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CHAPTER 2 1 Memory Consolidation

John T. Wixted and Denise J. Cai

Abstract Memory consolidation is a multifaceted concept. At a minimum, it refers to both cellular consolidation and systems consolidation. Cellular consolidation takes place in the hours after learning, stabilizing the memory trace—a process that may involve structural changes in hippocampal neurons. Systems consolidation refers to a more protracted process by which memories become independent of the hippocampus as they are established in cortical neurons—a process that may involve neural replay. Both forms of consolidation may preferentially unfold whenever the hippocampus is not encoding new information, although some theories hold that consolidation occurs exclusively during sleep. In recent years, the notion of reconsolidation has been added to the mix. According to this idea, previously consolidated memories, when later retrieved, undergo consolidation all over again. With new findings coming to light seemingly every day, the concept of consolidation will likely evolve in interesting and unpredictable ways in the years to come. Key Words: cellular consolidation, systems consolidation, reconsolidation, sleep and consolidation

Th e idea that memories require time to consoli- position of the interfering list within the retention date has a long history, but the understanding of interval mattered such that interference occurring what consolidation means has evolved over time. soon after learning had a more disruptive eff ect than In 1900, the German experimental psychologists interference occurring later in the retention inter- Georg Müller and Alfons Pilzecker published a val. Th is led them to propose that memories require monograph in which a new theory of memory and time to consolidate and that retroactive interference forgetting was proposed, one that included—for is a force that compromises the integrity of recently the fi rst time—a role for consolidation. Th eir basic formed (and not-yet-consolidated) memories. In method involved asking subjects to study a list of this chapter, we review the major theories of consol- paired-associate nonsense syllables and then testing idation—beginning with the still-relevant account their memory using cued recall after a delay of several proposed by Müller and Pilzecker (1900)—and we minutes. Typically, some of the list items were for- consider a variety of recent developments in what gotten, and to investigate why that occurred, Müller has become a rapidly evolving fi eld. and Pilzecker (1900) presented subjects with a sec- ond, interfering list of items to study before mem- Th e Early View: Consolidation and ory for the target list was tested. Th ey found that Resistance to Interference this interpolated list reduced memory for the target According to Müller and Pilzecker’s (1900) list compared with a control group that was not view, consolidation consists of “trace hardening” exposed to any intervening activity. Critically, the (cf. Wickelgren, 1974) in the sense that some

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physiological process perseverates and eventually become stronger, so it is important to keep in mind renders the memory trace less vulnerable to inter- which meaning of a “stronger memory trace” applies ference caused by new learning. Th e kind of inter- in any discussion of consolidation. One way that a ference that a consolidated trace theoretically resists trace might become stronger is that it comes to more diff ers from the kind of interference that most accurately refl ect past experience than it did when it experimental psychologists have in mind when was fi rst formed, much like a snapshot taken from a they study forgetting. In the fi eld of experimental Polaroid camera comes into sharper focus over time. psychology, new learning has long been thought to A trace that consolidated in this manner would yield generate interference by creating competing asso- an ever-clearer memory of the encoding event in ciations linked to a retrieval cue, not by aff ecting response to the same retrieval cue. Another way that the integrity of a fragile memory trace (e.g., Keppel, a trace might become stronger is that it becomes 1968; Underwood, 1957; Watkins & Watkins, ever more likely to spring to mind in response to 1975). Traditionally, this kind of interference has a retrieval cue (even more likely than it was when been investigated using an A-B, A-C paired-associ- the memory was fi rst formed). A memory trace that ates paradigm in which the same cue words (the A consolidated in either of these two ways would sup- items) are paired with diff erent to-be-remembered port a higher level of performance than it did at the target words across two lists (the B and C items, end of training, as if additional learning occurred respectively). In a standard retroactive interference despite the absence of additional training. paradigm, for example, the memory test consists of Still another way that a trace can become stron- presenting the A items and asking participants to ger is that it becomes hardened against the destruc- recall the B items. Having learned the A-C associa- tive forces of interference. A trace that hardens over tions after learning the A-B associations, the abil- time (i.e., a trace that consolidates in that sense) ity of participants to recall the B items is typically may simultaneously become degraded over time impaired, and this impairment is usually assumed due to the interfering force of new learning or to to refl ect retrieval competition from the C items. some other force of decay. As an analogy, a clay Th e powerful eff ect of this kind of “cue overload” replica of the Statue of Liberty will be at its fi nest interference on retention has been well established when it has just been completed and the clay is still by decades of psychological research, but it is almost wet, but it will also be at its most vulnerable. With certainly not the only kind of interference that the passage of time, however, the statue dries and causes forgetting. becomes more resistant to damage even though it Th e kind of interference envisioned by Müller may now be a less accurate replica than it once was and Pilzecker (1900) does not involve overloading (because of the damage that occurred before the a retrieval cue but instead involves directly com- clay dried). Müller and Pilzecker’s (1900) original promising the integrity of a partially consolidated view of consolidation, which was later elaborated by memory trace. In what even today seems like a Wickelgren (1974), was analogous to this. Th at is, radical notion to many experimental psycholo- the consolidation process was not thought to render gists, Müller and Pilzecker (1900) assumed that the the trace more representative of past experience or interference was nonspecifi c in the sense that the to render it more likely to come to mind than it was interfering material did not have to be similar to at the time of formation; instead, consolidation was the originally memorized material for interference assumed to render the trace (or its association with to occur. Instead, mental exertion of any kind was a retrieval cue) more resistant to interference even thought to be the interfering force (Lechner et al., while the integrity of the trace was gradually being 1999). “Mental exertion” is fairly vague concept, and compromised by interference. Wixted (2004a) suggested that the kind of inter- Th ese considerations suggest a relationship vening mental exertion that Müller and Pilzecker between Müller and Pilzecker’s (1900) view of con- (1900) probably had in mind consists specifi cally solidation and the time course of forgetting. More of new learning. Th e basic idea is that new learning, specifi cally, the fact that a memory trace hardens per se, serves as an interfering force that degrades in such a way as to become increasingly resistant recently formed and still fragile memory traces. to interference even as the trace fades may help to Loosely speaking, it can be said that Müller and explain the general shape of the forgetting func- Pilzecker (1900) believed that the memory trace tion (Wixted, 2004b). Since the seminal work becomes strengthened by the process of consolidation. of Ebbinghaus (1885), a consistent body of evi- However, there is more than one way that a trace can dence has indicated that the proportional rate of

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forgetting is rapid at fi rst and then slows to a point long ago by Ribot (1881/1882), but he had no at which almost no further forgetting occurs. Th is way of knowing what brain structures were cen- general property is captured by the power law of trally involved in this phenomenon. Th e experience forgetting (Anderson & Schooler, 1991; Wixted & of H.M. made it clear that the relevant structures Carpenter, 2007; Wixted & Ebbesen, 1991), and it reside in the MTL, and the phenomenon of tem- is enshrined in Jost’s law of forgetting, which states porally graded retrograde amnesia suggests an that if two memory traces have equal strength but extended but time-limited role for the MTL in the diff erent ages, the older trace will decay at a slower encoding and retrieval of new memories. Th at is, rate than the younger one from that moment on the MTL is needed to encode new memories, and it (Jost, 1897). One possibility is that the continuous is needed for a time after they are encoded, but it is reduction in the rate of forgetting as a trace ages is a not needed indefi nitely. Th e decreasing dependence refl ection of the increased resistance to interference of memories on the MTL is known as systems consol- as the trace undergoes a slow process of consolida- idation (Frankland & Bontempi, 2005; McGaugh, tion (Wickelgren, 1974; Wixted, 2004b). 2000). As a result of this process, which may last as long as several years in humans, memories are even- Modern Views of Consolidation tually reorganized and established in the neocortex Th e view of consolidation advanced by the pio- in such a way that they become independent of the neering experimental psychologists Müller and MTL (Squire et al., 2001). Note that this is a dif- Pilzecker was not embraced by the fi eld of experimen- ferent view of consolidation than the resistance-to- tal psychology in the latter half of the twentieth cen- interference view proposed by Müller and Pilzecker tury. Ironically, during that same period of time, the (1900). notion that memories consolidate became the “stan- Th e temporal gradient of retrograde amnesia dard story” in the fi eld of neuroscience. Th e impetus exhibited by patient H.M. (documented during for this way of thinking among neuroscientists can be early years after surgery) prompted more controlled traced in large part to the realization that the structures investigations using both humans and nonhumans. of medial temporal lobe (MTL) play a critical role Th ese studies have shown that the temporal gradi- in the formation of new memories. Th e importance ent is real and that it is evident even when bilat- of these structures became clear when patient H.M. eral lesions are limited to the hippocampus (a received a bilateral medial temporal lobe resection in central structure of the MTL). For example, in a an eff ort to control his epileptic seizures (Scoville & particularly well-controlled study, Anagnostaras Milner, 1957). Although successful in that regard, et al. (1999) investigated the eff ect of hippocam- H.M. was also unexpectedly left with a profound pal lesions in rats using a context fear-conditioning case of anterograde amnesia (i.e., the inability to form paradigm. In this task, a tone conditional stimulus new memories from that point on) despite retain- (CS) is paired with a shock unconditional stimulus ing normal perceptual and intellectual functioning, (US) several times in a novel context. Such training including normal working memory capacity. Another results in a fear of both the tone and the training outcome—one that is relevant to the issue of consol- context (measured behaviorally as the proportion idation—was that H.M. also exhibited temporally of time spent freezing), and memory for the con- graded retrograde amnesia (Scoville & Milner, 1957; text-shock association in particular is known to Squire, 2009). Th at is, memories that were formed depend on the hippocampus. Anagnostaras et al. before surgery were also impaired, and the degree of (1999) trained a group of rats in two diff erent con- impairment was greater for memories that had been texts, and this training was later followed by surgi- formed just before surgery than for memories that had cal lesions of the hippocampus. Each rat received been formed well before. Although memories of up to training in Context A 50 days before surgery and 3 years before his surgery were seemingly impaired, training in Context B 1 day before surgery. Th us, at H.M.’s older memories appeared to be largely intact the time lesions were induced, memory for learning (Scoville & Milner, 1957). Th is result suggests that in Context A was relatively old, whereas memory the brain systems involved in the maintenance of for learning in Context B was still new. A later test memory change over time. of retention showed that remote (i.e., 50-day-old) memory for contextual fear was similar to that of Systems Consolidation controls, whereas recent (i.e., 1-day-old) memory Th e temporal gradient of retrograde amnesia for contextual fear was greatly impaired. Th us, in that is associated with injury and disease was noted rats, hippocampus-dependent memories appear to

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become independent of the hippocampus in a mat- performed on unimpaired subjects, though the rel- ter of weeks. evant literature is somewhat mixed in this regard. Controlled studies in humans sometimes suggest Although some studies found more activity in the that the time course of systems consolidation often MTL during the recollection of recent semantic plays out over a much longer period of time period, memories compared with remote semantic memo- a fi nding that is consistent with the time window ries (Douville et al., 2005; Haist et al., 2001; Smith of retrograde amnesia observed for H.M. However, & Squire, 2009), other studies found no diff erence the time course is rather variable, and the basis for (e.g., Bernard et al., 2004; Maguire et al., 2001; the variability is not known. Both semantic and epi- Maguire & Frith, 2003). For example, using func- sodic memory have been assessed in studies investi- tional magnetic resonance imaging (fMRI), Bernard gating the temporal gradient of retrograde amnesia. et al. (2004) identifi ed brain regions associated with Semantic memory refers to memory for factual recognizing famous faces from two diff erent periods: knowledge (e.g., what is the capital of Texas?), people who became famous in the 1960s to 1970s whereas episodic memory refers to memory for spe- and people who became famous in the 1990s. Th ey cifi c events (e.g., memory for a recently presented found that the hippocampus was similarly active list of words or memory for an autobiographical during the recognition of faces from both periods event, such as a trip to the Bahamas). (i.e., no temporal gradient was observed). It is not clear why studies vary in this regard, but one pos- Temporal Gradient of Semantic Memory sibility is that the detection of a temporal gradient is Semantic knowledge is generally acquired gradu- more likely when multiple time points are assessed, ally across multiple episodes of learning and is forgot- especially during the several years immediately ten slowly, so it seems reasonable to suppose that the preceding memory impairment, than when only systems consolidation of such knowledge would be two time points are assessed (as in Bernard et al., extended in time. In one recent study of this issue, 2004). Manns et al. (2003) measured factual knowledge In an imaging study that was patterned after in six amnesic patients with damage limited to the the lesion study reported by Manns et al. (2003), hippocampal region. Participants were asked ques- Smith and Squire (2009) measured brain activity tions about news events that had occurred from while subjects recalled news events from multiple 1950 to early 2002 (e.g., Which tire manufacturer time points over the past 30 years. In agreement recalled thousands of tires? [Firestone] What soft- with the lesion study, they found that regions in ware company was accused of running a monopoly? the MTL exhibited a decrease in brain activity as [Microsoft]). Th e data for a particular patient (and a function of the age of the memory over a 12-year for several controls matched to that patient) were period (whereas activity was constant for memories analyzed according to the year in which the patient from 13 to 30 years ago). In addition, they found became amnesic. As might be expected, memory for that regions in the frontal lobe, temporal lobe, and factual knowledge was reduced for the period of time parietal lobe exhibited an increase in activity as a following the onset of memory impairment. Th us, for function of the age of the trace. Th us, it seems that example, if a patient became amnesic in 1985, then the (systems) consolidation of semantic memories is memory for news events that occurred after 1985 was a slow process that may require years to complete. impaired (i.e., anterograde amnesia was observed). In addition, and more to the point, factual knowledge Temporal Gradient of Autobiographical for news events that occurred during the several years (Episodic) Memory immediately before the onset of memory impairment Although lesion studies and neuroimaging (e.g., 1980 to 1985) was also impaired, particularly studies point to a temporal gradient for semantic when memory was measured by free recall rather than memory lasting years, there is some debate about by recognition. However, memory for events that whether episodic memory—in particular autobio- occurred 11 to 30 years before the onset of memory graphical memory—exhibits any temporal gradient impairment (e.g., 1955 to 1974) was intact. Th ese at all. For example, some recent studies performed older memories, it seems, had become fully consoli- on H.M. that were conducted not long before he dated in the neocortex and were no longer dependent passed away in 2008 showed that his memory for on the structures of the MTL. remote personal experiences, unlike his memory Th e fi ndings from lesion studies have some- for remote factual knowledge, was not preserved times been corroborated by neuroimaging studies (Steinvorth, Levine, & Corkin, 2005). In addition,

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a number of case studies of memory-impaired the hippocampus and temporal neocortex associated patients have reported impairments of childhood with memory for two sets of paired-associate fi gures memories (Cipolotti et al., 2001; Eslinger, 1998; that subjects had previously memorized. One set Hirano & Noguchi, 1998; Kitchener et al., 1998; was studied 8 weeks before the memory test (old Maguire et al., 2006; Rosenbaum et al., 2004). memories), and the other was studied immediately Th ese fi ndings appear to suggest that the MTL before the memory test (new memories). Overall plays a role in recalling personal episodes even if accuracy at the time of test was equated for the two they happened long ago, and the apparent impli- conditions by providing extra study time for the cation is that autobiographical memories do not items that were studied 8 weeks before. Th us, any undergo systems consolidation. However, by the diff erences in activity associated with old and new time H.M.’s remote autobiographical memory memories could not be attributed to diff erences in impairment was documented, he was an elderly memory strength. Th e results showed that a region patient, and his brain was exhibiting signs of corti- in right hippocampus was associated with greater cal thinning, abnormal white matter, and subcorti- activity during retrieval of new memories than old cal infarcts (Squire, 2009). Th us, these late-life brain memories, whereas in left temporal neocortex, the abnormalities could account for the loss of remote opposite activation pattern (i.e., old > new) was memories. In addition, in most of the case stud- observed. Th ese results are consistent with a decreas- ies that have documented remote autobiographical ing role of the hippocampus and increasing role of memory impairment, damage was not restricted to the neocortex as memories age over a period as short the MTL. To compare the remote memory eff ects as 50 days (cf. Takashima et al., 2006), a time scale of limited MTL damage and damage that also of consolidation that is similar to that observed involved areas of the neocortex, Bayley et al. (2005) in experimental animals (e.g., Anagnostaras et al., measured the ability of eight amnesic patients to 1999). recollect detailed autobiographical memories from An even shorter time scale for systems consolida- their early life. Five of the patients had damage lim- tion was evident in a recent fMRI study reported ited to the MTL, whereas three had damage to the by Takashima et al. (2009). Subjects in that study neocortex in addition to MTL damage. Th ey found memorized two sets of face–location stimuli, one that the remote autobiographical memories of the studied 24 hours before the memory test (old mem- fi ve MTL patients were quantitatively and quali- ories) and the other studied 15 minutes before the tatively similar to the recollections of the control memory test (new memories). To control for diff er- group, whereas the autobiographical memories of ences in memory strength, they compared activity the three patients with additional neocortical dam- for high-confi dence hits associated with the old and age were severely impaired. Th is result suggests that new memories and found that hippocampal activ- semantic memory and episodic memory both even- ity decreased and neocortical activity increased over tually become independent of the MTL through a the course of 24 hours. In addition, the connectiv- process of systems consolidation, but the tempo- ity between the hippocampus and the neocortical ral gradient of retroactive amnesia associated with regions decreased, whereas cortico-cortical con- that process can be obscured if damage extends to nectivity increased (all over the course of only 24 the neocortex. MacKinnon and Squire (1989) also hours). Results like these suggest that the process of found that the temporal gradient of autobiographi- systems consolidation can occur very quickly. cal memories for fi ve MTL patients was similar in What determines whether the temporal gradi- duration to the multiyear gradient associated with ent is short or long? Th e answer is not known, but semantic memory. Frankland and Bontempi (2006) suggested that the critical variable may be the richness of the memo- Temporal Gradients Involving a Shorter rized material. To-be-remembered stimuli presented Time Scale in a laboratory are largely unrelated to a subject’s Recent neuroimaging studies have documented personal history and thus might be integrated with a temporal gradient of activity for memory of sim- prior knowledge represented in the cortex in a ple laboratory stimuli on a time scale that is vastly rather sparse (yet rapid) manner. Autobiographical shorter than the multiyear process of consolidation memories, by contrast, are generally related to suggested by lesion studies of semantic memory a large preexisting knowledge base. Th e integra- and autobiographical memory. For example, using tion of such memories into an intricate knowledge fMRI, Yamashita et al. (2009) measured activity in base may require more extended dialogue between

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the hippocampus and neocortex (McClelland, In agreement with this possibility, a series of McNaughton, & O’Reilly, 1995). Alternatively, trace eyeblink conditioning studies conducted by Tse et al. (2007) suggested that when memories Takehara-Nishiuchi and colleagues has shown that can be incorporated into an associative “schema” an area of the medial prefrontal cortex (mPFC) in of preexisting knowledge (i.e., when newly learned rats becomes increasingly necessary for the retrieval information is compatible with previously learned of memories as they become decreasingly depen- information), the process of systems consolida- dent on the hippocampus over the course of several tion is completed very rapidly (within 48 hours for weeks. Th is was shown both by lesion studies and rats). However, it is not clear whether this idea can by direct neural recordings of task-related activ- account for the rapid systems consolidation that is ity in the mPFC (Takehara, Kawahara, & Kirino, apparent for memories of arbitrary laboratory-based 2003; Takehara-Nishiuchi & McNaughton, 2008). stimuli in humans (e.g., Takashima et al., 2009). In one particularly relevant experiment, Takehara- Th e as-yet-unresolved question of why memories Nishiuchi and McNaughton (2008) showed that vary in how quickly they undergo systems consoli- task-related activity of mPFC neurons in rats dation seems likely to remain a focus of research in increased over the course of several weeks even in this area for some time to come. the absence of further training. In a conceptually related study, Frankland et al. (2004) trained mice Decreasing Hippocampal Activity Versus in a fear-conditioning procedure and tested mem- Increasing Neocortical Activity ory either 1 day (recent) or 36 days (remote) after Th e fi ndings discussed above support the view training. Th ey found that activity in multiple asso- that memories undergo a process of systems con- ciation cortical regions (measured by the expression solidation in which the structures of the MTL play of activity-regulated genes) was greater for remote a decreasing role with the passage of time. An inter- than for recent memories. In addition, they found esting feature of several of the neuroimaging studies that the increased cortical activity for remote mem- discussed above is that not only does MTL activ- ories was not evident in mice with a gene mutation ity often decrease with time, but also neocortical that selectively impairs remote memory. Results like activity increases over time (Smith & Squire, 2009; these would seem to provide direct evidence of the Takashima et al., 2009; Yamashita et al., 2009). kind of cortical reorganization that has long been What might that increased activity signify? thought to underlie systems consolidation. Th e memory of a past experience that is elicited by a retrieval cue presumably consists of the reac- Cellular Consolidation tivation of distributed neocortical areas that were Systems consolidation is not what Müller and active at the time the trace was initially encoded Pilzecker (1900) had in mind when they fi rst intro- (Damasio, 1989; Hoff man & McNaughton, duced the concept of consolidation. Th eir view was 2002; Johnson, McDuff , Rugg, & Norman, 2009; that a memory trace becomes increasingly resistant McClelland, McNaughton, & O’Reilly, 1995; to interference caused by new learning as the trace Squire & Alvarez, 1995). Th e primary sensory consolidates, not that the trace becomes reorganized areas of the brain (e.g., the brain areas activated in the neocortex (and, therefore, less dependent on by the sights, sounds, and smells associated with the MTL) over time. a visit to the county fair) converge on associa- Whereas a role for systems consolidation came tion areas of the brain, which, in turn, are heav- into sharper focus in the years following the recog- ily interconnected with the MTL. Conceivably, nition of H.M.’s memory impairment, evidence for memories are stored in widely distributed neocor- a second kind of consolidation began to emerge in tical areas from the outset, but the hippocampus the early 1970s. Th is kind of consolidation—called and other structures of the MTL are required to cellular consolidation —occurs at the level of neurons bind them together until cortico-cortical associa- (not brain systems) and takes place over the hours tions develop, eventually rendering the memory (and, perhaps, days) after a memory is formed in trace independent of the MTL (Wixted & Squire, the hippocampus (McGaugh, 2000). Cellular con- 2011). In studies using fMRI, the increasing role solidation seems more directly relevant to the trace- of the direct cortico-cortical connections may hardening physiological processes that Müller and be refl ected in increased neocortical activity as Pilzecker (1900) had in mind, and it had its origins time passes since the memory trace was formed in the discovery of a phenomenon known as long- (Takashima et al., 2009). term potentiation (LTP; Bliss & Lomo, 1973).

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LTP is a relatively long-lasting enhancement of What does LTP have to do with the story of synaptic effi cacy that is induced by a brief burst of consolidation? Th e induction of LTP unleashes a high-frequency electrical stimulation (a tetanus) deliv- molecular cascade in postsynaptic neurons that con- ered to presynaptic neurons (Bliss & Collingridge, tinues for hours and results in structural changes to 1993). Before the tetanus, a single (weak) test pulse those neurons. Th e postsynaptic changes are pro- of electrical stimulation applied to the presynaptic tein-synthesis dependent and involve morphologi- neuron elicits a certain baseline response in the post- cal changes in dendritic spines (Yuste & Bonhoeff er, synaptic neuron, but after the tetanus, that same test 2001) and the insertion of additional AMPA recep- pulse elicits a greater response. Th e enhanced reac- tors into dendritic membranes (Lu et al., 2001). tivity typically lasts hours or days (and sometimes Th ese changes are generally thought to stabilize weeks), so it presumably does not represent the way LTP because LTP degrades rapidly if they do not in which memories are permanently coded. Still, occur (or are prevented from occurring by the use LTP is readily induced in hippocampal neurons, of a protein synthesis inhibitor). and it is, by far, the leading approach to modeling LTP exhibits all of the characteristics of consoli- the neural basis of initial memory formation (Bliss, dation envisioned by Müller and Pilzecker (1900). Collingridge, & Morris, 2003; Martin, Grimwood, In their own work, Müller and Pilzecker (1900) & Morris, 2000). In this model, tetanic stimulation used an original learning phase (L1), followed by is analogous to the eff ect of a behavioral experience, an interfering learning phase (L2), followed by and the enhanced effi cacy of the synapse is analo- a memory test for the original list (T1). Holding gous to the memory of that experience. the retention interval between L1 and T1 constant, Although LTP looks like neural memory for an they essentially showed that L1-L2-----T1 yields experience (albeit an artifi cial experience consisting greater interference than L1---L2---T (where the of a train of electrical impulses), what reason is there dashes represent units of time). In experimental to believe that a similar process plays a role in real animals, memories formed in the hippocampus and memories? Th e induction of LTP in hippocampal LTP induced in the hippocampus both exhibit a neurons involves the opening of calcium channels similar temporal gradient with respect to retroac- in postsynaptic N -methyl- D -aspartate (NMDA) tive interference (Izquierdo et al., 1999; Xu et al., receptors (Bliss & Collingridge, 1993). When those 1998). Whether L1 and L2 both involve hippocam- receptors are blocked by an NMDA antagonist, pus-dependent learning tasks (e.g., L1 = one-trial high-frequency stimulation fails to induce LTP. inhibitory avoidance learning, L2 = exploration Perhaps not coincidentally, NMDA antagonists of a novel environment), as reported by Izquierdo have often been shown to impair the learning of et al. (1999), or one involves the induction of LTP hippocampus-dependent tasks in animals (e.g., (L1) while the other involves exposure to a learning Morris et al., 1986; Morris, 1989), as if an LTP-like task (L2), as reported by Xu et al. (1998), the same process in the hippocampus plays an important role pattern emerges. Specifi cally, L2 interferes with L1 in the formation of new episodic memories. One when the time between them is relatively short (e.g., study suggests that the encoding of actual memo- 1 hour), but not when the time between them is ries (not just an artifi cial train of electrical pulses) relatively long (e.g., 6 or more hours). Moreover, if also gives rise to LTP in the hippocampus. Whitlock an NMDA antagonist is infused into the hippocam- et al. (2006) trained rats on an inhibitory avoidance pus before L2 (thereby blocking the induction of task (a task known to be dependent on the hip- interfering LTP that might be associated with the pocampus), and they were able to fi nd neurons in learning of a potentially interfering task), no inter- the hippocampus that exhibited sustained LTP after ference eff ect is observed even when the L1-L2 tem- training (not after an artifi cial tetanus). In addition, poral interval is short. tetanic stimulation applied to these neurons after Th e point is that hippocampus-dependent training now had a lesser eff ect (as if those neurons memories and hippocampal LTP both appear to were already close to ceiling levels of LTP) than be vulnerable to interference early on and then tetanic stimulation applied to the neurons of ani- become more resistant to interference with the mals who had not received training. Th ese fi ndings passage of time. Moreover, the interfering force is suggest that LTP may be more than just a model the formation of new memories (or, analogously, for memory formation; it may, in fact, be part of the induction of LTP). Newly induced LTP, like a the mechanism that underlies the initial encoding newly encoded memory, begins life in a fragile state. of memory. Over time, as the process of cellular consolidation

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unfolds, recently formed LTP and recently encoded again formed. If so, then less forgetting should be memories become more stable, which is to say that observed than would otherwise be the case. they become more resistant to interference caused All of these fi ndings are easily understood in by the induction of new LTP or by the encoding of terms of cellular consolidation (not systems consoli- new memories. dation), but a recent explosion of research on the Th e use of an NMDA antagonist in rats is not role of sleep and consolidation has begun to suggest the only way to induce a temporary period of that the distinction between cellular consolidation anterograde amnesia (thereby protecting recently and systems consolidation may not be as sharp as induced LTP or recently formed memories). In previously thought. suffi cient quantities, alcohol and benzodiazepines have been shown to do the same in humans. Sleep and Consolidation Moreover, like NMDA antagonists, these drugs In recent years, the idea that sleep plays a spe- not only induce anterograde amnesia but also cial role in the consolidation of both declarative and inhibit the induction of LTP in the hippocampus nondeclarative memory has received a great deal of (Del Cerro et al., 1992; Evans & Viola-McCabe, attention. Declarative memory consists of the con- 1996; Givens & McMahon, 1995; Roberto et al., scious remembrance of either factual information 2002, Sinclair & Lo, 1986). Interestingly, they also (i.e., semantic memory) or past experience (i.e., result in a phenomenon known as retrograde facili- episodic memory), and it is the kind of memory tation. Th at is, numerous studies have reported that that we have discussed thus far in connection with even though alcohol induces amnesia for informa- systems consolidation and cellular consolidation. tion studied under the infl uence of the drug, it Nondeclarative memory, on the other hand, refers actually results in improved memory for material to the acquisition and retention of nonconscious studied just before consumption (e.g., Bruce & skills and abilities, with the prototypical example Pihl, 1997; Lamberty, Beckwith, & Petros, 1990; being the ability to ride a bike. With practice, one’s Mann, Cho-Young, & Vogel-Sprott, 1984; Parker riding ability improves, but the memory of how to et al., 1980, 1981). Similar fi ndings have been balance on two wheels is not realized by consciously frequently reported for benzodiazepines such as remembering anything about the past (as in the diazepam and triazolam (Coenen & Van Luijtelaar, case of declarative memory). Instead, that memory 1997; Fillmore et al., 2001; Ghoneim, Hinrichs, & is realized by climbing on the bike and discovering Mewaldt, 1984; Hinrichs, Ghoneim, & Mewaldt, that you can ride it without falling off . Whereas 1984; Weingartner et al., 1995). Predrug memo- declarative memory depends on the structures of ries, it seems, are protected from interference that the MTL, nondeclarative memories do not (Squire, would have been created during the postdrug 1992; Squire & Zola, 1996). As a result, amnesic amnesic state. patients with MTL damage have an impairment of It is important to emphasize that postlearning declarative memory (both anterograde amnesia and amnesia-inducing agents (such as NMDA antago- temporally graded retrograde amnesia), but they are nists used in rats or alcohol and benzodiazepines generally unimpaired at learning and retaining pro- used in humans) do not enhance predrug memo- cedural skills (Squire, 1992). An amnesic could, for ries in an absolute sense. Th at is, in response to example, learn to ride a bike as easily as you could, these drugs, the memories do not more accurately but, unlike you, the amnesic would have no con- represent past experience and are not more likely scious declarative memory of the practice sessions. to be retrieved than they were at the end of learn- Recent research suggests that sleep plays a role in the ing. Instead, memories formed before drug intake consolidation of both declarative and nondeclara- are forgotten to a lesser degree than memories tive memories. formed before placebo. By limiting the formation Because sleep is not an undiff erentiated state, of new memories, alcohol and benzodiazepines one focus of this line of research has been to iden- (like NMDA antagonists) may protect memories tify the specifi c stage of sleep that is important for that were formed just before drug intake. While consolidation. Sleep is divided into fi ve stages that protected from the trace-degrading force of new occur in a regular sequence within 90-minute cycles memory formation, these memories may be allowed throughout the night. Stages 1 through 4 refer to to consolidate (via cellular consolidation) in a way ever-deeper levels of sleep, with stages 3 and 4 often that hardens them against the interference they being referred to as slow-wave sleep. Rapid eye will later encounter when new memories are once movement (REM) sleep is a lighter stage of sleep

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associated with vivid dreams. Although every stage Slow-Wave Sleep and Cellular of sleep occurs during each 90-minute sleep cycle, Consolidation the early sleep cycles of the night are dominated by Why is slow-wave sleep more protective of slow-wave sleep, and the later sleep cycles are domi- recently formed memories than REM sleep? One nated by REM sleep. For declarative memory, the possibility is that slow-wave sleep is more conducive benefi cial eff ects of sleep have been almost exclu- to cellular consolidation than REM sleep. In experi- sively associated with slow-wave sleep, and this is ments performed on sleeping rats, Jones Leonard true of its possible role in systems consolidation and et al. (1987) showed that LTP can be induced in cellular consolidation. For nondeclarative memo- the hippocampus during REM sleep but not during ries, the benefi cial eff ects of sleep are more often slow-wave sleep. Whereas slow-wave sleep inhibits associated with REM sleep. the induction of LTP, it does not disrupt the main- tenance of previously induced LTP (Bramham & Sleep-Related Consolidation of Declarative Srebo 1989). In that sense, slow-wave sleep is like Memory the NMDA antagonists discussed earlier (i.e., they Much evidence dating back at least to Jenkins block the induction of new LTP but not the mainte- and Dallenbach (1924) has shown that less for- nance of previously induced LTP). By contrast, with getting occurs if one sleeps during the retention regard to synaptic plasticity in the hippocampus, interval than if one remains awake. A reduction in REM sleep is similar to the awake state (i.e., LTP interference is generally thought to play some role can be induced during REM). in this sleep-related benefi t, but there appears to Even during a night of sleep, interference may be much more to the story than that. In particu- occur, especially during REM sleep, when con- lar, consolidation is an important part of the story, siderable mental activity (mainly vivid dreaming) and the diff erent stages of sleep play very diff erent takes place and memories can be encoded in the roles. hippocampus. But memories are probably never Ekstrand and colleagues (Ekstrand, 1972; formed during slow-wave sleep. Th is is true despite Yaroush, Sullivan, & Ekstrand, 1971) were the fi rst the fact that a considerable degree of mental activity to address the question of whether the diff erent (consisting of static visual images, thinking, refl ect- stages of sleep diff erentially benefi t what we now call ing, etc.) occurs during slow-wave sleep. Indeed, declarative memory. Th ese researchers took advan- perhaps half as much mental activity occurs dur- tage of the fact that most REM sleep occurs in the ing non-REM sleep as during REM sleep (Nielsen, second half of the night, whereas most non-REM 2000). However, mental activity and the formation sleep occurs in the fi rst half. Some subjects in this of memories are not one and the same. Th e mental experiment learned a list, went to sleep immediately, activity that occurs during slow-wave sleep is not and were awakened 4 hours later for a test of recall. remembered, perhaps because it occurs during a time Th ese subjects experienced mostly slow-wave sleep when hippocampal plasticity is minimized. Because during the 4-hour retention interval. Others slept no new memories are formed in the hippocampus for 4 hours, were awakened to learn a list, slept for during this time, cellular consolidation can presum- another 4 hours, and then took a recall test. Th ese ably proceed in the absence of interference. During subjects experienced mostly REM sleep during the REM sleep, however, electroencephalogram (EEG) 4-hour retention interval. Th e control (i.e., awake) recordings suggest that the hippocampus is in an subjects learned a list during the day and were tested awake-like state, and LTP can be induced (and for recall 4 hours later. Th e subjects all learned the memories can be formed), so interference is more initial list to a similar degree, but the results showed likely to occur. that 4 hours of mostly non-REM sleep resulted in If slow-wave sleep protects recently formed less forgetting relative to the other two conditions, memories from interference while allowing cellu- which did not diff er from each other (i.e., REM sleep lar consolidation to move forward, then a temporal did not facilitate memory). Barrett and Ekstrand gradient of interference should be observed. Th at is, (1972) reported similar results in a study that con- sleep soon after learning should confer more protec- trolled for time-of-day and circadian rhythm con- tion than sleep that is delayed. Th is can be tested by founds, and the eff ect was later replicated in studies holding the retention interval between learning (L1) by Plihal and Born (1997, 1999). Slow-wave sleep and test (T1) constant (e.g., at 24 hours), with the may play a role in both cellular consolidation and location of sleep (S) within that retention interval systems consolidation. varied. Using the notation introduced earlier, the

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prediction would be that L1-S-----T1 will confer phenomenon of neural replay was initially observed greater protection than L1---S---T1. If a temporal in hippocampal cells of sleeping rats after they gradient is observed (i.e., if memory performance at had run along a familiar track, and its discovery T1 is greater in the fi rst condition than the second), was tied to the earlier discovery of place cells in the it would suggest that sleep does more than simply hippocampus. subtract out a period of retroactive interference that Long ago, it was discovered that the fi ring of par- would otherwise occur. Instead, it would suggest ticular hippocampal cells in awake rats is coupled to that sleep (presumably slow-wave sleep) also allows specifi c points in the rat’s environment (O’Keefe & the process of cellular consolidation to proceed in Dostrovsky, 1971). Th ese cells are known as “place the absence of interference. cells” because they fi re only when the rat traverses a Once again, Ekstrand (1972) performed the particular place in the environment. Usually, hip- pioneering experiment on this issue. In that experi- pocampal place cells fi re in relation to the rat’s posi- ment, memory was tested for paired-associate words tion on a running track. Th at is, as the rat traverses following a 24-hour retention interval in which sub- point A along the track, place cell 1 will reliably fi re. jects slept either during the 8 hours that followed As it traverses point B, place cell 2 will fi re (and list presentation or during the 8 hours that preceded so on). An intriguing fi nding that may be relevant the recall test. In the immediate sleep condition (in to the mechanism that underlies systems consolida- which L1 occurred at night, just before sleep), he tion is that cells that fi re in sequence in the hip- found that 81 percent of the items were recalled pocampus during a behavioral task tend to become 24 hours later; in the delayed sleep condition (in sequentially coactive again during sleep (Wilson & which L1 occurred in the morning), only 66 per- McNaughton, 1994). Th is is the phenomenon of cent were recalled. In other words, a clear temporal neural replay. gradient associated with the subtraction of retroac- Neural reply has most often been observed in tive interference was observed, one that is the mir- rats during slow-wave sleep. It has also occasion- ror image of the temporal gradient associated with ally been observed during REM sleep, but, in that the addition of retroactive interference reported case, it occurs at a rate that is similar to the neu- by Müller and Pilzecker (1900). More recent sleep ron fi ring that occurred during learning (Louie & studies have reinforced the idea that the temporal Wilson, 2001) and thus may simply refl ect dream- gradient of retrograde facilitation is a real phenom- ing. Th e neural replay that occurs during slow-wave enon, and they have addressed various confounds sleep occurs at a rate fi ve to ten times faster than that could have accounted for the results that it did during the waking state (e.g., Ji & Wilson, Ekstrand (1972) obtained (Gais, Lucas, & Born, 2007) and may therefore refl ect a biological con- 2006; Talamini et al., 2008). Th e temporal gradient solidation process separate from mental activity like associated with sleep, like the LTP and animal learn- dreaming. It is as if the hippocampus is replaying ing research described earlier, is consistent with the the earlier behavioral experience, perhaps as a way notion that when memory formation is temporarily to reorganize the representation of that experience halted, recently formed and still-fragile memories in the neocortex. are protected from interference. As a result, they Th e fact that replay of sequential place cell activ- are given a chance to become hardened against the ity in the hippocampus occurs during slow-wave forces of retroactive interference that they will later sleep does not, by itself, suggest anything about encounter (perhaps through a process of cellular communication between the hippocampus and the consolidation). neocortex (the kind of communication that is pre- sumably required for systems consolidation to take Slow-Wave Sleep and Systems place). However, Ji and Wilson (2007) reported Consolidation that hippocampal replay during slow-wave sleep Recent sleep studies have also shed light on the in rats was coordinated with fi ring patterns in the mechanism that may account for systems consoli- visual cortex, which is consistent with the idea that dation, which presumably involves some relatively this process underlies the reorganization of mem- long-lasting form of communication between the ories in the neocortex. In addition, Lansink et al. hippocampus and the neocortex (Marr, 1971). Th e (2009) performed multineuron recordings from mechanism of communication is not known, but a the hippocampus and ventral striatum during wak- leading candidate is neural replay, and most of the ing and sleeping states. While the rats were awake, work on this topic comes from sleep studies. Th e the hippocampal cells fi red when the rat traversed a

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particular point in the environment (i.e., they were In both these studies, the hippocampal reactiva- place cells), whereas the striatal cells generally fi red tion (perhaps refl ective of hippocampo-neocortical in response to rewards. During slow-wave sleep (but dialogue) occurred within hours of the learning not during REM sleep), they found that the hip- episode, a time course of consolidation ordinarily pocampal and striatal cells reactivated together. Th e associated with cellular consolidation. Th e timing coordinated fi ring was particularly evident for pairs observed in these studies is not unlike that observed in which the hippocampal place cell fi red before the in a neuroimaging study discussed earlier in which striatal reward-related neuron. Th us, the hippocam- hippocampal activity decreased, and neocorti- pus leads reactivation in a projection area, and this cal activity increased, over a period as short as 24 mechanism may underlie the systems consolidation hours (Takashima et al., 2009). Moreover, the tim- of place–reward associations. ing fi ts with studies in rats showing that learning- One concern about studies of neural replay is related neural replay is evident in the fi rst slow-wave that the animals are generally overtrained, so little sleep episode that follows learning (Peyrache et al., or no learning actually occurs. Th us, it is not clear 2009). whether learning-related neural replay takes place. In a sleep-deprivation study that also points to However, Peyrache et al. (2009) recorded neurons an almost immediate role for systems-level con- in prefrontal cortex during the course of learning. solidation processes, Sterpenich et al. (2009), using Rats were trained on a Y-maze task in which they human subjects, investigated memory for emo- learned to select the rewarded arm using one rule tional and neutral pictures 6 months after encod- (e.g., choose the left arm) that changed to a diff er- ing. Half the subjects were deprived of sleep on ent rule as soon as a criterion level of performance the fi rst postencoding night, and half were allowed was achieved (e.g., choose the right arm). Th ey to sleep (and then all subjects slept normally each identifi ed sets of neuronal assemblies with reliable night thereafter). Six months later, subjects com- coactivations in prefrontal cortex, and some of pleted a recognition test in the scanner in which these coactivations became stronger when the rat each test item was given a judgment of “remem- started the fi rst run of correct trials associated with ber” (previously seen and subjectively recollected), the acquisition of the new rule. Following these “know” (previously seen but not subjectively recol- sessions, replay during slow-wave sleep mainly lected), or “new” (not previously seen). A contrast involved the learning-related coactivations. Th us, between activity associated with remembered items learning-related replay—the mechanism that may and known items yielded a smaller diff erence in the underlie systems consolidation—can be identi- sleep-deprived subjects across a variety of brain areas fi ed and appears to get underway very soon after (ventral mPFC, precuneus, amygdala, and occipital learning. cortex), even though the items had been memorized Other evidence suggests that something akin to 6 months earlier, and these results were interpreted neural replay occurs in humans as well. An intrigu- to mean that sleep during the fi rst postencoding ing study by Rasch et al. (2007) showed that cuing night infl uences the long-term systems-level con- recently formed odor-associated memories by odor solidation of emotional memory. re-exposure during slow-wave sleep—but not dur- Th e unmistakable implication from all of these ing REM sleep—prompted hippocampal activation studies is that the process thought to underlie sys- (as measured by fMRI) and resulted in less forget- tems consolidation—namely, neural replay (or neu- ting after sleep compared with a control group. ral reactivation)—begins to unfold in a measurable Th is result is consistent with the notion that sys- way along a time course ordinarily associated with tems consolidation results from the reactivation of cellular consolidation. Th at is, in the hours after a newly encoded hippocampal representations during trace is formed, hippocampal LTP stabilizes, and slow-wave sleep. In a conceptually related study, neural replay in the hippocampus gets underway. Peigneux et al. (2004) measured regional cerebral Th ese fi ndings would seem to raise the possibility blood fl ow and showed that hippocampal areas that that the molecular cascade that underlies cellular were activated during route learning in a virtual consolidation also plays a role in initiating neural town (a hippocampus-dependent, spatial learning replay (Mednick, Cai, Shuman, Anagnostaras, & task) were activated again during subsequent slow- Wixted, 2011). If interference occurs while the trace wave sleep. Moreover, the degree of activation dur- is still fragile, then LTP will not stabilize, and pre- ing slow-wave sleep correlated with performance on sumably, neural replay will not be initiated. In that the task the next day. case, the memory will be lost. But if hippocampal

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LTP is allowed to stabilize (e.g., if potentially inter- it is the kind of fi nding that raises the possibility that fering memories are blocked, or if a period of slow- sleep-related consolidation can sometimes increase wave sleep ensues after learning), then (1) the LTP the probability that a memory will be retrieved (i.e., will stabilize and become more resistant to interfer- it can strengthen memories in that sense). ence and (2) neural replay in the hippocampus will commence and the memory will start to become Role of Brain Rhythms in the Encoding reorganized in the neocortex. Th us, on this view, and Consolidation States of the cellular consolidation is an early component of sys- Hippocampus tems consolidation. Most of the work on hippocampal replay of past With these considerations in mind, it is interest- experience has looked for the phenomenon during ing to consider why Rasch et al. (2007) and Peigneux sleep, as if it might be a sleep-specifi c phenomenon. et al. (2004) both observed performance benefi ts However, the key condition for consolidation to associated with reactivation during slow-wave sleep. occur may not be sleep, per se. Instead, the key con- Results like these suggest that reactivation not only dition may arise whenever the hippocampus is not serves to reorganize the memory trace in the neocor- in an encoding state, with slow-wave sleep being tex but also strengthens the memory trace in some an example of such a condition. Indeed, Karlsson way. But in what way is the trace strengthened? Did and Frank (2009) found frequent awake replay of the reactivation process that occurred during slow- sequences of hippocampal place cells in the rat. Th e wave sleep act as a kind of rehearsal, strengthening rats were exposed to two environments (i.e., two the memory in much the same way that ordinary diff erent running tracks) each day, and each envi- conscious rehearsal strengthens a memory (increas- ronment was associated with a diff erent sequence ing the probability that the memory will later be of place cell activity. Th e interesting fi nding was retrieved)? Or did the reactivation instead serve to that during pauses in awake activity in environment render the memory trace less dependent on the hip- 2, replay of sequential place cell activity associated pocampus and, in so doing, protect the trace from with environment 1 was observed (replay of the interference caused by the encoding of new memo- local environment was also observed). Th e fi nding ries in the hippocampus (e.g., Litman & Davachi, that the hippocampus exhibits replay of the remote 2008)? Either way, less forgetting would be (and environment while the rat is awake suggests that the was) observed following a period of reactivation hippocampus may take advantage of any down time compared with a control condition. (including, but not limited to, sleep) to consolidate Th e available evidence showing that increased memory. Th at is to say, the processes that under- reactivation during slow-wave sleep results in lie systems consolidation may unfold whenever the decreased forgetting after a night of sleep does not hippocampus is not encoding new memories (e.g., shed any direct light on why reactivation causes the Buzsáki, 1989). information to be better retained. Evidence uniquely In a two-stage model advanced by Buzsáki favoring a rehearsal-like strengthening mechanism (1989), the hippocampus is assumed to alternate (as opposed to protection from interference) would between what might be referred to as an “encod- come from a study showing that reactivation during ing state” and a “consolidating state.” In the encod- sleep can be associated with an actual enhancement ing state, the hippocampus receives (and encodes) of performance beyond the level that was observed information from the sensory and association areas at the end of training. Very few declarative memory of the neocortex. In the consolidating state, the hip- studies exhibit that pattern, but one such study pocampus sends encoded information back to the was reported by Cai, Shuman, Gorman, Sage, and neocortex. Hasselmo (1999) argued that changes in Anagnostaras (2009). Using a Pavlovian fear-con- the level of acetylcholine (Ach) mediate the direc- ditioning task, they found that hippocampus-de- tional fl ow of information to and from the hip- pendent contextual memory in mice was enhanced pocampus. High levels of Ach, which occur during (in an absolute sense) following a period of sleep both active-awake and REM sleep, are associated whether the sleep phase occurred immediately after with the encoding state, whereas low levels of Ach, training or 12 hours later. More specifi cally, follow- which occur during both quiet awake (i.e., when ing sleep, the percentage of time spent freezing (the the animal is passive) and slow-wave sleep, are asso- main dependent measure of memory) increased ciated with the consolidating state. Th us, according beyond that observed at the end of training. Th is is to this view, the consolidating state is not specifi c a rare pattern in studies of declarative memory, but to sleep, but it does occur during sleep. Critically,

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the encoding and consolidating states are also asso- within the hippocampal-entorhinal output network, ciated with characteristic rhythmic activity, and a and synchronized neural discharges tend to occur basic assumption of this account is that communi- along this pathway during sharp-wave/ripple events cation between the hippocampus and neocortex is (Buzsáki, 1986; Chrobak & Buzsáki, 1996). Th us, mediated by coordinated oscillatory rhythms across once again, rhythmic activity seems to coordinate diff erent structures of the brain (Sirota, Csicsvari, communication between adjacent brain structures, Buhl, & Buzsáki, 2003). and such communication has been found to occur In the encoding state, the cortex is characterized between more distant brain structures as well. For by beta oscillations (i.e., 12 to 20 Hz), whereas the example, ripples observed during hippocampal sharp hippocampus is characterized by theta oscillations waves have been correlated with the occurrence (i.e., 4 to 8 Hz). Hippocampal theta oscillations of spindles in prefrontal cortex (Siapas & Wilson, are thought to synchronize neural fi ring along an 1998). Moreover, the neural replay discussed earlier input pathway into the hippocampus. For example, preferentially takes place during the high-frequency in the presence of theta (but not in its absence), the bursts of spindle waves (Wilson & McNaughton, hippocampus receives rhythmic input from neu- 1994). All of this suggests that rhythmically based rons in the input layers of the adjacent entorhinal feedback activity from the hippocampus may serve cortex (Chrobak & Buzsáki, 1996). In addition, to “train” the neocortex and thus facilitate the pro- Siapas, Lubenov, and Wilson (2005) showed that cess of systems consolidation. When it occurs in neural activity in the prefrontal cortex of rats was the hours after learning, this kind of systems-level “phase-locked” to theta oscillations in the hip- communication presumably involves hippocampal pocampus in freely behaving (i.e., active-awake) neurons that have encoded information and that rats. Findings like these are consistent with the idea are successfully undergoing the process of cellular that theta rhythms coordinate the fl ow of informa- consolidation. If so, then, again, cellular consolida- tion into the hippocampus, and still other fi ndings tion could be regarded as an early component of the suggest that theta rhythms may facilitate the encod- systems consolidation process. ing of information fl owing into the hippocampus. During the high-Ach encoding state—which is a Sleep-Related Consolidation of time when hippocampal synaptic plasticity is high Nondeclarative Memory (Rasmusson, 2000)—electrical stimuli delivered at A novel line of research concerned with the role intervals equal to theta frequency are more likely of sleep in consolidation was initiated by a study to induce LTP than stimulation delivered at other suggesting that sleep also plays a role in the con- frequencies (Larson & Lynch, 1986). Th us, theta solidation of nondeclarative memories. Karni et al. appears to play a role both in organizing the fl ow of (1994) presented subjects with computer-generated information into the hippocampus and in facilitat- stimulus displays that sometimes contained a small ing the encoding of that information. target consisting of three adjacent diagonal bars Lower levels of Ach prevail during quite-awake (arranged either vertically or horizontally) embed- and slow-wave sleep, and this is thought to shift ded within a background of many horizontal bars. the hippocampus into the consolidating state (see Th e displays were presented very briefl y (10 ms) and Rasch, Born, & Gais, 2006). In this state, activity then occluded by a visual mask, and the subject’s along input pathways (ordinarily facilitated by theta job on a given trial was to indicate whether the tar- rhythms) is suppressed, and hippocampal plasticity get items were arranged vertically or horizontally in is low (i.e., hippocampal LTP is not readily induced). the just-presented display. Performance on this task As such, and as indicated earlier, recently induced improves with practice in that subjects can correctly LTP is protected from interference and is given a identify the target with shorter and shorter delays chance to stabilize as the process of cellular consoli- between the stimulus and the mask. dation unfolds. In addition, under these conditions, Th e detection of element orientation diff erences the cortex is characterized by low-frequency spindle in these visual displays is a preattentive process that oscillations (i.e., 7 to 14 Hz) and delta oscillations occurs rapidly and automatically (i.e., no deliber- (i.e., 4 Hz or less), whereas the hippocampus is asso- ate search is required). In addition, the learning ciated with a more broad-spectrum pattern punc- that takes place with practice presumably refl ects tuated by brief, high-frequency sharp waves (i.e., plasticity in the early processing areas of the visual 30 Hz or more) and very-high-frequency “ripples” cortex, which would account for why the learning is (about 200 Hz). Th ese sharp wave oscillations occur extremely specifi c to the trained stimuli (e.g., if the

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targets always appear in one quadrant of the screen such as the sequential fi nger-tapping task (Walker during training, no transfer of learning is appar- et al., 2002, 2003a, 2003b). In this task, subjects ent when the targets are presented in a diff erent learn a sequence of fi nger presses, and performance quadrant). Th us, the visual segregation task is not improves with training (i.e., the sequence is com- a hippocampus-dependent task involving conscious pleted with increasing speed) and improves still memory (i.e., it is not a declarative memory task); further following a night of sleep, with the degree instead, it is a nondeclarative memory task. of improvement often correlating with time spent A remarkable fi nding reported by Karni et al. in stage 2 sleep. Fischer, Hallschmid, Elsner, and (1994; Karni & Sagi, 1993) was that, following a Born (2002) reported similar results, except that night of normal sleep, performance improved on performance gains correlated with amount of REM this task to levels that were higher than the level sleep. However, one aspect of this motor-sequence- that had been achieved at the end of training—as learning phenomenon—namely, the fact that per- if further learning took place offl ine during sleep. formance improves beyond what was observed at Th is is unlike what is typically observed on declara- the end of training—has been called into question. tive memory tasks, which only rarely show an actual Rickard et al. (2008) recently presented evidence performance enhancement. Various control condi- suggesting that the apparent absolute enhance- tions showed that the enhanced learning eff ect was ment of performance on this task following sleep not simply due to a reduction in general fatigue. may have resulted from a combination of averag- Instead, some kind of performance-enhancing con- ing artifacts, time-of-day confounds (cf. Keisler, solidation apparently occurred while the subjects Ashe, & Willingham, 2007; Song et al., 2007), and slept. the buildup of fatigue (creating the impression of Karni et al. (1994) found that depriving subjects less presleep learning than actually occurred). Th is of slow-wave sleep after learning did not prevent result does not necessarily question the special role the improvement of postsleep performance from of sleep in the consolidation of motor-sequence occurring, but depriving them of REM sleep did. learning, but it does call into question the absolute Th us, REM sleep seems critical for the sleep-related increase in performance that has been observed fol- enhancement of procedural learning to occur, and lowing a period of sleep. similar results have been reported in a number of Somewhat more puzzling for the idea that other studies (Atienza et al., 2004; Gais et al., 2000; REM plays a special role in the consolidation of Mednick et al., 2002, 2003; Stickgold, James, & nondeclarative memory is that Rasch, Pommer, Hobson, 2000; Walker et al., 2005). Th ese fi nd- Diekelmann, and Born (2008) found that the use ings have been taken to mean that nondeclarative of antidepressant drugs, which virtually eliminate memories require a period of consolidation and that REM sleep, did not eliminate the apparent sleep- REM sleep in particular is critical for such consoli- related enhancement of performance on two non- dation to occur. Although most work has pointed to declarative memory tasks (mirror tracing and motor REM, some work has suggested a role for slow-wave sequence learning). Th is result would appear to sug- sleep as well. For example, using the same texture- gest that REM sleep, per se, is not critical for the discrimination task, Stickgold et al. (2000) found consolidation of learning on either task. Instead, that the sleep-dependent gains were correlated with conditions that happen to prevail during REM the amount of slow-wave sleep early in the night sleep (rather than REM sleep per se) may be criti- and with the amount of REM sleep late in the night cal. Consistent with this possibility, Rasch, Gais, (cf. Gais et al., 2000). and Born (2009) showed that cholinergic receptor In the case of nondeclarative memories, the evi- blockade during REM signifi cantly impaired motor dence for consolidation does not consist of decreas- skill consolidation. Th is fi nding suggests that the ing dependence on one brain system (as in systems consolidation of motor skill depends on the high consolidation) or of increasing resistance to interfer- cholinergic activity that typically occurs during ence (as in cellular consolidation). Instead, the evi- REM (and that presumably occurs even when REM dence consists of an enhancement of learning beyond is eliminated by antidepressant drugs). the level that was achieved at the end of training. At What consolidation mechanism is responsible the time Karni et al. (1994) published their fi ndings, for sleep-related enhancement of performance on this was an altogether new phenomenon, and it was perceptual learning tasks? Hippocampal replay followed by similar demonstrations of sleep-related discussed earlier seems like an unlikely candidate enhancement using other procedural memory tasks, because this is not a hippocampus-dependent

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task. However, some form of neural reactivation neocortex can reorganize without being disrupted in the cortex may be involved, as suggested by one by input from the MTL. study using positron emission tomography (PET). Specifi cally, Maquet et al. (2000) showed that pat- Reconsolidation terns of widely distributed brain activity evident In recent years, a great deal of attention has during the learning of an implicit serial reaction focused on the possibility that it is not just new time task were again evident during REM sleep. memories that are labile for a period of time; instead, Such offl ine rehearsal may refl ect a neural replay any recently reactivated memory—even one that mechanism that underlies the consolidation of pro- consolidated long ago—may become labile again as cedural learning, but the evidence on this point is a result of having been reactivated. Th at is, accord- currently quite limited. ing to this idea, an old declarative memory retrieved to conscious awareness again becomes vulnerable to Role of Sleep in Creative Problem- disruption and modifi cation and must undergo the Solving process of cellular consolidation (and, perhaps, sys- In addition to facilitating the consolidation tems consolidation) all over again. of rote perceptual and (perhaps) motor learning, Th e idea that recently retrieved memories REM might also be an optimal state for reorganiz- once again become labile was proposed long ago ing semantic knowledge (via spreading activation) (Misanin, Miller, & Lewis, 1968), but the recent in neocortical networks. Th is could occur because resurrection of interest in the subject was sparked hippocampal input to the neocortex is suppressed by Nader, Schafe, and Le Doux (2000). Rats in this during REM, thus allowing for cortical-cortical study were exposed to a fear-conditioning procedure communication without interference from the hip- in which a tone was paired with shock in one cham- pocampus. Consolidation of this kind could facili- ber (context A). Th e next day, the rats were placed tate insight and creative problem solving (Wagner in another chamber (context B) and presented with et al., 2004). In this regard, a recent study by Cai, the tone to reactivate memory of the tone–shock Mednick, Harrison, Kanady, and Mednick (2009) pairing. For half the rats, a protein synthesis inhibi- found that REM sleep, compared with quiet rest tor (anisomycin) was then infused into the amygdala and non-REM sleep, enhanced the integration of (a structure that is adjacent to the hippocampus and previously primed items with new unrelated items that is involved in the consolidation of emotional to create new and useful associations. Th ey used memory). If the tone-induced reactivation of the the Remote Associations Test, in which subjects fear memory required the memory to again undergo are asked to fi nd a fourth word that could serve as the process of consolidation in order to become sta- an associative link between three presented words bilized, then anisomycin should prevent that from (such as COOKIES, SIXTEEN, HEART). Th e happening, and the memory should be lost. Th is, in answer to this item is SWEET (cookies are sweet, fact, was what Nader et al. (2000) reported. Whereas sweet sixteen, sweetheart). It is generally thought control rats exhibited considerable freezing when that insight is required to hit upon solutions to the tone was presented again 1 day later (indicat- problems such as these because the correct answer ing long-term memory for the original tone–shock is usually not the strongest associate of any of the pairing), the anisomycin-treated rats did not (as if individual items. After priming the answers ear- they had forgotten the tone–shock pairing). lier in the day using an unrelated analogies task, In the absence of a protein synthesis inhibitor, subjects took an afternoon nap. Cai et al. (2009) a reactivated memory should consolidate over the found that quiet rest and non-REM sleep did not course of the next several hours. In accordance with facilitate performance on this task, but REM sleep this prediction, Nader et al. (2000) also reported did. Importantly, the ability to successfully create that when the administration of anisomycin was new associations was not attributable to conscious delayed for 6 hours after the memory was reactivated memory for the previously primed items because (thereby giving the memory a chance to reconsoli- there were no diff erences in recall or recognition date before protein synthesis was inhibited), little for the primed items between the quiet rest, non- eff ect on long-term learning was observed. More REM sleep, and REM sleep groups. Th is fi nding specifi cally, in a test 24 hours after reactivation, the reinforces the notion that REM sleep is important treated rats and the control rats exhibited a com- for nondeclarative memory, possibly by provid- parable level of freezing in response to the tone ing a brain state in which the association of the (indicating memory for the tone–shock pairing).

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All these results parallel the eff ects of anisomycin on more persistent in the consolidation group com- tone–shock memory when it is infused after a con- pared with the reconsolidation group. Still, this ditioning trial (Schafe & LeDoux, 2000). What was study adds to a large and growing literature showing remarkable about the Nader et al. (2000) results was that reactivated memories are in some way vulner- that similar consolidation eff ects were also observed able in a way that was not fully appreciated until well after conditioning and in response to the reacti- Nader et al. (2000) drove the point home with their vation of memory caused by the presentation of the compelling study. tone. Similar fi ndings have now been reported for other tasks and other species (see Nader & Hardt, Conclusion 2009, for a review). Th e idea that memories require time to consoli- Th e notion that a consolidated memory becomes date was proposed more than a century ago, but fragile again merely because it is reactivated might empirical inquiry into the mechanisms of consoli- seem implausible because personal experience does dation is now more intense than ever. With that not suggest that we place our memories at risk by inquiry has come the realization that the issue is retrieving them. In fact, the well-known testing complex, so much so that, used in isolation, the eff ect —the fi nding that successful retrieval enhances word “consolidation” no longer has a clear meaning. memory more than additional study—seems to sug- One can speak of consolidation in terms of memory gest that the opposite may be true (e.g., Roediger becoming less dependent on the hippocampus (sys- & Karpicke, 2006). However, a fragile trace is also tems consolidation) or in terms of a trace becoming a malleable trace, and it has been suggested that stabilized (cellular consolidation). Alternatively, one the updating of memory—not its erasure—may be can speak of consolidation in terms of enhanced a benefi t of what otherwise seems like a problem- performance (over and above the level of perfor- atic state of aff airs. As noted by Dudai (2004), the mance achieved at the end of training), in terms susceptibility to corruption of a retrieved memory of increased resistance to interference (i.e., less for- “might be the price paid for modifi ability” (p. 75). getting), or in terms of a presumed mechanism, If the reactivated trace is susceptible only to agents such as neural replay or neural reactivation. A clear such as anisomycin, which is not a drug that is implication is that any use of the word consolidation encountered on a regular basis, then the price for should be accompanied by a statement of what it modifi ability might be low indeed. On the other means. Similarly, any suggestion that consolidation hand, if the trace is vulnerable to corruption by new “strengthens” the memory trace should be accom- learning, as a newly learned memory trace appears panied by a clear statement of the way (or ways) to be, then the price could be considerably higher. in which the trace is thought be stronger than it In an intriguing new study, Monfi ls, Cowansage, was before. A more precise use of the terminology Klann, and LeDoux (2009) showed that contextual commonly used in this domain of investigation will fear memories in rats can be more readily eliminated help to make sense of the rapidly burgeoning lit- by extinction trials if the fear memory is fi rst reac- erature on the always fascinating topic of memory tivated by a reminder trial. For the fi rst time, this consolidation. raises the possibility that reactivated memories are vulnerable to disruption and modifi cation by new References learning (not just by protein synthesis inhibitors). Anagnostaras S. G. , Maren S. , & Fanselow M. S. ( 1999). Temporally-graded retrograde amnesia of contextual fear Much remains unknown about reconsolidation, after hippocampal damage in rats: Within-subjects examina- and there is some debate as to whether the disrup- tion . Journal of Neuroscience , 19 , 1106 –1114. tion of a recently retrieved trace is a permanent or Anderson , J. R. , & Schooler , L. J. 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Neuron , 46 , important variables such as prior learning experi- 799 –810. ence, they found that the anisomycin-induced defi - Bernard , F. A. , Bullmore , E. T. , Graham , K. S. , Th ompson , S. cit on a test of long-term memory was larger and A. , Hodges , J. R. , & Fletcher , P. C. ( 2004 ). Th e hippocampal

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