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emerged from the pattern of consequence of this dynamic process collectively caused by all these is that established , which reconsolidation different types of interventions. have reached a level of stability, can be appeared to bidirectionally modulated and modified: be a complex and quite prolonged they can be weakened, disrupted Cristina M. Alberini1 process, during which different types or enhanced, and be associated and Joseph E. LeDoux1,2 of amnestic manipulation were shown to parallel memory traces. These to disrupt different mechanisms in the possibilities for trace strengthening The formation, and use of series of changes occurring throughout or weakening, and also for qualitative memories is critical for normal adaptive the consolidation process. The initial modifications via retrieval and functioning, including the execution phase of consolidation is known to reconsolidation, have important of goal-directed behavior, thinking, require a number of regulated steps behavioral and clinical implications. and decision-making, of post-translational, translational and They offer opportunities for finding and is at the center of a variety of gene expression mechanisms, and strategies that could change cognitive, addictive, mood, anxiety, blockade of any of these can impede and memory to make it more efficient and developmental disorders. Memory the entire consolidation process. and adaptive, to prevent or rescue also significantly contributes to the A century of studies on memory memory impairments, and to help shaping of human personality and consolidation proposed that, despite treat diseases linked to abnormally character, and to social interactions. the fact that it is a long process that consolidated memories. As we will Hence, how memories progresses through a sequence of see below, however, reconsolidation are formed, stored, retrieved, modified, changes, memory formation involves a processes in different systems/ updated and used potentially impacts single type of stabilization process, and networks have distinctive features, many areas in human life, including once a memory reaches a consolidated suggesting that potential treatments . level it becomes insensitive to will need to be flexibly tailored to The traditional view of memory disruption. specific circumstances. storage assumes that each time we More recently, this classic view Reconsolidation has a variety of remember some past experience, the of the consolidation process has important theoretical and practical original memory trace is retrieved. undergone revision. Drawing upon implications, and has stirred a great This view has been challenged by earlier observations, a large number deal of debate. Many questions have data showing that when memories of studies over the last 15 or so been raised in numerous discussions. are retrieved they are susceptible to years have shown that consolidated Why does memory reconsolidate? How change, such that future retrievals memories, which should be insensitive general is this process? Is it simply a call upon the changed information. to amnesic agents, again revert to a duplication of consolidation or does This is called reconsolidation. That vulnerable state if they are retrieved it involve unique mechanisms? Is reconsolidation exists is not at issue, (the trace is reactivated). These active reconsolidation a true, independent but what really reconsolidation is, how (or reactivated) memories can then process, or is it a deceptive effect it occurs, and what it means are heavily again undergo another consolidation that actually involves the regulation of investigated and debated topics. process, which is in many ways similar other memory processes, like retrieval, to that of a new memory (Figure 1). This , and new learning? Can The classical view and the change additional process has hence been reconsolidation offer an opportunity For about a century, the process named memory reconsolidation. to weaken, even perhaps eliminate by which a persistent or long-term Reconsolidation has been found pathogenic memories? We will discuss memory is formed, stored and retrieved for a variety of different kinds of some of these issues here. was believed to be a singular, linear memories (explicit and implicit; process. In brief, it was that a aversive and appetitive) in many kinds Why does memory reconsolidate? freshly acquired memory trace remains of organisms (from invertebrates to What is the advantage of having in a fragile state for a limited time humans). It is clear from the results of established memories become labile during which it is sensitive to disruption the large number of studies that have and then restored? The general by a variety of means. Over this time, experimentally addressed the topic that advantage of reconsolidation is that the memory undergoes a series of consolidation is not a singular process it provides the ability to respond in changes in the brain that convert the of stabilization that occurs once for a flexible and adaptive manner to labile entity into one that is stable and each memory. Memories, in other continuously changing environments. long lasting. This stabilization process words, can reconsolidate after retrieval, Evidence revealed that reconsolidation by which a newly formed, labile and this may occur many times. allows changes in memory strength, memory is converted into a lasting and The picture that emerges is that and although still a subject of stable long-term memory is known as long-term memories are stabilized and debates, some authors propose that memory consolidation. then de-stabilized and re-stabilized reconsolidation mediates updating of In its early fragile state the memory according to the reactivation schedule memory content. is sensitive to many different types of of their traces. Hence they appear If a learning experience reoccurs, interference, including behavioral or to undergo many reconsolidation memory may become labile, and cognitive interference, brain trauma, cycles in the course of their existence. over time, through mechanisms of seizures, and pharmacological or Memory storage is thus a dynamic reconsolidation, be re-stabilized molecular manipulations. The definition process and a consolidated memory and strengthened. The same occurs and features of memory consolidation is far from being ‘fixed’. One important when instead of a second learning Special Issue R747 event the memory is retrieved by a Retrieval of reminder of the learned experience. experience Retrieving, hence reconsolidating, memories may provide the advantage of strengthening adaptive memories, without requiring re-exposure to Learning Storage Retrieval Retrieval the original learning situation. This is likely to be useful in the case of rewarding as well as aversive, painful and/or dangerous events, especially when the memories are acquired Retrieval of last after a single learning experience storage and cannot benefit from repetition. Clearly different conditions evoking reconsolidation, whether through Learning Storage Retrieval Storage Retrieval repetitions of the learning experience (multiple training trials) or different types of retrieval, may result in distinct storage patterns. With multiple Current Biology training trials the same experience is presented during the initial learning as Figure 1. Two views of memory. well as the reactivating trials; hence The conventional view was that memories are stored once and each time the memory is ac- the activation and recruitment of tivated (remembered) a trace of the original experience is retrieved (top). According to the re- similar networks are likely to occur. consolidation view, memories are susceptible to change each time they are retrieved. The next In contrast, reconsolidations evoked time the memory is activated the version stored during the last retrieval, rather than the version stored after the original experience, is called up. by other types of experience, such as retrieval events that are different from the original learning experience, are amnestic treatments, using these paired, motor memories, and in likely to activate and recruit different interferences does not distinguish hippocampal, and cortical- networks. The reverse is also true: whether there are parallel traces dependent memories. Although there through reconsolidation, memory of consolidation as opposed to are few examples of disagreement, in can also be weakened. For example, stabilization of an updated version of the majority of cases the disruption a threat stimulus that leads to the original trace via reconsolidation. of memory reconsolidation produces heightened physiological can Methods of selective dissociation a persistent decrease in memory result in a stronger memory but one between new consolidation and retention, as shown by molecular and that leads to less arousal can weaken reconsolidation will be needed to cellular readouts in animals, and also the memory. address this issue. A model that recently confirmed by imaging studies In addition to memory strengthening explains why the similarity between in humans. and weakening, retrievals can modify the events present at memory retrieval Many different types of reactivation the trace content. Hence one function and the previously stored experience can evoke reconsolidation. Typically of reconsolidation is considered to may lead to competition between new reconsolidation is studied using be memory updating. While evidence learning and memory updating (via a non-reinforced stimulus as a exists that reconsolidation mediates reconsolidation) has been proposed reactivating experience, but, as the updating brought on by incremental recently for -dependent mentioned above, reinforcing learning following re-exposure to memories: it suggests that low stimuli or a repetition of the whole an experience similar to the original similarity between the old and the training trial effectively returns the learning, the role of reconsolidation present experience would lead to new memory to a labile state, hence in adding distinct, novel information learning, but high similarity would lead inducing reconsolidation. The is debated. Some authors argue that to updating of the original memory. type of reactivating event controls reconsolidation mediates updating Whether this also occurs for other whether or not the memory becomes brought on by new experience co- forms of memory is not known. labile and reconsolidates, as well presented with reactivated memories, as the nature and features of that whereas others propose that, although Do all types of memory reconsolidate? reconsolidation, including its reactivation of the memory trace is Memories in more than 10 species, accompanying network activation, essential and mediates this updating, spanning from the nematode worm neurotransmission, temporal novel experiences that differ from the Caenorhabditis elegans to humans, progression and mechanisms. This original but that occur with reactivated have been reported to undergo also may account for differences memories may instead engage a new reconsolidation. The process also found between consolidation and consolidation process; hence the generalizes across memory paradigms reconsolidation, which seem to mostly updated memory actually constitutes and neural systems: reconsolidation indicate distinctions in the temporal a new memory that coexists in parallel occurs in aversive, appetitive, progression of the mechanisms or the with the old one. and neutral memories, in simple activity network involved rather than As both consolidation and and complex tasks, in emotional, profound mechanistic divergence. reconsolidation are sensitive to similar declarative, incidental, spatial, - Whether the interfering agent Current Biology Vol 23 No 17 R748

memory, which progresses according uncontrollable emotional event. Some β-AR NMDA-R to its history. studies suggest that overtrained or

POSTSYNAPTIC Perhaps the underlying sequential strongly reinforced memories do not AC LA NEURON Ca2+ progression of changes is what undergo reconsolidation if reactivated

PKA Arc leads to modifications in network the first few days after training, but do Egr-1 Npas4 representation of the more become sensitive to reconsolidation consolidated memories, as in the interferences with time (weeks after MAPK Protein synthesis case of the remote representations training), confirming that the intensity CREB of medial-temporal lobe-dependent of training in addition to the age of RNA mTOR synthesis memories. Memories that depend on the memory regulate reconsolidation NUCLEUS the medial temporal lobe network, but boundaries. One possible explanation Epigenetic regulation also other simpler memories, show a for the differences in reconsolidation temporal gradient of post-reactivation of strong vs. weak or milder training fragility, whereas more implicit types is the respective underlying network Figure 2. Working model of molecular mecha- of memories maintain their post- activations. Recent work, however, nisms putatively involved in reconsolidation reactivation vulnerability. Determining found that even strong new memories of Pavlovian threat () conditioning. whether and how reconsolidation are susceptible to disruption if new Molecules and processes in blue are known to be involved in the initiation of reconsolida- occurs in older memories and in information is added during retrieval. tion. Molecules and processes in black are which types of memories is important, known to be involved in reconsolidation of not only for understanding memory What are the mechanisms of memory fear conditioning. Purple labels denote mol- processes but also for potential clinical reconsolidation? ecules or elements whose role is not estab- applications. What appears to emerge A number of mechanisms have lished for fear conditioning but are part of an is that the age of the memory together been implicated in reconsolidation. established intracellular signaling pathway. AC, adenyl cyclase; AKAP, A-kinase anchor- with strength of training and extent of Although it should be kept in mind ing protein; Arc, activity-regulated cytoskel- reactivation interact to dictate whether that different types of memories or etal-associated protein; b-AR, b-adrenergic or not reconsolidation occurs. memory systems may recruit different receptor; BDNF, brain-derived neurotrophic At present, the reason why some mechanisms for their reconsolidation, factor; Ca2+, calcium; CREB, cAMP response types of memories are differentially here we will summarize the general element (CRE) binding protein; Egr-1, early sensitive to reconsolidation understanding obtained thus far. Most growth response protein 1; MAPK, mitogen- activated protein kinase; mTOR, mammalian interferences as they age is unclear, of the molecular mechanisms found to target of rapamycin; NMDA-R, N-methyl-d- but a reasonable hypothesis is that be critical for memory reconsolidation aspartate glutamate receptor; Npas4, neu- different types of memories may utilize are also engaged during consolidation. ronal PAS domain protein 4; RNA, ribonu- distinct storage mechanisms, hence A few molecular processes, like those cleic acid. Reproduced from Johansen et al. have different abilities to reconsolidate. engaging the transcription factors (2011). An amygdala-dependent memory, C/EBP and Zif268 and the kinase ERK, for example a memory of cued threat have been found to be differentially should be given before or after the conditioning, may rely on storage recruited in reconsolidation. However, reactivation is debated. mechanisms that, once reactivated, their distinctive implications in always become susceptible to reconsolidation versus consolidation Does the passage of time affect disruption. In contrast, medial temporal are probably due to differences in brain reconsolidation? lobe-dependent memories, which areas involved, temporal windows In several cases, but not all, are known to undergo hippocampal- or dosage, rather than being unique reconsolidation does not seem to cortical trace redistribution over selective molecules of each process. occur or becomes much harder to be time, may utilize different storage One interesting observation, however, evoked as time passes. The passage mechanisms or a more distributed, suggests that there may be a selective of time is a critical determinant of hence stronger, storage system as mechanism for each process: the memory formation and storage. It memory ages. In this case reactivation translation machinery required for allows critical progressions and of a remote memory may not trigger, new protein synthesis in the amygdala underlying sequences of mechanisms or not sufficiently trigger, mechanisms seems to differ during the consolidation necessary for going from short-term to that destabilize the memory. It is and reconsolidation processes of long-term memories, and is necessary also possible that not all temporal auditory fear conditioning. for selecting what needs to become a lobe-dependent memories undergo Upstream of the protein synthesis long-lasting memory. With the passage a strong consolidation that renders required for reconsolidation there may of time the memory trace is likely them invulnerable to reconsolidation be an initial destabilization process, reactivated many times by implicit or disruption as they age, and more named deconsolidation, which, explicit events. Implicit activations studies on the reconsolidation of old depending on the type of memory of the trace likely occur during rest and remote memories are needed. and brain region, may require protein and sleep, and explicit activations One additional interesting boundary degradation, cannabinoid receptors, occur upon the encounters of of reconsolidation and age of the histaminergic signaling and NR2B- reminders. The effects of these trace memory relates to very strong training containing NMDA receptors. Following reactivations with possible consequent or overtraining. This, as also detailed deconsolidation, reconsolidation then reconsolidation, as well as other below, is particularly relevant in severe engages L-type voltage-gated calcium processes that remain to be identified, and , where channels (L-VGCCs) to promote sequentially modify the storage of the the learning is a very intense and synaptic plasticity as well as many Special Issue R749 well-known plasticity mechanisms This has dramatic consequences in the exposure are often temporary. This that lead to memory re-consolidation. daily functioning of affected individuals has led to the search for that These include activation of signal and leads to the development of might enhance extinction learning and transduction pathways like those associated pathologies like depression, strengthen the effects of exposure, as mediated by ERK, PKA and CamKII, aggression, and high well as for identification of the post- which lead to the regulation of risk of suicide. reactivation time windows during translation and transcription. Gene The available treatments are not which the competing processes of expression programs required in long- very effective and novel intervention is extinction and reconsolidation favor term synaptic plasticity and memory needed. To date, two pharmacological long-term weakening of the original consolidation, like those mediated treatments that target memory fear memory. Recent studies in rats by the transcription factors CREB, reconsolidation have been tested and humans show that the effects C/EBP, and Zif268, are also required for in PTSD populations. One is the of exposure treatment are much memory reconsolidation, implying that, b-adrenergic more persistent if after the first similar to that which takes place during and the other is the exposure trial a delay is inserted to the consolidation of a new memory, immunosuppressor/blocker of the allow reconsolidation processes to reconsolidation is accompanied by mammalian target of rapamycin be initiated. If the delay is too long synaptic morphological changes. (mTOR) rapamycin. The suggestion that (if it is outside the reconsolidation In agreement, mechanisms that are propranolol could be a useful treatment window of approximately 4 hours), general regulators of gene expression, in PTSD stemmed from studies the treatment does not work. This like epigenetic modification and showing that this drug can disrupt approach has recently been used to /hormonal regulation, the reconsolidation of cued threat significantly reduce craving in drug control memory reconsolidation. Some conditioning in animal models and addicts. Addiction, like PTSD, is amygdala mechanisms involved in humans. Propranolol, however, does associated with very strong, persistent the reconsolidation of amygdala- not seem to be effective in disrupting maladaptive memories that are resilient dependent memories are illustrated in the reconsolidation of other, more to extinction. Developing strategies Figure 2. complex aversive memories in animal that target the reconsolidation of these It is not possible to apply a rule models, or all human fear-related memories may open new frontiers in of one size fits all when considering memories. One possibility is that treating these disorders. reconsolidation of different types propranolol preferentially affects the Importantly, most aversive of memories in different species at implicit emotional aspects of memory memories studied thus far in the present, and different subregulations stored through circuits involving the reconsolidation field are relatively may surface with more detailed and amygdala (but perhaps other circuits as mild and ‘controllable’, whereas the extended investigations. Nevertheless, well) without significantly affecting the threat in traumatic experiences that we can conclude that reconsolidation content or representation of complex lead to PTSD is so massive that it does seem to reopen a consolidation memories stored via the medial is hardly related to the stimuli used process. This conclusion greatly temporal lobe circuits necessary in reconsolidation studies — a mild affects our view of how memories are for . This difference electric body shock in rats or the maintained over time. may represent an advantage when memorization of emotional pictures the goal is to weaken the emotional by humans. The experience of a Can reconsolidation be used in the significance without decreasing the highly traumatic event or events is treatment of psychopathology? cognitive representation. More studies devastatingly threatening and terrifying, One of the most exciting results are needed to understand the target and this likely activates responses emerging from the re-discovery of mechanisms and the effects and/or not recruited after a mild threat. reconsolidation is that established boundary conditions of propranolol in Moreover, highly traumatic experiences memories can be disrupted when clinical applications. evolve over time in a very different reconsolidation is induced and Rapamycin, also known as sirolimus, way, and rather than decreasing and targeted with amnestic treatments. disrupts the reconsolidation of becoming more controllable, they lead Because a great deal of animal and both hippocampal- and amygdala- to ‘uncontrollable’ states of fear and human experiments on reconsolidation dependent threat memories in animal panic, and to an inability to extinguish have been done on aversive memories, models, suggesting that its effect the feeling of fear and associated it becomes apparent that memories may be more general than that of behavioral and physiological of traumas could be potentially propranolol. This compound has been responses. Hence, it is imperative that targeted for disruption by treatments recently used in a pilot study targeting studies aiming to inform the design of that interfere with reconsolidation, reconsolidation in male veterans and PTSD clinical trials also develop and with consequent amelioration of showed promising effects on veterans use more representative models of trauma-related pathologies. A of more recent combats than for traumatic memories. pathology particularly suitable for such veterans from remote wars. This is in intervention is post-traumatic stress agreement with the findings that the Conclusions disorder (PTSD). PTSD is characterized effect on memory reconsolidation can The identification of memory by strong traumatic memories that are be a function of the age of the memory. reconsolidation has significantly continuously retrieved in an intrusive Another approach for treating PTSD changed our understanding of the manner, causing re-experiencing of is extinction. Extinction (i.e. exposure) way memory storage and retrieval the original trauma, avoidance and is a standard treatment for anxiety are viewed. Reconsolidation research increased arousal and stress response. disorders. However, the effects of has offered an explanation for the Current Biology Vol 23 No 17 R750

dynamic nature of memory storage, oven after 15 minutes. When I see my and is shedding light on how long-term Quick guide colleague next, I need to remember memories are retained over time, and to share news about some interesting yet also allow behavioral flexibility and new data. When I pass the grocery adaptation to changing environments. store on the way home, I need to It may be possible to capitalize on remember to buy milk. Two types of flexibility in helping to ameliorate Jonathon D. Crystal triggers may reactivate or retrieve a maladaptive memories and potentiate memory at an appropriate point in adaptive behaviors in psychopathology. the future. In time-based prospective What is prospective memory? To memory, time serves as the trigger; Further reading err is human: a fundamental part time may involve a specific time of Alberini, C.M. (2011). The role of reconsolidation and the dynamic process of long-term memory of human nature includes making day (as in daycare schedules) or an formation and storage. Front. Behav. Neurosci. mistakes (and we hope forgiveness elapsing interval (as in cooking). In 5, 12. is another ingredient of the human event-based prospective memory, the Alberini, C.M. ed. (2013). Memory Reconsolidation (San Diego, CA: Elsevier). condition). In many cases, we occurrence of an event serves as the Besnard, A., Caboche, J., and Laroche, S. (2012). ‘remember to remember’, but trigger (the colleague or grocery store). Reconsolidation of memory: a decade of debate. Prog. Neurobiol. 1, 61–80. sometimes our mistakes are costly: Both types of prospective De˛biec, J., Bush, D.E, and LeDoux, J.E. (2011). a surgeon intends to remove an memory have been investigated Noradrenergic enhancement of reconsolidation instrument before closing the body in the laboratory. A great deal of in the amygdala impairs extinction of conditioned fear in rats--a possible mechanism cavity, only to discover later that an theoretical and applied interest for the persistence of traumatic memories in instrument is missing. A pilot intends focuses on understanding the causes PTSD. Depress. Anxiety 28, 186–193. Doyère, V., Debiec, J., Monfils, M.H., Schafe, G.E., to adjust the position of wing flaps of reactivation. According to one and LeDoux, J.E. (2007). Synapse specific before takeoff, which can cause or proposal, deferred are reconsolidation of distinct fear memories in the prevent a successful takeoff. A patient automatically (effortlessly) activated lateral amydala. Nat. Neurosci. 10, 414–416. Dudai, Y. (2012). The restless engram: consolidations intends to take her medication with when a target cue occurs. According never end. Annu. Rev. Neurosci. 35, 227–247. dinner, and treatment outcomes to an alternative proposal, active Johansen, J.P., Cain, C.K., Ostroff, L.E., and LeDoux, J.E. (2011) Molecular mechanisms of fear depend on successful fulfillment of the (effortful) monitoring is needed to learning and memory. Cell 147, 509–524. . A bank manager intends to detect the occurrence of a target Lattal, K.M., and Wood, M.A. (2013). Epigenetics lock the vault, and has literal cue. Finally, according to the and persistent memory: implications for reconsolidation and silent extinction beyond the costs. multiprocess view, both monitoring zero. Nat. Neurosci. 16, 124–129. These examples highlight what is and spontaneous retrieval are utilized Lewis, D.J. (1979). Psychobiology of active and prospective memory inactive memory. Psychol. Bull. 86, 1054–1083. known as — in prospective remembering. Milton, A.L., and Everitt, B.J. (2010). The remembering to execute delayed psychological and neurochemical mechanisms intentions. As the examples above Why is prospective memory of drug memory reconsolidation: implications for the treatment of addiction. Eur. J. Neurosci. highlight, our intentions are typically important? In addition to everyday 12, 2308–2319. interrupted by other pressing demands successes and failures to ‘remember Misanin ,J.R., Miller, R.R., and Lewis, D.J. of everyday life (performing surgery, (1968). produced by to remember’, prospective memory electroconvulsive shock after reactivation of other preparations for takeoff, is of great interest because it is a consolidated memory trace. Science 160, preparing dinner, assisting customers). implicated in cognitive decline. A 554–555. Monfils, M.H., Cowansage, K.K., Klann, E., and Interruptions of our intentions provide major area of interest is cognitive LeDoux, J.E. (2009). Extinction-reconsolidation a key ingredient that imposes a need decline associated with normal aging. boundaries: key to persistent attenuation of fear for memory. Although we initially memories. Science 324, 951–955. Prospective memory declines in the Nader, K., and Einarsson, E.O. (2010). Memory form the intention to act in the future, elderly. Additional major areas of reconsolidation: an update. Ann. N. Y. Acad. Sci. interruptions typically displace active interest focus on cognitive decline 1191, 27–41. Nader, K., Schafe, G.E., and LeDoux, J.E. (2000). processing of the intention. Instead, associated with human diseases. Fear memories require protein synthesis in the our intentions are temporarily put For example, prospective memory amygdala for reconsolidation after retrieval. on hold — stored in memory — to Nature 406, 722–726. impairments have been implicated in Sara, S.J. (2000). Retrieval and reconsolidation: be reactivated or retrieved at an mild cognitive impairment, Alzheimer’s toward a neurobiology of remembering. Learn. appropriate point in the future. We err disease, autism spectrum disorder, Mem. 7, 73–84. Schiller, D., and Phelps, E.A. (2011). Does when we fail to retrieve these stored traumatic brain injury, Parkinson’s reconsolidation occur in humans? Front. Behav. deferred-intentions. Prospective disease, HIV infection, and substance Neurosci. 5, 24. memory also includes other aspects of Stickgold, R., and Walker, M.P. (2007). Sleep- abuse. Understanding prospective dependent memory consolidation and , such as , executive memory impairments in normal reconsolidation. Sleep Med. 8, 331–343. control of cognitive function, episodic and clinical populations may be Tronson, N.C., and Taylor, J.R. (2007). Molecular mechanisms of memory reconsolidation. Nat. memory, and planning. valuable for understanding biological Rev. Neurosci. 8, 262–275. Additional everyday examples will mechanisms of prospective memory, Tronson, N.C., and Taylor, J.R. (2013). Addiction: help to underscore two approaches a drug-induced disorder of memory especially when combined with human reconsolidation. Curr. Opin. Neurobiol. 23, that are used in the burgeoning field techniques. Prospective 573-580. of prospective memory research. After memory screening may also have taking one’s children to daycare in the great potential if it facilitates early 1Center for Neural Science, New York morning, a parent needs to remember University, 4 Washington Place, New York, detection of cognitive decline (for NY 10003, USA. 2Nathan Kline Institute for to pick up the kids at the scheduled example, before the more dramatic Psychiatric Research, Orangeburg, NY, USA. time. When cooking, a chef needs to memory failures associated with early E-mail: [email protected] remember to remove the tray from the onset of Alzheimer’s disease). Another