingly, LTM training creates a potentiation in odor specific MBn:MBOn synapses regulated by this DAn. This long-term memory trace was long-lasting and dependent on protein synthesis. Third, unlike the synaptic depression based STM traces mentioned above, this LTM memory trace was not significantly affected by DAn modulation. These results indicate that DA→DAMB signaling is regulating transient forgetting through modifying yet unknown synaptic connections without eroding or altering the core memory trace that is stable and persistent, which explains the re-emergence of LTM with time. However, the specific cellular and synaptic mechanism by which DAMB mediates transient forgetting and how this interferes with retrieval of this LTM memory trace remain to be elucidated. In the future, it will be interesting to see if DA based transient forgetting of LTM involves similar downstream mechanisms as forgetting of STM, including Gαq coupling, Scribble scaffolding, Rac1 activation, or ER Ca2+ release.

Additionally, the ability to update already consolidated LTM was recently linked to the CoRest/Rpd3 transcriptional repressor complex and gene expression in MBn [61]. Spaced conditioning turns on CoRest-Rpd3 mediated gene expression required for initial consolidation, but this gene expression eventually turns off through a compositional shift in the CoRest/Rpd3 repressor. Remarkably, if expression is not turned off, the memory remains flexible and is easily updated. However, it remains unclear what genes must be turned off to stabilize consolidated LTM, and how these gene networks intersect with DAn signaling at engram synapses.

DA plays a profound role in learning in Drosophila and mammals so unsurprisingly its role in forgetting is also conserved. For example, DA has been implicated to contribute to incidental forgetting. In human studies, subjects with a loss-of-function allele for catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine, have higher levels of prefrontal cortex dopamine and higher levels of incidental forgetting [62]. At the DA receptor level, pharmacological inhibition of rat D1 dopamine receptors in the prefrontal cortex eliminates incidental forgetting while activation promotes it [63]. Additionally, injection of an antagonist to the D1 receptor in the rat hippocampus 12 hr after training enhances the persistence of 7-day food and cocaine-place conditioning memory [64]. Therefore, DA and D1 dopamine receptors are strongly implicated in mammalian active forgetting. Interestingly, mammalian DAn have also been shown to release co-transmitters like glutamate and GABA alongside DA [65, 66]. While it remains unclear if NO is also co-released in mammalian DAn, NO signaling in the mammalian cerebellum can drive either LTD [67] or LTP [68] based synaptic plasticity and thus could in theory be used for active forgetting like in Drosophila.

Actin cytoskeleton remodeling and forgetting

Active forgetting relies, in part, on remodeling the actin cytoskeleton within engram synapses. The actin cytoskeleton gives neurons their shape and shrinking or growing synaptic connections requires cytoskeleton remodeling. Long-term imaging of adult cortical networks indicates that, depending on the neuron type, 15-60% of synaptic connections are dynamic; formed or eliminated over a month [69]. Importantly, experience can enhance this dynamic of synaptic connections [70] with learning driving synapse formation [71]. In addition to forming or eliminating synapses, actin cytoskeleton dynamics also orchestrate changes in existing synapse size, which has been associated with proportional changes in synaptic strength including LTP and LTD [72–74]. This modulation of synaptic connections positions cytoskeleton remodeling as a central mediator of both learning and forgetting.

Actin dynamics are principally regulated by the Rho-family GTPases which include Rac1, Cdc42, and RhoA [75–77]. Recent studies in Drosophila indicate that both Rac1 and Cdc42 are powerful regulators of active forgetting but with interesting differences in the components of memory they regulate (Fig. 3) and their downstream pathways and cytoskeletal processes (Fig. 4). In Drosophila, a single trial of aversive olfactory conditioning yields at least two memory components: 1) a short-lived memory that is labile and sensitive to anesthesia (anesthesia sensitive memory, ASM), and 2) a delayed consolidated form of memory that is more long-lasting and resistant to anesthesia (anesthesia resistant memory, ARM) [9, 78, 79]. Remarkably, while Rac1 and Cdc42 are dispensable for the formation of either ASM and ARM, they independently regulate the forgetting of ASM and ARM, respectively [29, 80, 81]. Importantly, learning activates both GTPases as their phosphorylated and activated states significantly increase upon training. After learning, Rac1 is activated from 1–3 hours and regulates forgetting of ASM, whereas Cdc42 is activated by 3 hours and regulates forgetting of ARM between 3–6 hour (Fig. 3). Since both Rac1 and Cdc42 based forgetting pathways function within the MBn [29, 80, 81], they probably regulate two distinct cellular memory traces that rely on distinct actin cytoskeletal dynamics.Fig. 4 Multiple actin remodeling pathways differentially regulate forgetting of specific memory types in Drosophila.

Actin cytoskeletal remodeling regulates the forgetting of both labile (ASM) and consolidated (ARM) memories in Drosophila through independent actin regulators and pathways. Small GTPase Rac1 regulates forgetting of ASM through two distinct pathways. Downstream of DA signaling, Rac1 associates with Scribble and Pak3 to inhibit Cofilin and stop actin depolymerization. In parallel, Rac1 drives linear actin polymerization via SCAR mediated Dia activity. A portion of ASM is protected from disruption by Raf phosphorylation of MAPK and subsequent activation of the Myosin II motor. This could lead to translocation of actin filaments and tension that potentially supports enlarged synaptic size required to store memory. Another small GTPase Cdc42 regulates ARM by WASp mediated activation of the Arp2/3 complex to increase polymerization of branched actin.

Rac1 and Cdc42 direct actin dynamics through downstream signaling cascades leading to modulation of actin binding proteins. Actin remodeling processes are diverse and include depolymerization and polymerization, both linear and branched (Fig. 4). As mentioned earlier, DA→DAMB based forgetting requires the scaffolding protein Scribble to coordinate DA based signaling with cytoskeletal remodeling-based forgetting. Specifically, Scribble was found to interact with Rac1 physically and genetically as well as with canonical pathway members Pak3 and Cofilin [52]. Pak family members are serine/threonine kinases that phosphorylate and inactivate the actin-binding protein Cofilin thus halting its depolymerization function [82, 83]. Expression of constitutively active forms of Cofilin within MBn blocks active forgetting, including that mediated by Scribble [29, 52]. In addition to halting depolymerization, Rac1 can also drive linear polymerization [84, 85], and genetic epistasis experiments [81] revealed that Rac1 forgetting of ASM was in part through engaging the WASP (Wiskott-Aldrich syndrome protein) related protein SCAR and downstream actin binding Formin family protein Dia, a direct mediator of linear polymerization (Fig. 4) [86, 87]. It remains unclear if Cofilin and Dia signaling downstream of Rac1 control independent portions of ASM or work together.

Forgetting of consolidated ARM orchestrated by Cdc42 works through a different WASP family member WASp and downstream Arp2/3 complex [81], a pathway known to nucleate branched actin filaments [88]. Future research is needed to understand why linear and branched polymerization have differential effects on labile and consolidated memory, respectively. These studies suggest that different types and temporal phases of memory have dedicated actin cytoskeletal pathways for their erasure.

Labile memories are short-lived in part because they can be disrupted by sensory experiences that drive active forgetting. However, some actin cytoskeletal regulators protect labile memories from active forgetting. Heat-stress, electric shock stress, or odor exposure cause forgetting of labile memories and this type of forgetting appears independent of Rac1 [89]. The investigators found that the serine/threonine kinase Raf blocks this Rac1 independent active forgetting pathway (Figs. 3 and 4). Specifically, expression of a Raf-GOF (gain of function) transgene in adult MBn enhances the stability of labile memory and protects it from disruption by post-learning experiences. Combined expression of Raf-GOF and Rac1-DN (dominant negative) stabilized memory beyond that conferred by each individual transgene and strikingly no memory decay occurred in the first 3 hour after training. Furthermore, learning itself drives Raf dependent activation of MAPK in the MBn that persists for less than 1 hour. A screen for cytoskeletal effectors identified spaghetti squash (sqh), which encodes the regulatory light chain of Non-muscle Myosin II. Myosins are multiprotein machines that bind with actin filaments and use ATP energy to create movement and force that can be used to transport cargo or, interestingly, to propel actin filaments and produce tension [90]. Zhang et al. [89] report that learning leads to increased MBn synaptic size that is normally short lived, but with increased Raf signaling (via Raf-GOF expression) this increased size is maintained longer. Overall, the authors suggest that, in Drosophila, learning induced Raf activation protects labile memory by maintaining structural plasticity (increased MBn synapse size) through Myosin II function. While it remains unclear which exact Myosin II function is responsible for this protection, its ability to translocate large actin filaments is consistent with maintaining enlarged synaptic size. In mammals, Myosin II’s ability to translocate actin filaments is required for its effects on dendritic spine morphology [91].

How conserved is the role for actin cytoskeletal remodeling in forgetting across the animal kingdom? At a cellular level, both GTPases Rac1 and Cdc42 are known in mammals to modulate dendritic spine morphology by controlling actin dynamics [92] and thus in theory could both regulate forgetting in mammals. While no forgetting role for Cdc42 has been demonstrated outside of Drosophila, Rac1 has been shown to regulate forgetting of several types of memory in mice. Rac1 activity within the hippocampus increases after contextual fear conditioning and, importantly, pharmacological inhibition of Rac1 only after training produced enhanced memory performance [93]. Furthermore, genetic manipulation of Rac1 activity up or down within the hippocampus impaired or enhanced long-term contextual fear memory, respectively, with neither altering acquisition [94]. Similar findings have been found regarding Rac1 activity in the hippocampus and forgetting of episodic memory tested by novel object recognition [95], in a social discrimination paradigm [96], and social stress induced transient forgetting [97]. However, these studies did not investigate what actin regulatory proteins are involved downstream of Rac1, thus the role of mammalian Cofilin and Dia in active forgetting is unclear.

Regarding branched polymerization and forgetting, the Arp2/3 complex was found to be involved in forgetting in the worm C. elegans but with an opposite role. Whereas Arp2/3 supports active forgetting in Drosophila, in C. elegans it appears to prevent forgetting of associative memories [98]. Finally, Myosin II has a similar cytoskeletal and synaptic role in mammals. Acute knockdown of Myosin IIb in hippocampal neurons strongly de-stabilized early LTP at these synapses without altering the initial formation of the plasticity [99]. Importantly, Myosin IIb activity was required for rapid actin filament synthesis at the synapse that is required for LTP stabilization over time. Given that LTP is associated with increased synapse size, Myosin II has a conserved function in regulating actin dynamics to maintain increased synapse size that underlies synaptic plasticity and memory.

Glutamatergic receptor endocytosis

Like in Drosophila, memory engrams in mammals are encoded as modulations in strength of engram synapses, particularly of glutamatergic synapses (Fig. 5). This synaptic strength is governed by the synaptic abundance of an ionotropic glutamate receptor, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor (AMPAR) [100]. The trafficking of AMPARs to the post-synaptic site following a learning event enhances synaptic strength (via LTP) and facilitates the formation of specific types of memory [101]. For example, after auditory fear conditioning, the levels of Glu2a subunit containing AMPAR in the post synapse of amygdala neurons correlate with the strength of memory [102]. Conversely, the internalization of AMPARs weakens synaptic strength, and research indicates that this drives active forgetting [103]. Several groups have shown that inhibiting the internalization of Glu2a effectively blocks the decay of LTP and the natural forgetting of memory [102, 104]. Furthermore, extinction training protocols that erase long-term fear memories do so by synaptic removal of a calcium permeable AMPAR in the lateral amygdala [105]. These studies indicate that AMPAR trafficking to and from the post synaptic membrane is a tightly regulated process to acquire and forget memories.Fig. 5 Active forgetting pathways in mammals involve AMPAR trafficking.

Multiple forgetting pathways in mammals utilize glutamatergic receptor AMPAR endocytosis to modulate the strength of engram synapses. One such pathway involves the activation of Caspase-2, which subsequently increases GSK3β kinase activity. In turn, GSK3β phosphorylates AMPARs, initiating their internalization. A second and independent forgetting pathway involves Syt3 integral membrane protein and Ca2+ dependent internalization of AMPARs.

Multiple pathways have been shown to mediate this AMPAR trafficking. Caspase-2, a protease known for its role in apoptosis, is surprisingly also a memory suppressor gene that drives forgetting of episodic memories [106]. Reducing Caspase-2 expression slows the forgetting of spatial memory and impairs the internalization of hippocampal AMPARs. During forgetting, Caspase-2 activity increases that of GSK3β, a direct mediator of AMPAR internalization via phosphorylation. Another pathway for AMPAR internalization involves Synaptotagmin-3 (Syt3), an integral membrane protein that regulates Ca2+ dependent membrane recycling events. Mice lacking Syt3 fail to forget previously learned associations when presented a new learning event in the water maze due to a lack of AMPAR internalization [107]. In contrast to Caspase-2 and Syt3 pathways that drive internalization, researchers have identified that the kinase PKMζ plays a crucial role in the maintenance of AMPAR synaptic localization, thereby contributing to sustained synaptic potentiation. When PKMζ is disrupted in the dorsal hippocampus using the inhibitory peptide ZIP, mice were unable to remember the location of objects post training but could still identify the object [108]. However, there is an ongoing debate regarding the effectiveness of the ZIP peptide and PKMζ activity [109–112]. Even so, GluA2 receptor endocytosis presents an intriguing mechanism for active forgetting. Future research to unravel the signaling systems mobilized to remove the receptors will be enlightening.

Network level regulation of forgetting

The active forgetting mechanisms discussed above involve cellular signaling within engram cells to modulate their synaptic strength and accessibility of memories. However, these mechanisms are further tuned by factors external and internal to the animal, including environmental experience, physical activity, arousal, sleep, and neurogenesis. These factors modulate forgetting at the network level by regulating neural circuits that synapse onto engram cells, synaptic competition between engram cells, and microglial remodeling of synapses (Fig. 6). Thus, non-engram brain cells provide the platform for brain-wide and network level information to access engram synapses and regulate cellular forgetting pathways.Fig. 6 Network level regulation of forgetting.

Forgetting involves multiple network level mechanisms that regulate engram cell (EC) synapses. An existing memory engram is stored across engram cells and their synaptic connections (blue). These EC are modulated by external circuits (red) that respond to sensory experience or internal states and regulate EC synaptic strength and thus regulate forgetting. Additionally, neurogenesis drives the creation of new engram cells (purple) that compete for synaptic inputs and outputs with existing engram cells storing pre-existing memories. Here, “+” indicates the recent addition of a synapse between new EC and existing EC. Finally, weaker engram synapses are targeted for phagocytosis and elimination by microglia (green).

Sensory experience can modulate the rate of forgetting across the animal kingdom. As discussed above in Drosophila, sensory experiences like heat and electric shock stress, odor exposure, or even new learning can disrupt labile memory. Given that DAn are responsive to most of the sensory experiences above [38, 43] they are positioned as ideal conduits for sensory experience to modulate forgetting. Stimulating any of several different DAn circuits after learning is sufficient to simultaneously drive learning and forgetting of specific memory engrams [37, 49, 50]. Experiences seemingly unrelated to the original training can also drive forgetting via DAn. For example, mechanical stimulation induced arousal and locomotion accelerates forgetting of memories via enhancing the activity of the same DAn that encoded them [113]. Thus, DAn driven active forgetting mechanisms provide a biological explanation for interference-based forgetting. Finally, in worms, the presence of food activates forgetting of odor adaptation memory in engram neurons through the secretion of forgetting signals from separate sensory neurons [114].

Housing in environments enriched with increased levels of sensory, cognitive, and motor stimulation can modulate synaptic plasticity in rodents [115] and enhance cognitive flexibility in mice [116]. On the other hand, social isolation in an impoverished environment enhances forgetting of social recognition memories in mice via increasing Rac1 activity in the hippocampus [96]. So, the direction by which the environment modulates forgetting varies with the scenario and likely the relatedness between the training and post-training stimuli and context.

Internal brain states, like sleep, also modulate active forgetting mechanisms. Sleep consists of several stages with diverse effects on neural activity and has a well-established role in enhancing memory after learning across the animal kingdom, including in humans and fruit flies [113, 117–124]. In flies, sleep is associated with diverse changes in the activity of specific neural circuits across the brain, including DAn [113, 117]. The underlying mechanisms of sleep-dependent memory enhancement are still being defined and are diverse. One mechanism is that sleep enhances memory consolidation [118–121]. This is supported by studies showing that engram cells in the hippocampus are reactivated during sleep to promote memory consolidation [122, 123]. Another possible mechanism, not mutually exclusive with the first, is that sleep and rest inhibit active forgetting of labile memory, potentially protecting nascent memory traces from interference so they can be consolidated [113, 124]. Interestingly, the Drosophila DAn that drive forgetting of labile memory have a baseline level of ongoing activity that steadily releases DA onto the engram cell synapses and this increases with arousal and locomotion [48, 51, 113, 125, 126]. Efficient release of DA during this ongoing activity and forgetting requires the memory suppressor and cytoskeletal protein Sickie in presynaptic terminals of DAn [30, 126]. Importantly, Berry et al. [113] showed that sleep efficiently blocks this ongoing dopamine based forgetting signal and increases memory retention. This provides a biological explanation for how sleep retroactively facilitates memory by protecting it from interference. In contrast to enhancing memory retention, sleep has also been proposed to drive active forgetting in at least two ways. First, sleep leads to synaptic downscaling that broadly reduces synapse strength and thus theoretically could degrade engrams [127–129]. Second, a recent study identified a hypothalamic neural circuit that is active during sleep and inhibits hippocampal neuron activity to drive active forgetting [130]. Altogether, sleep modulates the persistence of memory in multiple ways to balance the consolidation of important memories and active forgetting of unimportant ones.

Additional non-engram neural circuits have been identified that drive active forgetting but have yet to be connected to internal or external factors. In Drosophila, two MB extrinsic circuits, a DAn and a MBOn, independently regulate active forgetting but are dispensable for learning [51]. Most interestingly, these forgetting circuits have a restricted forgetting function, regulating time-based forgetting without influencing interference-induced forgetting. Both circuits provide pre-synaptic input to many target neurons within specific MBn:MBOn synaptic regions [51, 131] and could in principle regulate engram synapses directly or indirectly. It will be interesting to find out what network level factors, internal or external, regulate these circuits and modulate forgetting.

In addition to circuit and cellular mechanisms that modulate existing engram synapses, the creation and addition of entirely new engram cells and their synaptic connections also drives active forgetting in mammals (Fig. 6 bottom). Throughout life, the dentate gyrus neurons in the hippocampus are continuously added through the process of neurogenesis. These new engram cells compete for synaptic inputs and outputs with older engram cells, including presumably those with stored information. Thus, neurogenesis has been proposed as an intriguing mechanism to forget old memories stored in old engram cells [132, 133]. Indeed, increasing hippocampal neurogenesis after learning accelerates forgetting, while reducing it attenuates it in mice [134–136]. At a synaptic level, suppressing neurogenesis creates a longer-lasting hippocampal LTP [137] and increased conditions that drive neurogenesis lead to a faster LTP decay [138]. The rate of neurogenesis depends on many factors mentioned above including physical activity and environmental enrichment [134–136]. Interestingly, neurogenesis might also be coordinated with the engram cellular mechanisms discussed above including Rac1. Rac1 is not required for basal neurogenesis but is required for learning evoked increases in neurogenesis [139]. If learning induces both Rac1 expression in engram synapses and neurogenesis, it opens the possibility that these forgetting systems are coordinated. However, it remains unclear if and how neurogenesis alters synaptic physiology of specific engram cells for a specific memory. Further experiments using tagged engram cells and their synapses will be required to measure the direct effects of neurogenesis on an engram.

Finally, neurons are only one type of brain cell that can regulate memory. Mammalian neuronal synapses are surrounded by the projections of small glial cells called microglia. Microglia recognize synapses that express specific complement proteins, engulf, and eliminate them in an activity dependent manner [140, 141]. A recent study demonstrated that natural forgetting involves microglia-dependent mechanisms [142]. Mice trained in contextual fear conditioning had reduced forgetting when microglia where pharmacological or genetic depleted after learning. Additionally, reducing activity of tagged engram cells in mice after learning led to forgetting that was entirely dependent on microglia. Given that microglia target weak synapses over strong [141], one possibility is that less active engram cell synapses are pruned by microglia leading to selective forgetting of infrequently used memories (Fig. 6 top right).

Summary and perspectives

A major conclusion offered here is that the brain has the inherent capacity and flexibility to forget information though dedicated networks and molecular cascades. This capability is not a passive process, but is active since pathways like Rac1, Cdc42, and NO are triggered by learning itself. Thus, active forgetting, along with acquisition, consolidation, and retrieval, are equally important parts of the brain’s memory management system. Across the animal kingdom, a common end “goal” of these pathways is to modulate engram cell synaptic strength, either through DA and NO mediated synaptic modulation as in flies, or through excitatory glutamatergic receptor endocytosis, neurogenesis, and microglia in mammals (Figs. 2, 5, 6).

A second conclusion we offer is that memory is both formed and forgotten in layers. The brain employs many molecular and cellular mechanisms to form robust and salient memories. We speculate that many of these mechanisms may have their own independent forgetting mechanisms to reverse the changes made to the neuron’s structure and/or function. It follows that distinct forgetting pathways will exist for memories of different temporal phases (STM, LTM, etc) and kind (aversive, appetitive, episodic, motor, etc.). For instance, Rac1 regulates memory decay prior to that of Kdm4B/Bur and Cdc42, but forgetting continues beyond these time domains. This suggests that remote memory may be slowly forgotten by mechanisms independent of Rac1, Kdm4B/ Bur, and Cdc42 (Fig. 3). Additionally, reward memory is insensitive to Rac1-Dia based active forgetting in Drosophila, suggesting distinct pathways depending on valence [143].

A third conclusion is that cellular forgetting in engram cells is heavily influenced by non-engram brain cells and circuits and by newly born engram cells. This feature allows internal brain states and external experience to fine-tune active forgetting within engram cells. For example, the internal state of sleep can decrease active forgetting signals from DAn to protect nascent memory and facilitate consolidation. Furthermore, enriched environments and physical exercise increase adult neurogenesis of future engram cells that will outcompete older engram cells for synaptic inputs and outputs and drive the forgetting of old unused memories. Interestingly, there is evidence that forgetting mechanisms at different levels of complexity work together. Learning induced neurogenesis requires Rac1 [139] and microglial remodeling [142] suggesting that cellular forgetting pathways may be coordinated with neurogenesis and microglial remodeling. There are probably many other network-level active forgetting mechanisms that will be uncovered from future genetic and circuit level screening in model organisms.

Finally, we offer the perspective that alterations in active forgetting participate in the pathophysiology of human brain disorders. In addition to the direct evidence for impairments in intentional and incidental forgetting in individuals with neuropsychiatric diseases discussed above, evidence has emerged suggesting that some types of autism spectrum disorder in both human subjects and mouse genetic models are associated with reversal learning or active forgetting deficits [144, 145]. Moreover, recent research has uncovered a role of Rac1 in the accelerated forgetting associated with neurodegeneration in Alzheimer’s disease (AD) [146, 147]. Thus, dissecting the mechanisms of active forgetting promises a wealth of information and a renewed understanding on how a normal and abnormal brain manages the incomprehensible amount of information that it processes daily. It also offers the promise of identifying new molecular targets for cognitive enhancers that could fine-tune forgetting. Although the neuroscience mechanisms for active forgetting are just beginning to emerge with some clarity, it is not too early to imagine how current and future mechanisms yet to be discovered are involved in neuropsychiatric diseases and brain disorders that affect memory retention.

Acknowledgements

Active forgetting research in the laboratory of J.A.B. is supported by Natural Sciences and Engineering Research Council grant RGPIN-2021-02545. Research in the laboratory of R.L.D. is supported by NIH grant R35NS097224.

Author contributions

All authors contributed to organizing and writing the original draft and reviewing and editing the manuscript into its final form.

Competing interests

The authors declare no competing interests.

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

1. Herculano-Houzel S The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost Proc Natl Acad Sci USA 2012 109 10661 8 10.1073/pnas.1201895109 22723358
Herculano-Houzel S. The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost. Proc Natl Acad Sci USA. 2012;109:10661–8.22723358
2. Squire LR Memory and Brain. Oxford University Press, 1987.
3. Dudai Y Memory From A to Z: Keywords, Concepts, and Beyond. Oxford University Press, 2004.
4. Davis RL Traces of Drosophila memory Neuron 2011 70 8 19 10.1016/j.neuron.2011.03.012 21482352
Davis RL. Traces of Drosophila memory. Neuron. 2011;70:8–19.21482352
5. Tonegawa S Liu X Ramirez S Redondo R Memory engram cells have come of age Neuron 2015 87 918 31 10.1016/j.neuron.2015.08.002 26335640
Tonegawa S, Liu X, Ramirez S, Redondo R. Memory engram cells have come of age. Neuron. 2015;87:918–31.26335640
6. Menzel R Muller U Learning and memory in honeybees: from behavior to neural substrates Annu Rev Neurosci 1996 19 379 404 10.1146/annurev.ne.19.030196.002115 8833448
Menzel R, Muller U. Learning and memory in honeybees: from behavior to neural substrates. Annu Rev Neurosci. 1996;19:379–404.8833448
7. McGaugh JL Memory-–a century of consolidation Science 2000 287 248 51 10.1126/science.287.5451.248 10634773
McGaugh JL. Memory-–a century of consolidation. Science. 2000;287:248–51.10634773
8. Dudai Y The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol 2004 55 51 86 10.1146/annurev.psych.55.090902.142050 14744210
Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004;55:51–86.14744210
9. Davis RL Olfactory memory formation in Drosophila: from molecular to systems neuroscience Annu Rev Neurosci 2005 28 275 302 10.1146/annurev.neuro.28.061604.135651 16022597
Davis RL. Olfactory memory formation in Drosophila: from molecular to systems neuroscience. Annu Rev Neurosci. 2005;28:275–302.16022597
10. Shema R Sacktor TC Dudai Y Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta Science 2007 317 951 3 10.1126/science.1144334 17702943
Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. Science. 2007;317:951–3.17702943
11. Jonides J Lewis RL Nee DE Lustig CA Berman MG Moore KS The mind and brain of short-term memory Annu Rev Psychol 2008 59 193 224 10.1146/annurev.psych.59.103006.093615 17854286
Jonides J, Lewis RL, Nee DE, Lustig CA, Berman MG, Moore KS. The mind and brain of short-term memory. Annu Rev Psychol. 2008;59:193–224.17854286
12. Wang S-H Redondo RL Morris RGM Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory Proc Natl Acad Sci USA 2010 107 19537 42 10.1073/pnas.1008638107 20962282
Wang S-H, Redondo RL, Morris RGM. Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc Natl Acad Sci USA. 2010;107:19537–42.20962282
13. Johansen JP Cain CK Ostroff LE LeDoux JE Molecular mechanisms of fear learning and memory Cell 2011 147 509 24 10.1016/j.cell.2011.10.009 22036561
Johansen JP, Cain CK, Ostroff LE, LeDoux JE. Molecular mechanisms of fear learning and memory. Cell. 2011;147:509–24.22036561
14. Kandel ER Dudai Y Mayford MR The molecular and systems biology of memory Cell 2014 157 163 86 10.1016/j.cell.2014.03.001 24679534
Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014;157:163–86.24679534
15. Dudai Y Karni A Born J The consolidation and transformation of memory Neuron 2015 88 20 32 10.1016/j.neuron.2015.09.004 26447570
Dudai Y, Karni A, Born J. The consolidation and transformation of memory. Neuron. 2015;88:20–32.26447570
16. Nicoll RA A brief history of long-term potentiation Neuron 2017 93 281 90 10.1016/j.neuron.2016.12.015 28103477
Nicoll RA. A brief history of long-term potentiation. Neuron. 2017;93:281–90.28103477
17. Hernandez PJ Abel T The role of protein synthesis in memory consolidation: Progress amid decades of debate Neurobiol Learn Mem 2008 89 293 311 10.1016/j.nlm.2007.09.010 18053752
Hernandez PJ, Abel T. The role of protein synthesis in memory consolidation: Progress amid decades of debate. Neurobiol Learn Mem. 2008;89:293–311.18053752
18. Frankland PW Josselyn SA Köhler S The neurobiological foundation of memory retrieval Nat Neurosci 2019 22 1576 85 10.1038/s41593-019-0493-1 31551594
Frankland PW, Josselyn SA, Köhler S. The neurobiological foundation of memory retrieval. Nat Neurosci. 2019;22:1576–85.31551594
19. Devere R Dementia Insights: Cognitive impairment in primary psychiatric disorders: Role in the diagnosis of cognitive disorders in clinical neurology. Pract Neurol. 2013; 27–33.
20. Pittenger C Disorders of memory and plasticity in psychiatric disease Dialogues Clin Neurosci 2013 15 455 63 10.31887/DCNS.2013.15.4/cpittenger 24459412
Pittenger C. Disorders of memory and plasticity in psychiatric disease. Dialogues Clin Neurosci. 2013;15:455–63.24459412
21. Guo JY Ragland JD Carter CS Memory and cognition in schizophrenia Mol Psychiatry 2019 24 633 42 10.1038/s41380-018-0231-1 30242229
Guo JY, Ragland JD, Carter CS. Memory and cognition in schizophrenia. Mol Psychiatry. 2019;24:633–42.30242229
22. Anderson MC Hulbert JC Active Forgetting: Adaptation of memory by prefrontal control Annu Rev Psychol 2021 72 1 36 10.1146/annurev-psych-072720-094140 32928060
Anderson MC, Hulbert JC. Active Forgetting: Adaptation of memory by prefrontal control. Annu Rev Psychol. 2021;72:1–36.32928060
23. Nørby S Forgetting and emotion regulation in mental health, anxiety, and depression Memory 2018 26 342 36 10.1080/09658211.2017.1346130 28697639
Nørby S. Forgetting and emotion regulation in mental health, anxiety, and depression. Memory. 2018;26:342–36.28697639
24. Samuelson KW Post-traumatic stress disorder and declarative memory functioning: a review Dialogues Clin Neurosci 2011 13 346 51 10.31887/DCNS.2011.13.2/ksamuelson 22033732
Samuelson KW. Post-traumatic stress disorder and declarative memory functioning: a review. Dialogues Clin Neurosci. 2011;13:346–51.22033732
25. Perry CJ Zbukvic I Kim JH Lawrence AJ Role of cues and contexts on drug-seeking behaviour Br J Pharm 2014 171 4636 72 10.1111/bph.12735
Perry CJ, Zbukvic I, Kim JH, Lawrence AJ. Role of cues and contexts on drug-seeking behaviour. Br J Pharm. 2014;171:4636–72.
26. Koller WN Cannon TD Aberrant memory and delusional ideation: A pernicious partnership? Clin Psychol Rev 2023 99 102231 10.1016/j.cpr.2022.102231 36469975
Koller WN, Cannon TD. Aberrant memory and delusional ideation: A pernicious partnership? Clin Psychol Rev. 2023;99:102231.36469975
27. Anderson MC Hanslmayr S Neural mechanisms of motivated forgetting Trends Cogn Sci 2014 18 279 92 10.1016/j.tics.2014.03.002 24747000
Anderson MC, Hanslmayr S. Neural mechanisms of motivated forgetting. Trends Cogn Sci. 2014;18:279–92.24747000
28. Costanzi M Cianfanelli B Santirocchi A Lasaponara S Spataro P Rossi-Arnaud C Forgetting unwanted memories: Active forgetting and implications for the development of psychological disorders J Pers Med 2021 11 241 10.3390/jpm11040241 33810436
Costanzi M, Cianfanelli B, Santirocchi A, Lasaponara S, Spataro P, Rossi-Arnaud C, et al. Forgetting unwanted memories: Active forgetting and implications for the development of psychological disorders. J Pers Med. 2021;11:241.33810436
29. Shuai Y Lu B Hu Y Wang L Sun K Zhong Y Forgetting is regulated through Rac activity in Drosophila Cell 2010 140 579 89 10.1016/j.cell.2009.12.044 20178749
Shuai Y, Lu B, Hu Y, Wang L, Sun K, Zhong Y. Forgetting is regulated through Rac activity in Drosophila. Cell. 2010;140:579–89.20178749
30. Walkinshaw E Gai Y Farkas C Richter D Nicholas E Keleman K Identification of genes that promote or inhibit olfactory memory formation in Drosophila Genetics 2015 199 1173 82 10.1534/genetics.114.173575 25644700
Walkinshaw E, Gai Y, Farkas C, Richter D, Nicholas E, Keleman K, et al. Identification of genes that promote or inhibit olfactory memory formation in Drosophila. Genetics. 2015;199:1173–82.25644700
31. Noyes NC Phan A Davis RL Memory suppressor genes: Modulating acquisition, consolidation, and forgetting Neuron 2021 109 3211 27 10.1016/j.neuron.2021.08.001 34450024
Noyes NC, Phan A, Davis RL. Memory suppressor genes: Modulating acquisition, consolidation, and forgetting. Neuron. 2021;109:3211–27.34450024
32. Davis RL Olfactory learning Neuron 2004 44 31 48 10.1016/j.neuron.2004.09.008 15450158
Davis RL. Olfactory learning. Neuron. 2004;44:31–48.15450158
33. Aso Y Hattori D Yu Y Johnston RM Iyer NA Ngo T-T The neuronal architecture of the mushroom body provides a logic for associative learning eLife 2014 3 e04577 10.7554/eLife.04577 25535793
Aso Y, Hattori D, Yu Y, Johnston RM, Iyer NA, Ngo T-T, et al. The neuronal architecture of the mushroom body provides a logic for associative learning. eLife. 2014;3:e04577.25535793
34. Campbell RAA Honegger KS Qin H Li W Demir E Turner GC Imaging a population code for odor identity in the Drosophila mushroom body J Neurosci 2013 33 10568 81 10.1523/JNEUROSCI.0682-12.2013 23785169
Campbell RAA, Honegger KS, Qin H, Li W, Demir E, Turner GC. Imaging a population code for odor identity in the Drosophila mushroom body. J Neurosci. 2013;33:10568–81.23785169
35. Yagi R Mabuchi Y Mizunami M Tanaka NK Convergence of multimodal sensory pathways to the mushroom body calyx in Drosophila melanogaster Sci Rep 2016 6 29481 10.1038/srep29481 27404960
Yagi R, Mabuchi Y, Mizunami M, Tanaka NK. Convergence of multimodal sensory pathways to the mushroom body calyx in Drosophila melanogaster. Sci Rep. 2016;6:29481.27404960
36. Hige T Aso Y Rubin GM Turner GC Plasticity-driven individualization of olfactory coding in mushroom body output neurons Nature 2015 526 258 62 10.1038/nature15396 26416731
Hige T, Aso Y, Rubin GM, Turner GC. Plasticity-driven individualization of olfactory coding in mushroom body output neurons. Nature. 2015;526:258–62.26416731
37. Berry JA Phan A Davis RL Dopamine neurons mediate learning and forgetting through bidirectional modulation of a memory trace Cell Rep 2018 25 651 62.e5 10.1016/j.celrep.2018.09.051 30332645
Berry JA, Phan A, Davis RL. Dopamine neurons mediate learning and forgetting through bidirectional modulation of a memory trace. Cell Rep. 2018;25:651–62.e5.30332645
38. Mao Z Davis RL Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity Front Neural Circuits 2009 3 5 10.3389/neuro.04.005.2009 19597562
Mao Z, Davis RL. Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity. Front Neural Circuits. 2009;3:5.19597562
39. Schwaerzel M Monastirioti M Scholz H Friggi-Grelin F Birman S Heisenberg M Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila J Neurosci 2003 23 10495 502 10.1523/JNEUROSCI.23-33-10495.2003 14627633
Schwaerzel M, Monastirioti M, Scholz H, Friggi-Grelin F, Birman S, Heisenberg M. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila. J Neurosci. 2003;23:10495–502.14627633
40. Kim Y-C Lee H-G Han K-A D1 Dopamine receptor dDA1 is required in the mushroom body neurons for aversive and appetitive learning in Drosophila J Neurosci 2007 27 7640 7 10.1523/JNEUROSCI.1167-07.2007 17634358
Kim Y-C, Lee H-G, Han K-A. D1 Dopamine receptor dDA1 is required in the mushroom body neurons for aversive and appetitive learning in Drosophila. J Neurosci. 2007;27:7640–7.17634358
41. Claridge-Chang A Roorda RD Vrontou E Sjulson L Li H Hirsh J Writing memories with light-addressable reinforcement circuitry Cell 2009 139 405 15 10.1016/j.cell.2009.08.034 19837039
Claridge-Chang A, Roorda RD, Vrontou E, Sjulson L, Li H, Hirsh J, et al. Writing memories with light-addressable reinforcement circuitry. Cell. 2009;139:405–15.19837039
42. Liu C Placais P-Y Yamagata N Pfeiffer BD Aso Y Friedrich AB A subset of dopamine neurons signals reward for odour memory in Drosophila Nature 2012 488 512 6 10.1038/nature11304 22810589
Liu C, Placais P-Y, Yamagata N, Pfeiffer BD, Aso Y, Friedrich AB, et al. A subset of dopamine neurons signals reward for odour memory in Drosophila. Nature. 2012;488:512–6.22810589
43. Tomchik SM Dopaminergic neurons encode a distributed, asymmetric representation of temperature in Drosophila J Neurosci 2013 33 2166 76 10.1523/JNEUROSCI.3933-12.2013 23365252
Tomchik SM. Dopaminergic neurons encode a distributed, asymmetric representation of temperature in Drosophila. J Neurosci. 2013;33:2166–76.23365252
44. Owald D Waddell S Olfactory learning skews mushroom body output pathways to steer behavioral choice in Drosophila Curr Opin Neurobiol 2015 35 178 84 10.1016/j.conb.2015.10.002 26496148
Owald D, Waddell S. Olfactory learning skews mushroom body output pathways to steer behavioral choice in Drosophila. Curr Opin Neurobiol. 2015;35:178–84.26496148
45. Owald D Felsenberg J Talbot CB Das G Perisse E Huetteroth W Activity of defined mushroom body output neurons underlies learned olfactory behavior in Drosophila Neuron 2015 86 417 27 10.1016/j.neuron.2015.03.025 25864636
Owald D, Felsenberg J, Talbot CB, Das G, Perisse E, Huetteroth W, et al. Activity of defined mushroom body output neurons underlies learned olfactory behavior in Drosophila. Neuron. 2015;86:417–27.25864636
46. Sabandal JM Berry JA Davis RL Dopamine-based mechanism for transient forgetting Nature 2021 591 426 30 10.1038/s41586-020-03154-y 33473212
Sabandal JM, Berry JA, Davis RL. Dopamine-based mechanism for transient forgetting. Nature. 2021;591:426–30.33473212
47. Plaçais P-Y Trannoy S Friedrich AB Tanimoto H Preat T Two pairs of mushroom body efferent neurons are required for appetitive long-term memory retrieval in Drosophila Cell 2013 5 769 80
Plaçais P-Y, Trannoy S, Friedrich AB, Tanimoto H, Preat T. Two pairs of mushroom body efferent neurons are required for appetitive long-term memory retrieval in Drosophila. Cell Rep. 2013;5:769–80.
48. Berry JA Cervantes-Sandoval I Nicholas EP Davis RL Dopamine is required for learning and forgetting in Drosophila Neuron 2012 74 530 42 10.1016/j.neuron.2012.04.007 22578504
Berry JA, Cervantes-Sandoval I, Nicholas EP, Davis RL. Dopamine is required for learning and forgetting in Drosophila. Neuron. 2012;74:530–42.22578504
49. Aso Y Rubin GM Dopaminergic neurons write and update memories with cell-type-specific rules eLife 2016 5 e16135 10.7554/eLife.16135 27441388
Aso Y, Rubin GM. Dopaminergic neurons write and update memories with cell-type-specific rules. eLife. 2016;5:e16135.27441388
50. Aso Y Ray RP Long X Bushey D Cichewicz K Ngo T-T Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics eLife 2019 8 e49257 10.7554/eLife.49257 31724947
Aso Y, Ray RP, Long X, Bushey D, Cichewicz K, Ngo T-T, et al. Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics. eLife. 2019;8:e49257.31724947
51. Shuai Y Hirokawa A Ai Y Zhang M Li W Zhong Y Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory Proc Natl Acad Sci USA 2015 112 E6663 72 10.1073/pnas.1512792112 26627257
Shuai Y, Hirokawa A, Ai Y, Zhang M, Li W, Zhong Y. Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory. Proc Natl Acad Sci USA. 2015;112:E6663–72.26627257
52. Cervantes-Sandoval I Chakraborty M MacMullen C Davis RL Scribble scaffolds a signalosome for active forgetting Neuron 2016 90 1230 42 10.1016/j.neuron.2016.05.010 27263975
Cervantes-Sandoval I, Chakraborty M, MacMullen C, Davis RL. Scribble scaffolds a signalosome for active forgetting. Neuron. 2016;90:1230–42.27263975
53. Handler A Graham TGW Cohn R Morantte I Siliciano AF Zeng J Distinct dopamine receptor pathways underlie the temporal sensitivity of associative learning Cell 2019 178 60 75.e19 10.1016/j.cell.2019.05.040 31230716
Handler A, Graham TGW, Cohn R, Morantte I, Siliciano AF, Zeng J, et al. Distinct dopamine receptor pathways underlie the temporal sensitivity of associative learning. Cell. 2019;178:60–75.e19.31230716
54. Himmelreich S Masuho I Berry JA MacMullen C Skamangas NK Martemyanov KA Dopamine receptor DAMB signals via Gq to mediate forgetting in Drosophila Cell 2017 21 2074 81
Himmelreich S, Masuho I, Berry JA, MacMullen C, Skamangas NK, Martemyanov KA, et al. Dopamine receptor DAMB signals via Gq to mediate forgetting in Drosophila. Cell Rep. 2017;21:2074–81.
55. Karagas NE Venkatachalam K Roles for the endoplasmic reticulum in regulation of neuronal calcium homeostasis Cells 2019 8 1232 10.3390/cells8101232 31658749
Karagas NE, Venkatachalam K. Roles for the endoplasmic reticulum in regulation of neuronal calcium homeostasis. Cells. 2019;8:1232.31658749
56. Zhang C Wu B Beglopoulos V Wines-Samuelson M Zhang D Dragatsis I Presenilins are essential for regulating neurotransmitter release Nature 2009 460 632 6 10.1038/nature08177 19641596
Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, et al. Presenilins are essential for regulating neurotransmitter release. Nature. 2009;460:632–6.19641596
57. Singh N Bartol T Levine H Sejnowski T Nadkarni S Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses Commun Biol 2021 4 1 13 33398033
Singh N, Bartol T, Levine H, Sejnowski T, Nadkarni S. Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses. Commun Biol. 2021;4:1–13.33398033
58. Cervantes-Sandoval I Davis RL Berry JA Rac1 impairs forgetting-induced cellular plasticity in mushroom body output neurons Front Cell Neurosci 2020 14 258 10.3389/fncel.2020.00258 33061890
Cervantes-Sandoval I, Davis RL, Berry JA. Rac1 impairs forgetting-induced cellular plasticity in mushroom body output neurons. Front Cell Neurosci. 2020;14:258.33061890
59. Takakura M Lam YH Nakagawa R Ng MY Hu X Bhargava P Differential second messenger signaling via dopamine neurons bidirectionally regulates memory retention Proc Natl Acad Sci USA 2023 120 e2304851120 10.1073/pnas.2304851120 37639608
Takakura M, Lam YH, Nakagawa R, Ng MY, Hu X, Bhargava P, et al. Differential second messenger signaling via dopamine neurons bidirectionally regulates memory retention. Proc Natl Acad Sci USA. 2023;120:e2304851120.37639608
60. Guan Z Saraswati S Adolfsen B Littleton JT Genome-wide transcriptional changes associated with enhanced activity in the Drosophila nervous system Neuron 2005 48 91 107 10.1016/j.neuron.2005.08.036 16202711
Guan Z, Saraswati S, Adolfsen B, Littleton JT. Genome-wide transcriptional changes associated with enhanced activity in the Drosophila nervous system. Neuron. 2005;48:91–107.16202711
61. Takakura M Nakagawa R Ota T Kimura Y Ng MY Alia AG Rpd3/CoRest-mediated activity-dependent transcription regulates the flexibility in memory updating in Drosophila Nat Commun 2021 12 628 10.1038/s41467-021-20898-x 33504795
Takakura M, Nakagawa R, Ota T, Kimura Y, Ng MY, Alia AG, et al. Rpd3/CoRest-mediated activity-dependent transcription regulates the flexibility in memory updating in Drosophila. Nat Commun. 2021;12:628.33504795
62. Wimber M Schott BH Wendler F Seidenbecher CI Behnisch G Macharadze T Prefrontal dopamine and the dynamic control of human long-term memory Transl Psychiatry 2011 1 e15 10.1038/tp.2011.15 22832518
Wimber M, Schott BH, Wendler F, Seidenbecher CI, Behnisch G, Macharadze T, et al. Prefrontal dopamine and the dynamic control of human long-term memory. Transl Psychiatry. 2011;1:e15.22832518
63. Gallo FT Zanoni Saad MB Silva A Morici JF Miranda M Anderson MC Dopamine modulates adaptive forgetting in medial prefrontal cortex J Neurosci 2022 42 6620 36 10.1523/JNEUROSCI.0740-21.2022 35853718
Gallo FT, Zanoni Saad MB, Silva A, Morici JF, Miranda M, Anderson MC, et al. Dopamine modulates adaptive forgetting in medial prefrontal cortex. J Neurosci. 2022;42:6620–36.35853718
64. Castillo Díaz F Hernandez MA Capellá T Medina JH Dopamine Neurotransmission in the ventral tegmental area promotes active forgetting of cocaine-associated memory Mol Neurobiol 2019 56 6206 17 10.1007/s12035-019-1516-3 30739236
Castillo Díaz F, Hernandez MA, Capellá T, Medina JH. Dopamine Neurotransmission in the ventral tegmental area promotes active forgetting of cocaine-associated memory. Mol Neurobiol. 2019;56:6206–17.30739236
65. Tecuapetla F Patel JC Xenias H English D Tadros I Shah F Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens J Neurosci 2010 30 7105 10 10.1523/JNEUROSCI.0265-10.2010 20484653
Tecuapetla F, Patel JC, Xenias H, English D, Tadros I, Shah F, et al. Glutamatergic signaling by mesolimbic dopamine neurons in the nucleus accumbens. J Neurosci. 2010;30:7105–10.20484653
66. Tritsch NX Ding JB Sabatini BL Dopaminergic neurons inhibit striatal output through non-canonical release of GABA Nature 2012 490 262 6 10.1038/nature11466 23034651
Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012;490:262–6.23034651
67. Shibuki K Okada D Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum Nature 1991 349 326 8 10.1038/349326a0 1702879
Shibuki K, Okada D. Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature. 1991;349:326–8.1702879
68. Lev-Ram V Wong ST Storm DR Tsien RY A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP Proc Natl Acad Sci 2002 99 8389 93 10.1073/pnas.122206399 12048250
Lev-Ram V, Wong ST, Storm DR, Tsien RY. A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP. Proc Natl Acad Sci. 2002;99:8389–93.12048250
69. Paola VD Holtmaat A Knott G Song S Wilbrecht L Caroni P Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex Neuron 2006 49 861 75 10.1016/j.neuron.2006.02.017 16543134
Paola VD, Holtmaat A, Knott G, Song S, Wilbrecht L, Caroni P, et al. Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron. 2006;49:861–75.16543134
70. Holtmaat A De Paola V Wilbrecht L Knott GW Imaging of experience-dependent structural plasticity in the mouse neocortex in vivo Behav Brain Res 2008 192 20 5 10.1016/j.bbr.2008.04.005 18501438
Holtmaat A, De Paola V, Wilbrecht L, Knott GW. Imaging of experience-dependent structural plasticity in the mouse neocortex in vivo. Behav Brain Res. 2008;192:20–5.18501438
71. Xu T Yu X Perlik AJ Tobin WF Zweig JA Tennant K Rapid formation and selective stabilization of synapses for enduring motor memories Nature 2009 462 915 9 10.1038/nature08389 19946267
Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature. 2009;462:915–9.19946267
72. Matsuzaki M Honkura N Ellis-Davies GCR Kasai H Structural basis of long-term potentiation in single dendritic spines Nature 2004 429 761 6 10.1038/nature02617 15190253
Matsuzaki M, Honkura N, Ellis-Davies GCR, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–6.15190253
73. Zhou Q Homma KJ Poo M Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses Neuron 2004 44 749 57 10.1016/j.neuron.2004.11.011 15572107
Zhou Q, Homma KJ, Poo M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron. 2004;44:749–57.15572107
74. Holtmaat A Svoboda K Experience-dependent structural synaptic plasticity in the mammalian brain Nat Rev Neurosci 2009 10 647 58 10.1038/nrn2699 19693029
Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009;10:647–58.19693029
75. Murakoshi H Wang H Yasuda R Local, persistent activation of Rho GTPases during plasticity of single dendritic spines Nature 2011 472 100 4 10.1038/nature09823 21423166
Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–4.21423166
76. Etienne-Manneville S Hall A Rho GTPases in cell biology Nature 2002 420 629 35 10.1038/nature01148 12478284
Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.12478284
77. Duman JG Mulherkar S Tu YK X Cheng J Tolias KF Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses Neurosci Lett 2015 601 4 10 10.1016/j.neulet.2015.05.034 26003445
Duman JG, Mulherkar S, Tu YK, X Cheng J, Tolias KF. Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses. Neurosci Lett. 2015;601:4–10.26003445
78. Heisenberg M Mushroom body memoir: from maps to models Nat Rev Neurosci 2003 4 266 75 10.1038/nrn1074 12671643
Heisenberg M. Mushroom body memoir: from maps to models. Nat Rev Neurosci. 2003;4:266–75.12671643
79. Margulies C Tully T Dubnau J Deconstructing memory in Drosophila Curr Biol 2005 15 R700 13 10.1016/j.cub.2005.08.024 16139203
Margulies C, Tully T, Dubnau J. Deconstructing memory in Drosophila. Curr Biol. 2005;15:R700–13.16139203
80. Zhang X Li Q Wang L Liu Z-J Zhong Y Cdc42-dependent forgetting regulates repetition effect in prolonging memory retention Cell Rep 2016 16 817 25 10.1016/j.celrep.2016.06.041 27396329
Zhang X, Li Q, Wang L, Liu Z-J, Zhong Y. Cdc42-dependent forgetting regulates repetition effect in prolonging memory retention. Cell Rep. 2016;16:817–25.27396329
81. Gao Y Shuai Y Zhang X Peng Y Wang L He J Genetic dissection of active forgetting in labile and consolidated memories in Drosophila Proc Natl Acad Sci USA 2019 116 21191 7 10.1073/pnas.1903763116 31488722
Gao Y, Shuai Y, Zhang X, Peng Y, Wang L, He J, et al. Genetic dissection of active forgetting in labile and consolidated memories in Drosophila. Proc Natl Acad Sci USA. 2019;116:21191–7.31488722
82. Yang N Higuchi O Ohashi K Nagata K Wada A Kangawa K Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization Nature 1998 393 809 12 10.1038/31735 9655398
Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature. 1998;393:809–12.9655398
83. Edwards DC Sanders LC Bokoch GM Gill GN Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics Nat Cell Biol 1999 1 253 9 10.1038/12963 10559936
Edwards DC, Sanders LC, Bokoch GM, Gill GN. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol. 1999;1:253–9.10559936
84. Luo L Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity Annu Rev Cell Dev Biol 2002 18 601 35 10.1146/annurev.cellbio.18.031802.150501 12142283
Luo L. Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol. 2002;18:601–35.12142283
85. Ridley AJ Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking Trends Cell Biol 2006 16 522 9 10.1016/j.tcb.2006.08.006 16949823
Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16:522–9.16949823
86. Miki H Takenawa T Regulation of actin dynamics by WASP family proteins J Biochem 2003 134 309 13 10.1093/jb/mvg146 14561714
Miki H, Takenawa T. Regulation of actin dynamics by WASP family proteins. J Biochem. 2003;134:309–13.14561714
87. Kovar DR Molecular details of formin-mediated actin assembly Curr Opin Cell Biol 2006 18 11 17 10.1016/j.ceb.2005.12.011 16364624
Kovar DR. Molecular details of formin-mediated actin assembly. Curr Opin Cell Biol. 2006;18:11–17.16364624
88. Rotty JD Wu C Bear JE New insights into the regulation and cellular functions of the ARP2/3 complex Nat Rev Mol Cell Biol 2013 14 7 12 10.1038/nrm3492 23212475
Rotty JD, Wu C, Bear JE. New insights into the regulation and cellular functions of the ARP2/3 complex. Nat Rev Mol Cell Biol. 2013;14:7–12.23212475
89. Zhang X Li Q Wang L Liu Z-J Zhong Y Active protection: Learning-activated Raf/MAPK activity protects labile memory from Rac1-independent forgetting Neuron 2018 98 142 55.e4 10.1016/j.neuron.2018.02.025 29551489
Zhang X, Li Q, Wang L, Liu Z-J, Zhong Y. Active protection: Learning-activated Raf/MAPK activity protects labile memory from Rac1-independent forgetting. Neuron. 2018;98:142–55.e4.29551489
90. Kneussel M Wagner W Myosin motors at neuronal synapses: drivers of membrane transport and actin dynamics Nat Rev Neurosci 2013 14 233 47 10.1038/nrn3445 23481482
Kneussel M, Wagner W. Myosin motors at neuronal synapses: drivers of membrane transport and actin dynamics. Nat Rev Neurosci. 2013;14:233–47.23481482
91. Hodges JL Newell-Litwa K Asmussen H Vicente-Manzanares M Horwitz AR Myosin IIB activity and phosphorylation status determines dendritic spine and post-synaptic density morphology PLOS ONE 2011 6 e24149 10.1371/journal.pone.0024149 21887379
Hodges JL, Newell-Litwa K, Asmussen H, Vicente-Manzanares M, Horwitz AR. Myosin IIB activity and phosphorylation status determines dendritic spine and post-synaptic density morphology. PLOS ONE. 2011;6:e24149.21887379
92. Chen C Wirth A Ponimaskin E Cdc42: an important regulator of neuronal morphology Int J Biochem Cell Biol 2012 44 447 51 10.1016/j.biocel.2011.11.022 22172377
Chen C, Wirth A, Ponimaskin E. Cdc42: an important regulator of neuronal morphology. Int J Biochem Cell Biol. 2012;44:447–51.22172377
93. Jiang L Mao R Zhou Q Yang Y Cao J Ding Y Inhibition of Rac1 activity in the hippocampus impairs the forgetting of contextual fear memory Mol Neurobiol 2016 53 1247 53 10.1007/s12035-015-9093-6 25613020
Jiang L, Mao R, Zhou Q, Yang Y, Cao J, Ding Y, et al. Inhibition of Rac1 activity in the hippocampus impairs the forgetting of contextual fear memory. Mol Neurobiol. 2016;53:1247–53.25613020
94. Lv L Liu Y Xie J Wu Y Zhao J Li Q Interplay between α2-chimaerin and Rac1 activity determines dynamic maintenance of long-term memory Nat Commun 2019 10 5313 10.1038/s41467-019-13236-9 31757963
Lv L, Liu Y, Xie J, Wu Y, Zhao J, Li Q, et al. Interplay between α2-chimaerin and Rac1 activity determines dynamic maintenance of long-term memory. Nat Commun. 2019;10:5313.31757963
95. Liu Y Du S Lv L Lei B Shi W Tang Y Hippocampal activation of Rac1 regulates the forgetting of object recognition memory Curr Biol 2016 26 2351 7 10.1016/j.cub.2016.06.056 27593377
Liu Y, Du S, Lv L, Lei B, Shi W, Tang Y, et al. Hippocampal activation of Rac1 regulates the forgetting of object recognition memory. Curr Biol. 2016;26:2351–7.27593377
96. Liu Y Lv L Wang L Zhong Y Social isolation induces Rac1-dependent forgetting of social memory Cell 2018 25 288 95.e3
Liu Y, Lv L, Wang L, Zhong Y. Social isolation induces Rac1-dependent forgetting of social memory. Cell Rep. 2018;25:288–95.e3.
97. Lei B Lv L Hu S Tang Y Zhong Y Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity Proc Natl Acad Sci 2022 119 e2116844119 10.1073/pnas.2116844119 35377811
Lei B, Lv L, Hu S, Tang Y, Zhong Y. Social experiences switch states of memory engrams through regulating hippocampal Rac1 activity. Proc Natl Acad Sci. 2022;119:e2116844119.35377811
98. Hadziselimovic N Vukojevic V Peter F Milnik A Fastenrath M Fenyves BG Forgetting is regulated via Musashi-mediated translational control of the Arp2/3 complex Cell 2014 156 1153 66 10.1016/j.cell.2014.01.054 24630719
Hadziselimovic N, Vukojevic V, Peter F, Milnik A, Fastenrath M, Fenyves BG, et al. Forgetting is regulated via Musashi-mediated translational control of the Arp2/3 complex. Cell. 2014;156:1153–66.24630719
99. Rex CS Gavin CF Rubio MD Kramar EA Chen LY Jia Y Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation Neuron 2010 67 603 17 10.1016/j.neuron.2010.07.016 20797537
Rex CS, Gavin CF, Rubio MD, Kramar EA, Chen LY, Jia Y, et al. Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation. Neuron. 2010;67:603–17.20797537
100. Turrigiano GG Nelson SB Thinking globally, acting locally: AMPA receptor turnover and synaptic strength Neuron 1998 21 933 5 10.1016/S0896-6273(00)80607-8 9856445
Turrigiano GG, Nelson SB. Thinking globally, acting locally: AMPA receptor turnover and synaptic strength. Neuron. 1998;21:933–5.9856445
101. Malenka RC Synaptic plasticity and AMPA receptor trafficking Ann N. Y Acad Sci 2003 1003 1 11 10.1196/annals.1300.001 14684431
Malenka RC. Synaptic plasticity and AMPA receptor trafficking. Ann N. Y Acad Sci. 2003;1003:1–11.14684431
102. Migues PV Liu L Archbold GEB Einarsson EÖ Wong J Bonasia K Blocking synaptic removal of GluA2-containing AMPA receptors prevents the natural forgetting of long-term memories J Neurosci 2016 36 3481 94 10.1523/JNEUROSCI.3333-15.2016 27013677
Migues PV, Liu L, Archbold GEB, Einarsson EÖ, Wong J, Bonasia K, et al. Blocking synaptic removal of GluA2-containing AMPA receptors prevents the natural forgetting of long-term memories. J Neurosci. 2016;36:3481–94.27013677
103. Hardt O Nader K Wang Y-T GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: possible mechanisms for forgetting of short- and long-term memories Philos Trans R Soc Lond B Biol Sci 2014 369 20130141 10.1098/rstb.2013.0141 24298143
Hardt O, Nader K, Wang Y-T. GluA2-dependent AMPA receptor endocytosis and the decay of early and late long-term potentiation: possible mechanisms for forgetting of short- and long-term memories. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130141.24298143
104. Dong Z Han H Li H Bai Y Wang W Tu M Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis J Clin Invest 2015 125 234 47 10.1172/JCI77888 25437879
Dong Z, Han H, Li H, Bai Y, Wang W, Tu M, et al. Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J Clin Invest. 2015;125:234–47.25437879
105. Clem RL Huganir RL Calcium-permeable AMPA receptor dynamics mediate fear memory erasure Science 2010 330 1108 12 10.1126/science.1195298 21030604
Clem RL, Huganir RL. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science. 2010;330:1108–12.21030604
106. Xu Z-X Tan J-W Xu H Hill CJ Ostrovskaya O Martemyanov KA Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling Nat Commun 2019 10 3622 10.1038/s41467-019-11575-1 31399584
Xu Z-X, Tan J-W, Xu H, Hill CJ, Ostrovskaya O, Martemyanov KA, et al. Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling. Nat Commun. 2019;10:3622.31399584
107. Awasthi A Ramachandran B Ahmed S Benito E Shinoda Y Nitzan N Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting Science 2019 363 eaav1483 10.1126/science.aav1483 30545844
Awasthi A, Ramachandran B, Ahmed S, Benito E, Shinoda Y, Nitzan N, et al. Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science. 2019;363:eaav1483.30545844
108. Hardt O Migues PV Hastings M Wong J Nader K PKMzeta maintains 1-day- and 6-day-old long-term object location but not object identity memory in dorsal hippocampus Hippocampus 2010 20 691 5 10.1002/hipo.20708 19806657
Hardt O, Migues PV, Hastings M, Wong J, Nader K. PKMzeta maintains 1-day- and 6-day-old long-term object location but not object identity memory in dorsal hippocampus. Hippocampus. 2010;20:691–5.19806657
109. Sacktor TC How does PKMζ maintain long-term memory? Nat Rev Neurosci 2011 12 9 15 10.1038/nrn2949 21119699
Sacktor TC. How does PKMζ maintain long-term memory? Nat Rev Neurosci. 2011;12:9–15.21119699
110. Lee AM Kanter BR Wang D Lim JP Zou ME Qiu C Prkcz null mice show normal learning and memory Nature 2013 493 416 9 10.1038/nature11803 23283171
Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, et al. Prkcz null mice show normal learning and memory. Nature. 2013;493:416–9.23283171
111. Volk LJ Bachman JL Johnson R Yu Y Huganir RL PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory Nature 2013 493 420 3 10.1038/nature11802 23283174
Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL. PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature. 2013;493:420–3.23283174
112. Tsokas P Hsieh C Yao Y Lesburguères E Wallace EJC Tcherepanov A Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice Elife 2016 5 e14846 10.7554/eLife.14846 27187150
Tsokas P, Hsieh C, Yao Y, Lesburguères E, Wallace EJC, Tcherepanov A, et al. Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. Elife. 2016;5:e14846.27187150
113. Berry JA Cervantes-Sandoval I Chakraborty M Davis RL Sleep facilitates memory by blocking dopamine neuron-mediated forgetting Cell 2015 161 1656 67 10.1016/j.cell.2015.05.027 26073942
Berry JA, Cervantes-Sandoval I, Chakraborty M, Davis RL. Sleep facilitates memory by blocking dopamine neuron-mediated forgetting. Cell. 2015;161:1656–67.26073942
114. Inoue A Sawatari E Hisamoto N Kitazono T Teramoto T Fujiwara M Forgetting in C. elegans is accelerated by neuronal communication via the TIR-1/JNK-1 pathway Cell 2013 3 808 19
Inoue A, Sawatari E, Hisamoto N, Kitazono T, Teramoto T, Fujiwara M, et al. Forgetting in C. elegans is accelerated by neuronal communication via the TIR-1/JNK-1 pathway. Cell Rep. 2013;3:808–19.
115. Nithianantharajah J Hannan AJ Enriched environments, experience-dependent plasticity and disorders of the nervous system Nat Rev Neurosci 2006 7 697 709 10.1038/nrn1970 16924259
Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7:697–709.16924259
116. Zeleznikow-Johnston A Burrows EL Renoir T Hannan AJ Environmental enrichment enhances cognitive flexibility in C57BL/6 mice on a touchscreen reversal learning task Neuropharmacology 2017 117 219 26 10.1016/j.neuropharm.2017.02.009 28196627
Zeleznikow-Johnston A, Burrows EL, Renoir T, Hannan AJ. Environmental enrichment enhances cognitive flexibility in C57BL/6 mice on a touchscreen reversal learning task. Neuropharmacology. 2017;117:219–26.28196627
117. Tainton-Heap LAL Kirszenblat LC Notaras ET Grabowska MJ Jeans R Feng K A paradoxical kind of sleep in Drosophila melanogaster Curr Biol 2021 31 578 90.e6 10.1016/j.cub.2020.10.081 33238155
Tainton-Heap LAL, Kirszenblat LC, Notaras ET, Grabowska MJ, Jeans R, Feng K, et al. A paradoxical kind of sleep in Drosophila melanogaster. Curr Biol. 2021;31:578–90.e6.33238155
118. Diekelmann S Born J The memory function of sleep Nat Rev Neurosci 2010 11 114 26 10.1038/nrn2762 20046194
Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11:114–26.20046194
119. Donlea JM Thimgan MS Suzuki Y Gottschalk L Shaw PJ Inducing sleep by remote control facilitates memory consolidation in Drosophila Science 2011 332 1571 6 10.1126/science.1202249 21700877
Donlea JM, Thimgan MS, Suzuki Y, Gottschalk L, Shaw PJ. Inducing sleep by remote control facilitates memory consolidation in Drosophila. Science. 2011;332:1571–6.21700877
120. Stickgold R Walker MP Sleep-dependent memory triage: evolving generalization through selective processing Nat Neurosci 2013 16 139 45 10.1038/nn.3303 23354387
Stickgold R, Walker MP. Sleep-dependent memory triage: evolving generalization through selective processing. Nat Neurosci. 2013;16:139–45.23354387
121. Lei Z Henderson K Keleman K A neural circuit linking learning and sleep in Drosophila long-term memory Nat Commun 2022 13 609 10.1038/s41467-022-28256-1 35105888
Lei Z, Henderson K, Keleman K. A neural circuit linking learning and sleep in Drosophila long-term memory. Nat Commun. 2022;13:609.35105888
122. Girardeau G Benchenane K Wiener SI Buzsáki G Zugaro MB Selective suppression of hippocampal ripples impairs spatial memory Nat Neurosci 2009 12 1222 3 10.1038/nn.2384 19749750
Girardeau G, Benchenane K, Wiener SI, Buzsáki G, Zugaro MB. Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci. 2009;12:1222–3.19749750
123. Gridchyn I Schoenenberger P O’Neill J Csicsvari J Assembly-specific disruption of hippocampal replay leads to selective memory deficit Neuron 2020 106 291 300.e6 10.1016/j.neuron.2020.01.021 32070475
Gridchyn I, Schoenenberger P, O’Neill J, Csicsvari J. Assembly-specific disruption of hippocampal replay leads to selective memory deficit. Neuron. 2020;106:291–300.e6.32070475
124. Mednick SC Cai DJ Shuman T Anagnostaras S Wixted JT An opportunistic theory of cellular and systems consolidation Trends Neurosci 2011 34 504 14 10.1016/j.tins.2011.06.003 21742389
Mednick SC, Cai DJ, Shuman T, Anagnostaras S, Wixted JT. An opportunistic theory of cellular and systems consolidation. Trends Neurosci. 2011;34:504–14.21742389
125. Plaçais P-Y Trannoy S Isabel G Aso Y Siwanowicz I Belliart-Guérin G Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila Nat Neurosci 2012 15 592 9 10.1038/nn.3055 22366756
Plaçais P-Y, Trannoy S, Isabel G, Aso Y, Siwanowicz I, Belliart-Guérin G, et al. Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila. Nat Neurosci. 2012;15:592–9.22366756
126. Zhang X Sabandal JM Tsaprailis G Davis RL Active forgetting requires Sickie function in a dedicated dopamine circuit in Drosophila Proc Natl Acad Sci USA 2022 119 e2204229119 10.1073/pnas.2204229119 36095217
Zhang X, Sabandal JM, Tsaprailis G, Davis RL. Active forgetting requires Sickie function in a dedicated dopamine circuit in Drosophila. Proc Natl Acad Sci USA. 2022;119:e2204229119.36095217
127. Tononi G Cirelli C Sleep function and synaptic homeostasis Sleep Med Rev 2006 10 49 62 10.1016/j.smrv.2005.05.002 16376591
Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. 2006;10:49–62.16376591
128. de Vivo L Bellesi M Marshall W Bushong EA Ellisman MH Tononi G Ultrastructural evidence for synaptic scaling across the wake/sleep cycle Science 2017 355 507 10 10.1126/science.aah5982 28154076
de Vivo L, Bellesi M, Marshall W, Bushong EA, Ellisman MH, Tononi G, et al. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science. 2017;355:507–10.28154076
129. Torrado Pacheco A Bottorff J Gao Y Turrigiano GG Sleep promotes downward firing rate homeostasis Neuron 2021 109 530 44.e6 10.1016/j.neuron.2020.11.001 33232655
Torrado Pacheco A, Bottorff J, Gao Y, Turrigiano GG. Sleep promotes downward firing rate homeostasis. Neuron. 2021;109:530–44.e6.33232655
130. Izawa S Chowdhury S Miyazaki T Mukai Y Ono D Inoue R REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories Science 2019 365 1308 13 10.1126/science.aax9238 31604241
Izawa S, Chowdhury S, Miyazaki T, Mukai Y, Ono D, Inoue R, et al. REM sleep-active MCH neurons are involved in forgetting hippocampus-dependent memories. Science. 2019;365:1308–13.31604241
131. Li F Lindsey JW Marin EC Otto N Dreher M Dempsey G The connectome of the adult Drosophila mushroom body provides insights into function eLife 2020 9 e62576 10.7554/eLife.62576 33315010
Li F, Lindsey JW, Marin EC, Otto N, Dreher M, Dempsey G, et al. The connectome of the adult Drosophila mushroom body provides insights into function. eLife. 2020;9:e62576.33315010
132. Feng R Rampon C Tang YP Shrom D Jin J Kyin M Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces Neuron 2001 32 911 26 10.1016/S0896-6273(01)00523-2 11738035
Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, et al. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001;32:911–26.11738035
133. Deisseroth K Singla S Toda H Monje M Palmer TD Malenka RC Excitation-neurogenesis coupling in adult neural stem/progenitor cells Neuron 2004 42 535 52 10.1016/S0896-6273(04)00266-1 15157417
Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron. 2004;42:535–52.15157417
134. Akers KG Martinez-Canabal A Restivo L Yiu AP De Cristofaro A Hsiang H-LL Hippocampal neurogenesis regulates forgetting during adulthood and infancy Science 2014 344 598 602 10.1126/science.1248903 24812394
Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang H-LL, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.24812394
135. Epp JR Silva Mera R Köhler S Josselyn SA Frankland PW Neurogenesis-mediated forgetting minimizes proactive interference Nat Commun 2016 7 10838 10.1038/ncomms10838 26917323
Epp JR, Silva Mera R, Köhler S, Josselyn SA, Frankland PW. Neurogenesis-mediated forgetting minimizes proactive interference. Nat Commun. 2016;7:10838.26917323
136. Gao A Xia F Guskjolen AJ Ramsaran AI Santoro A Josselyn SA Elevation of hippocampal neurogenesis induces a temporally graded pattern of forgetting of contextual fear memories J Neurosci 2018 38 3190 8 10.1523/JNEUROSCI.3126-17.2018 29453206
Gao A, Xia F, Guskjolen AJ, Ramsaran AI, Santoro A, Josselyn SA, et al. Elevation of hippocampal neurogenesis induces a temporally graded pattern of forgetting of contextual fear memories. J Neurosci. 2018;38:3190–8.29453206
137. Kitamura T Saitoh Y Takashima N Murayama A Niiibori Y Ageta H Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory Cell 2009 139 814 27 10.1016/j.cell.2009.10.020 19914173
Kitamura T, Saitoh Y, Takashima N, Murayama A, Niiibori Y, Ageta H, et al. Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell. 2009;139:814–27.19914173
138. Abraham WC Logan B Greenwood JM Dragunow M Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus J Neurosci 2002 22 9626 34 10.1523/JNEUROSCI.22-21-09626.2002 12417688
Abraham WC, Logan B, Greenwood JM, Dragunow M. Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci. 2002;22:9626–34.12417688
139. Haditsch U Anderson MP Freewoman J Cord B Babu H Brakebusch C Neuronal Rac1 Is required for learning-evoked neurogenesis J Neurosci 2013 33 12229 41 10.1523/JNEUROSCI.2939-12.2013 23884931
Haditsch U, Anderson MP, Freewoman J, Cord B, Babu H, Brakebusch C, et al. Neuronal Rac1 Is required for learning-evoked neurogenesis. J Neurosci. 2013;33:12229–41.23884931
140. Stevens B Allen NJ Vazquez LE Howell GR Christopherson KS Nouri N The classical complement cascade mediates CNS synapse elimination Cell 2007 131 1164 78 10.1016/j.cell.2007.10.036 18083105
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.18083105
141. Schafer DP Lehrman EK Kautzman AG Koyama R Mardinly AR Yamasaki R Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner Neuron 2012 74 691 705 10.1016/j.neuron.2012.03.026 22632727
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.22632727
142. Wang C Yue H Hu Z Shen Y Ma J Li J Microglia mediate forgetting via complement-dependent synaptic elimination Science 2020 367 688 94 10.1126/science.aaz2288 32029629
Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367:688–94.32029629
143. Yang Q Zhou J Wang L Hu W Zhong Y Li Q Spontaneous recovery of reward memory through active forgetting of extinction memory Curr Biol 2023 33 838 48.e3 10.1016/j.cub.2023.01.022 36731465
Yang Q, Zhou J, Wang L, Hu W, Zhong Y, Li Q. Spontaneous recovery of reward memory through active forgetting of extinction memory. Curr Biol. 2023;33:838–48.e3.36731465
144. Micheau J Vimeney A Normand E Mulle C Riedel G Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice Hippocampus 2014 24 1059 69 10.1002/hipo.22290 24753134
Micheau J, Vimeney A, Normand E, Mulle C, Riedel G. Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice. Hippocampus. 2014;24:1059–69.24753134
145. D’Cruz A-M Mosconi MW Ragozzino ME Cook EH Sweeney JA Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders Transl Psychiatry 2016 6 e916 10.1038/tp.2016.161 27727243
D’Cruz A-M, Mosconi MW, Ragozzino ME, Cook EH, Sweeney JA. Alterations in the functional neural circuitry supporting flexible choice behavior in autism spectrum disorders. Transl Psychiatry. 2016;6:e916.27727243
146. Wu W Du S Shi W Liu Y Hu Y Xie Z Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease Protein Cell 2019 10 745 59 10.1007/s13238-019-0641-0 31321704
Wu W, Du S, Shi W, Liu Y, Hu Y, Xie Z, et al. Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease. Protein Cell. 2019;10:745–59.31321704
147. Kaldun JC Lone SR Camps AMH Fritsch C Widmer YF Stein JV Dopamine, sleep, and neuronal excitability modulate amyloid-β–mediated forgetting in Drosophila PLOS Biol 2021 19 e3001412 10.1371/journal.pbio.3001412 34613972
Kaldun JC, Lone SR, Camps AMH, Fritsch C, Widmer YF, Stein JV, et al. Dopamine, sleep, and neuronal excitability modulate amyloid-β–mediated forgetting in Drosophila. PLOS Biol. 2021;19:e3001412.34613972
148. Stramaccia DF Penolazzi B Monego AL Manzan A Castelli L Galfano G Suppression of competing memories substance-related and addictive disorders: A retrieval-induced forgetting study Clin Psychol Sci 2017 5 410 7 10.1177/2167702616671780
Stramaccia DF, Penolazzi B, Monego AL, Manzan A, Castelli L, Galfano G. Suppression of competing memories substance-related and addictive disorders: A retrieval-induced forgetting study. Clin Psychol Sci. 2017;5:410–7.
149. Saunders J Retrieval-induced forgetting deficits in high anxious individuals Memory 2012 20 794 802 10.1080/09658211.2012.703676 22905745
Saunders J. Retrieval-induced forgetting deficits in high anxious individuals. Memory. 2012;20:794–802.22905745
150. Gómez-Ariza CJ Iglesias-Parro S Garcia-Lopez LJ Díaz-Castela MM Espinosa-Fernández L Muela JA Selective intentional forgetting in adolescents with social anxiety disorder Psychiatry Res 2013 208 151 5 10.1016/j.psychres.2012.09.027 23068080
Gómez-Ariza CJ, Iglesias-Parro S, Garcia-Lopez LJ, Díaz-Castela MM, Espinosa-Fernández L, Muela JA. Selective intentional forgetting in adolescents with social anxiety disorder. Psychiatry Res. 2013;208:151–5.23068080
151. Storm BC White HA ADHD and retrieval-induced forgetting: evidence for a deficit in the inhibitory control of memory Memory 2010 18 265 71 10.1080/09658210903547884 20209425
Storm BC, White HA. ADHD and retrieval-induced forgetting: evidence for a deficit in the inhibitory control of memory. Memory. 2010;18:265–71.20209425
152. Udai AH Oygarden B Egeland J Malt UF Groholt B Memory in early onset bipolar disorder and attention-deficit/hyperactivity disorder: similarities and differences J Abnorm Child Psychol 2012 40 1179 92 10.1007/s10802-012-9631-x 22622490
Udai AH, Oygarden B, Egeland J, Malt UF, Groholt B. Memory in early onset bipolar disorder and attention-deficit/hyperactivity disorder: similarities and differences. J Abnorm Child Psychol. 2012;40:1179–92.22622490
153. Groome D Sterkaj F Retrieval-induced forgetting and clinical depression Cogn Emot 2010 24 63 70 10.1080/02699930802536219
Groome D, Sterkaj F. Retrieval-induced forgetting and clinical depression. Cogn Emot. 2010;24:63–70.
154. Soriano MF Jiménez JF Román P Bajo MT Inhibitory processes in memory are impaired in schizophrenia: evidence from retrieval induced forgetting Br J Psychol 2009 100 661 73 10.1348/000712609X418912 19309536
Soriano MF, Jiménez JF, Román P, Bajo MT. Inhibitory processes in memory are impaired in schizophrenia: evidence from retrieval induced forgetting. Br J Psychol. 2009;100:661–73.19309536
155. Patrick RE Christensen BK Reduced directed forgetting for negative words suggests schizophrenia-related disinhibition of emotional cues Psychol Med 2013 43 2289 99 10.1017/S0033291713000445 23510530
Patrick RE, Christensen BK. Reduced directed forgetting for negative words suggests schizophrenia-related disinhibition of emotional cues. Psychol Med. 2013;43:2289–99.23510530
156. Wang Y Chan RCK Shum DHK Schizophrenia and prospective memory impairments: a review Clin Neuropsychol 2018 32 836 57 10.1080/13854046.2017.1406144 29161969
Wang Y, Chan RCK, Shum DHK. Schizophrenia and prospective memory impairments: a review. Clin Neuropsychol. 2018;32:836–57.29161969
