The Biology of Forgetting—A Perspective
2017; Cell Press; Volume: 95; Issue: 3 Linguagem: Inglês
10.1016/j.neuron.2017.05.039
ISSN1097-4199
Autores Tópico(s)Zebrafish Biomedical Research Applications
ResumoPioneering research studies, beginning with those using Drosophila, have identified several molecular and cellular mechanisms for active forgetting. The currently known mechanisms for active forgetting include neurogenesis-based forgetting, interference-based forgetting, and intrinsic forgetting, the latter term describing the brain’s chronic signaling systems that function to slowly degrade molecular and cellular memory traces. The best-characterized pathway for intrinsic forgetting includes “forgetting cells” that release dopamine onto engram cells, mobilizing a signaling pathway that terminates in the activation of Rac1/Cofilin to effect changes in the actin cytoskeleton and neuron/synapse structure. Intrinsic forgetting may be the default state of the brain, constantly promoting memory erasure and competing with processes that promote memory stability like consolidation. A better understanding of active forgetting will provide insights into the brain’s memory management system and human brain disorders that alter active forgetting mechanisms. Pioneering research studies, beginning with those using Drosophila, have identified several molecular and cellular mechanisms for active forgetting. The currently known mechanisms for active forgetting include neurogenesis-based forgetting, interference-based forgetting, and intrinsic forgetting, the latter term describing the brain’s chronic signaling systems that function to slowly degrade molecular and cellular memory traces. The best-characterized pathway for intrinsic forgetting includes “forgetting cells” that release dopamine onto engram cells, mobilizing a signaling pathway that terminates in the activation of Rac1/Cofilin to effect changes in the actin cytoskeleton and neuron/synapse structure. Intrinsic forgetting may be the default state of the brain, constantly promoting memory erasure and competing with processes that promote memory stability like consolidation. A better understanding of active forgetting will provide insights into the brain’s memory management system and human brain disorders that alter active forgetting mechanisms. The human brain has the remarkable capacity to acquire, store, and recall information across decades of time. The acquisition of information, or learning, alters the physiological state of certain neurons in ways that encode memory (Figure 1). These state changes, or molecular and cellular memory traces, can be, in principle, any change in the activity of the cell that is induced by learning that becomes part of the neural code for that memory. For instance, changes can occur in the expression or function of ion channels that cause neurons to be more or less excitable and therefore more or less capable of conducting action potentials or other electrical signals. Learning may mobilize neuronal growth processes that establish new connections, or neurite retraction to remove existing connections. The changes may include adaptations in cell signaling that alter the neuron’s overall ability to integrate inputs from different types of cues, and morphological or functional changes in synapses that increase or decrease the neuron’s ability to stimulate its synaptic partners. The collection of all molecular and cellular memory traces that are induced by learning across all neurons engaged by the learning event together comprise the overall memory engram (Squire, 1987Squire L.R. Memory and Brain. Oxford University Press, 1987Google Scholar, Dudai, 2002Dudai Y. Memory, from A to Z. Oxford University Press, 2002Google Scholar, Davis, 2011Davis R.L. Traces of Drosophila memory.Neuron. 2011; 70: 8-19Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar) that can guide behavior upon subsequent retrieval. The number of “engram neurons” (Tonegawa et al., 2015Tonegawa S. Liu X. Ramirez S. Redondo R. Memory engram cells have come of age.Neuron. 2015; 87: 918-931Abstract Full Text Full Text PDF PubMed Google Scholar) that form a specific memory and the number of molecular and cellular memory traces that form in these neurons due to acquisition is unknown but must depend on the nature of the memory formed and its strength. But both numbers are likely to be vast. It is also unknown how many memories are formed and stored by the human brain on an average day and how many memory engrams accumulate across an 80- to 90-year lifetime. But again, the number must be extraordinarily large. It seems possible that the brain might simplify each memory engram after initial encoding into “index” engram cells, like the perceptual concept of grandmother cells (Gross, 2002Gross C.G. Genealogy of the “grandmother cell”.Neuroscientist. 2002; 8: 512-518Crossref PubMed Google Scholar) to streamline the logistics of memory management. Alternatively, the cells comprising the engram might become interconnected at acquisition, losing their independence, so that a retrieval stimulus reactivates the circuit of interconnected cells (Tonegawa et al., 2015Tonegawa S. Liu X. Ramirez S. Redondo R. Memory engram cells have come of age.Neuron. 2015; 87: 918-931Abstract Full Text Full Text PDF PubMed Google Scholar). But irrespective of whether the brain simplifies memory engrams and their traces, it must have an extremely efficient memory management system to catalog each engram so that retrieval is seamless and efficient. In addition, because of the extraordinary large number of memory engrams that can accumulate in the brain across time, it seems logical that the brain must have, as one part of its memory management system, a mechanism or series of mechanisms to remove memories that become unused. These mechanisms make up what we term as “active forgetting.” Traditional studies in the neuroscience of learning and memory have emphasized other aspects of the brain’s memory management system, such as the major processes of acquisition and consolidation (Figure 2; Squire, 1987Squire L.R. Memory and Brain. Oxford University Press, 1987Google Scholar, Menzel and Muller, 1996Menzel R. Muller U. Learning and memory in honeybees: From behavior to neural substrates.Annu. Rev. Neurosci. 1996; 19: 379-404Crossref PubMed Google Scholar, McGaugh, 2000McGaugh J.L. Memory—a century of consolidation.Science. 2000; 287: 248-251Crossref PubMed Google Scholar, Dudai, 2004Dudai Y. 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For instance, seminal studies from multiple researchers revealed that consolidation into protein synthesis-dependent memory involves a molecular cascade initiated by changes in gene expression at acquisition within engram cells through cAMP-dependent mechanisms that include Creb, C/EBP, and other transcription factor families (Yin et al., 1994Yin J.C.P. Wallach J.S. Del Vecchio M. Wilder E.L. Zhou H. Quinn W.G. Tully T. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.Cell. 1994; 79: 49-58Abstract Full Text PDF PubMed Scopus (738) Google Scholar, Bailey et al., 1996Bailey C.H. Bartsch D. Kandel E.R. Toward a molecular definition of long-term memory storage.Proc. Natl. Acad. Sci. USA. 1996; 93: 13445-13452Crossref PubMed Scopus (535) Google Scholar, Dudai, 2004Dudai Y. The neurobiology of consolidations, or, how stable is the engram?.Annu. Rev. 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Neurosci. 2002; 19: 171-177Crossref PubMed Google Scholar, Barco et al., 2003Barco A. Pittenger C. Kandel E.R. CREB, memory enhancement and the treatment of memory disorders: Promises, pitfalls and prospects.Expert Opin. Ther. Targets. 2003; 7: 101-114Crossref PubMed Scopus (0) Google Scholar, Lynch et al., 2011Lynch G. Palmer L.C. Gall C.M. The likelihood of cognitive enhancement.Pharmacol. Biochem. Behav. 2011; 99: 116-129Crossref PubMed Scopus (0) Google Scholar). However, we argue that forgetting, the flip side of acquisition and consolidation, is equally important and that the traditional emphasis on mechanisms of acquisition and consolidation needs to be rebalanced with more effort to understand the biology of active forgetting (Figure 2). This is the focus of this perspective. Although forgetting can occur due to failed retrieval of an intact engram, we emphasize active forgetting through the likely biological degradation of molecular and cellular memory traces or the engram cell circuit. Active forgetting may eliminate all traces and engram cells for a given memory, but it is more likely that forgetting occurs initially from erosion of only some of the molecular and cellular memory traces, or when a fraction of the engram cells become disconnected from the engram circuit. This would make the memory engram incomplete and unresponsive to recall mechanisms. There are at least two other factors that weigh into any consideration of active forgetting. First, memory comes in different temporally and mechanistically distinct forms that are represented by distinct engrams. Acquisition leads to short-term memories (STMs) that persist for seconds or minutes, intermediate-term memories that persist for a few hours, and long-term memory (LTM) that can persist for years or decades. An early declarative memory might be encoded by a group of hippocampal neurons but the engram becomes distributed to engram cells in other brain regions through the process of systems consolidation (Kandel et al., 2014Kandel E.R. Dudai Y. Mayford M.R. The molecular and systems biology of memory.Cell. 2014; 157: 163-186Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, Dudai et al., 2015Dudai Y. Karni A. Born J. The consolidation and transformation of memory.Neuron. 2015; 88: 20-32Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, Rubin et al., 2015Rubin A. Geva N. Sheintuch L. Ziv Y. Hippocampal ensemble dynamics timestamp events in long-term memory.eLife. 2015; 4: e12247Crossref PubMed Scopus (33) Google Scholar, Attardo et al., 2015Attardo A. Fitzgerald J.E. Schnitzer M.J. Impermanence of dendritic spines in live adult CA1 hippocampus.Nature. 2015; 523: 592-596Crossref PubMed Scopus (80) Google Scholar). Although rudimentary, our current knowledge of active forgetting suggests that mechanisms for active forgetting for different temporal forms of memory may be distinct. Second, there are multiple types of memory that can overlap temporally but are mechanistically different. These include working memory and short-term episodic and classical conditioning memory to name a few. It also seems likely based on current evidence discussed below that different mechanisms will be employed to erode these distinct types of memory. Experimental psychologists have debated for more than 50 years whether forgetting occurs through an active involvement of external or internal factors or whether it occurs through passive mechanisms. Although the constructs for forgetting from psychological studies proposed by different researchers have fuzzy edges, the term passive forgetting has often been used to describe the biological decay of memory traces due to constitutive molecular turnover (natural decay), the incidental accumulation across time of similar memory traces that impede proper retrieval of the wanted one, and changes in the memory’s context between acquisition and retrieval that impair efficient recall (Figure 1; Wixted, 2004Wixted J.T. The psychology and neuroscience of forgetting.Annu. Rev. Psychol. 2004; 55: 235-269Crossref PubMed Scopus (443) Google Scholar, Anderson and Hanslmayr, 2014Anderson M.C. Hanslmayr S. Neural mechanisms of motivated forgetting.Trends Cogn. Sci. 2014; 18: 279-292Abstract Full Text Full Text PDF PubMed Google Scholar, Baddeley et al., 2015Baddeley A. Eysenck M.W. Anderson M.C. Memory.Second Edition. Psychology Press, 2015Crossref Google Scholar, Ricker et al., 2015Ricker T.J. Vergauwe E. Cowan N. Decay theory of immediate memory: From Brown (1958) to today (2014).Q. J. Exp Psychol. 2015; 9: 1969-1995Google Scholar). The psychological viewpoint of passive forgetting does not consider the brain as having the capacity to actively degrade the substrates of memory, even though it is widely accepted as the biological machine that forms and stores memory. An alternative point of view is that forgetting is active and triggered by defined external or internal factors (Figure 1; Wixted, 2004Wixted J.T. The psychology and neuroscience of forgetting.Annu. Rev. Psychol. 2004; 55: 235-269Crossref PubMed Scopus (443) Google Scholar, Ricker et al., 2015Ricker T.J. Vergauwe E. Cowan N. Decay theory of immediate memory: From Brown (1958) to today (2014).Q. J. Exp Psychol. 2015; 9: 1969-1995Google Scholar). Interference-based forgetting has been widely studied in experimental contexts and posits that brain activity due to new information presented prior to the learning event (proactive interference) or after the learning event (retroactive interference) attenuates memory expression. Wixted, 2004Wixted J.T. The psychology and neuroscience of forgetting.Annu. Rev. Psychol. 2004; 55: 235-269Crossref PubMed Scopus (443) Google Scholar generalized this idea with the notion that normal mental activity and memory formation utilize the resources of the hippocampus and interfere with the process of consolidation, providing an explanation for retroactive interference based on the failure to develop, maintain, or transfer the appropriate memory traces. This forgetting mechanism is active in the sense that it requires a trigger, the retroactive interfering stimulus, but does not embrace the idea that the brain is built with biological mechanisms to erode memory traces. Rather, it emphasizes a possible process that interferes with the forces of consolidation to stabilize memories. Nevertheless, the majority of the psychological literature has focused on the model whereby interfering stimuli create a problem with retrieval due to accumulated and competing memory traces (Figure 1; Bahrick and Hall, 1991Bahrick H.P. Hall L.K. Preventative and corrective maintenance of access to knowledge.Appl. Cogn. Psychol. 1991; 5: 1-18Crossref Scopus (3) Google Scholar, Anderson and Neely, 1996Anderson M.C. Neely J.H. Interference and inhibition in memory retrieval.in: Bjork E.L. Bjork R.A. Memory. Academic Press, 1996: 237-311Crossref Google Scholar, Anderson, 2003Anderson M.C. Rethinking interference theory: Executive control and the mechanisms of forgetting.J. Mem. Lang. 2003; 49: 415-445Crossref Scopus (489) Google Scholar), placing it in the passive, “retrieval interference” category as noted above. For instance, one might fail to retrieve on a particular day the location of one’s car in the parking lot used daily due to competition from similar memory traces accumulated across the prior month. There is no clear active process underlying this failure of memory retrieval, and so it can be considered passive in nature. However, competing memories formed shortly before or after acquisition of another may also interfere actively with memory storage as discussed above. Thus, forgetting through interference mechanisms can be viewed as both passive and active depending on when the interfering material was learned and whether it maintains or erodes memory traces (Figure 1). Motivated forgetting refers to forgetting processes under our own cognitive control and ones that generally contain an emotional motive, such as processes imposed on memories that threaten a positive self-image, run counter to strongly held beliefs or attitudes, or evoke sadness, guilt, or embarrassment (Anderson and Green, 2001Anderson M.C. Green C. Suppressing unwanted memories by executive control.Nature. 2001; 410: 366-369Crossref PubMed Scopus (507) Google Scholar, Anderson and Hanslmayr, 2014Anderson M.C. Hanslmayr S. Neural mechanisms of motivated forgetting.Trends Cogn. Sci. 2014; 18: 279-292Abstract Full Text Full Text PDF PubMed Google Scholar, Baddeley et al., 2015Baddeley A. Eysenck M.W. Anderson M.C. Memory.Second Edition. Psychology Press, 2015Crossref Google Scholar). If such memories are recalled during encoding or consolidation, suppressing the memories voluntarily may disrupt the process of forming a stable engram, leading to forgetting (Fawcett et al., 2016Fawcett J.M. Lawrence M.A. Taylor T.L. The representational consequences of intentional forgetting: Impairments to both the probability and fidelity of long-term memory.J. Exp. Psychol. Gen. 2016; 145: 56-81Crossref PubMed Scopus (6) Google Scholar). Top-down suppression can also occur during the retrieval of stable memories. Retrieval can be suppressed but the effect is time limited, suggesting that in this case retrieval processes of an intact memory engram are just temporarily disrupted. Retrieval-induced forgetting is produced by interference and can be illustrated after learning a series of items in different categories such as orange and lemon within fruits, and vodka and rum within drinks (Anderson and Bjork, 1994Anderson M.C. Bjork R.A. 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There is debate over whether retrieval-induced forgetting occurs from inhibition overlaid on the non-practiced items by the recall of target items from the same category (Murayama et al., 2014Murayama K. Miyatsu T. Buchli D. Storm B.C. Forgetting as a consequence of retrieval: A meta-analytic review of retrieval-induced forgetting.Psychol. Bull. 2014; 140: 1383-1409Crossref PubMed Scopus (0) Google Scholar, Anderson and Hanslmayr, 2014Anderson M.C. Hanslmayr S. Neural mechanisms of motivated forgetting.Trends Cogn. Sci. 2014; 18: 279-292Abstract Full Text Full Text PDF PubMed Google Scholar, Wimber et al., 2015Wimber M. Alink A. Charest I. Kriegeskorte N. Anderson M.C. Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression.Nat. Neurosci. 2015; 18: 582-589Crossref PubMed Scopus (46) Google Scholar), competition from memory traces associated with the same cue during attempted recall (Verde, 2013Verde M.F. 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However, a recent and impressive fMRI study of word-picture associations showed a weakening of the blood-flow-based memory traces for the non-practiced items, providing support for the hypothesis of forgetting by overlaid inhibition (Wimber et al., 2015Wimber M. Alink A. Charest I. Kriegeskorte N. Anderson M.C. Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression.Nat. Neurosci. 2015; 18: 582-589Crossref PubMed Scopus (46) Google Scholar). Irrespective of the mechanism for retrieval-induced forgetting, spontaneous recovery can occur with time (Miguez et al., 2014Miguez G. Mash L.E. Polack C.W. Miller R.R. Failure to observe renewal following retrieval-induced forgetting.Behav. Processes. 2014; 103: 43-51Crossref PubMed Scopus (4) Google Scholar), indicating that a retrieval failure of perhaps an intact engram may often underlie this phenomenon. This does not preclude the possibility that overlaid inhibition may produce a retrieval failure, and this failure might subsequently erode the suppressed engram. These observations and those discussed below lead us to speculate that there exist many different mechanisms for forgetting, some of which affect the integrity of the memory engram and others that disrupt retrieval of relatively intact memory engrams. Although forgetting due to retrieval errors is of high interest, we focus our discussion on forgetting mechanisms that likely disrupt the integrity of the memory engram. We posit that, unlike the active forgetting due to retroactive interference that potentially disrupts consolidation described above, the brain also has the inherent biological capacity to erode memory traces using signaling systems like those used for acquisition and consolidation (Kasai et al., 2010Kasai H. Fukuda M. Watanabe S. Hayashi-Takagi A. Noguchi J. Structural dynamics of dendritic spines in memory and cognition.Trends Neurosci. 2010; 33: 121-129Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). We term this type of active forgetting, which is unrecognized in the experimental psychology literature, as “intrinsic forgetting” because it functions through molecular signaling systems and neuronal circuits that are intrinsic to the brain (Figure 1, and below). We note, however, that forgetting currently is generally monitored through behavior, and neuroscience-based studies are just nearing the point of being able to fully address the issue of whether memory traces are actually eroded for some types of forgetting. Nevertheless, in some of the discussed cases the accumulated evidence is supportive of the idea that memory traces may be eroded and cause behavioral forgetting. Furthermore, although studies from experimental psychology have provided some concepts about the types of forgetting (Figure 1; Wixted, 2004Wixted J.T. The psychology and neuroscience of forgetting.Annu. Rev. Psychol. 2004; 55: 235-269Crossref PubMed Scopus (443) Google Scholar, Anderson and Hanslmayr, 2014Anderson M.C. Hanslmayr S. Neural mechanisms of motivated forgetting.Trends Cogn. Sci. 2014; 18: 279-292Abstract Full Text Full Text PDF PubMed Google Scholar, Ricker et al., 2015Ricker T.J. Vergauwe E. Cowan N. Decay theory of immediate memory: From Brown (1958) to today (2014).Q. J. Exp Psychol. 2015; 9: 1969-1995Google Scholar, Baddeley et al., 2015Baddeley A. Eysenck M.W. Anderson M.C. Memory.Second Edition. Psychology Press, 2015Crossref Google Scholar), resolving the biological basis for forgetting and providing a robust delineation of each type will emerge only after elucidating the underlying circuit and cellular mechanisms. The phenomenon of retroactive facilitation (Figure 1) plays an important role in our discussion and account for active forgetting. Several different experiences, including an episode of sleep or rest, or sedation produced by alcohol consumption or benzodiazepine administration, can facilitate the memory of events learned just prior to the sleep or drug experience (Wixted, 2004Wixted J.T. The psychology and neuroscience of forgetting.Annu. Rev. Psychol. 2004; 55: 235-269Crossref PubMed Scopus (443) Google Scholar). Although the consensus of thought has accepted the idea that sleep enhances the process of consolidation (Cipolli et al., 2013Cipolli C. Mazzetti M. Plazzi G. Sleep-dependent memory consolidation in patients with sleep disorders.Sleep Med. Rev. 2013; 17: 91-103Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar), and perhaps plays an active role in selecting the memories to be consolidated (Stickgold and Walker, 2013Stickgold R. Walker M.P. 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