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Journal of Integrative Neuroscience, Vol. 7, No. 1 (2008) 117–184c© Imperial College Press

Topical Review

THE ROLE OF THE HIPPOCAMPUS IN LONG-TERMMEMORY: IS IT MEMORY STORE OR COMPARATOR?

V. I. KRYUKOV∗

St. Daniel Monastery, Danilovsky Val22 Moscow, 115191, Russia

kryukov@msdm.ru

Received 2 November 2007Accepted 16 January 2008

Several attempts have been made to reconcile a number of rival theories on the role ofthe hippocampus in long-term memory. Those attempts fail to explain the basic effectsof the theories from the same point of view. We are reviewing the four major theories,and shall demonstrate, with the use of mathematical models of attention and memory,that only one theory is capable of reconciling all of them by explaining the basic effectsof each theory in a unified fashion, without altogether sacrificing their individual con-tributions. The key issue here is whether or not a memory trace is ever stored in thehippocampus itself, and there is no reconciliation unless the answer to that question isthat there is not. As a result of the reconciliation that we are proposing, there is a sim-ple solution to several outstanding problems concerning the neurobiology of memory suchas: consolidation and reconsolidation, persistency of long term memory, novelty detection,habituation, long-term potentiation, and the multifrequency oscillatory self-organization ofthe brain.

Keywords: Comparator; Long-term memory; Oscillatory model; Phase-locked loop; Septo-hippocampal system.

1. Introduction. The Basic Questions

The hippocampus has a critical role to play in many forms of learning and mem-ory [44], but the matter of its specific function has been debated for many years,perhaps without “asking the right questions” [208], still presenting “unsolved mys-teries” [96], which is an issue that is “desperately seeking resolution” [212]. One ofthe influential theories is based on a hypothesis that treats the hippocampus as astorage place for spatial information, while some other theories maintain that it isresponsible for declarativea/relationalb memory [47, 49]. There are also many other

∗Alias: Hegumen TheophanaThe conscious recollection of facts (semantic memory) and episodes (episodic memory).bThe recollection of relationship between different internal representations.

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important theories and hypotheses, where a recent review of them can be found in[45, 90, 160, 177, 178]. The following questions are compiled from current literaturewhich we believe must be resolved from a single point of view if we are going tounderstand the role of the hippocampus in long term memory.

(1) “The basic tenet of the cognitive map theory, that the processing and stor-age of spatial information is the primary and perhaps the exclusive role of thehippocampus in the rat” [192, p. 352]. Is spatial mapping a primary role ofthe hippocampus, or does it have a more general role in memory. “Is it spatialmemory, or memory space?” [49].

(2) “Spatial and object information may be linked together in memory in the hip-pocampus, and perhaps in the entorhinal cortex” [150, p. 1400]. How and wheredoes the hippocampus link spatial and non-spatial information? [235].

(3) “Hippocampal memory can, like other forms of memory, be divided into fourprocesses: encoding, storage, consolidation, and retrieval. We argue that synap-tic plasticity is critical for the encoding and intermediate storage of memorytraces that are automatically recorded in the hippocampus” [174, p. 773]. Issynaptic plasticity in the hippocampus critical to specific memory formation, ordoes it play a less specific supporting role? [147].

(4) “Semantic memories . . . can be retrieved independently of the hippocampus.Even semantic memories, however, can have episodic elements associated withthem that continue to depend on the hippocampus” [177, p. 35]. Is there a cleardistinction between the treatment of episodic and semantic information in thehippocampus? [237,238].

(5) “The question of what it is that physically persists in long-term memory is fun-damental, yet it is infrequently discussed explicitly in neurobiological literature.It is futile to try to understand consolidation,c or the possibility of reconsolida-tion without addressing the issue of persistence” [45, p. 78].

(6) “How, for how long, and what type of memory is stored in the hippocampus?”[95].

We consider the last question as the most important of all, because it definesthe specific theory that should be used to answer all of the remaining questionsfrom a single point of view. In this respect, there are four major theories or ratherhypotheses that relate to memory in the hippocampus: The Cognitive Map The-ory [194], which asserts the primary role of the hippocampus is processing andstoring spatial information; the Standard Consolidation Theory [1], which claimsthat the hippocampus does not accommodate long-term memory, but serves as atemporary store for declarative memory for a certain period of time required forthe consolidation of such memory; the Multiple Traces Theory [183], which arguesthat the hippocampus is indeed a place of long-term storage, although not for the

cThe progressive post-acquisition stabilization of the engram.

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entire declarative memory, but for some part of it, i.e., the neocortical index or thememory location, and the Theta-Regulated Attention Theory [260], which explicitlyregards the neocortex, but not the hippocampus as the storage place for all forms ofmemory. Obviously, all four are in conflict with respect to the last question, althoughnot necessarily so with the remaining questions. We omit many other hippocampaltheories (e.g., [145], and his numerous followers reviewed in [215]), because they aregenerally not so influential now, and are often incorporated with the above majortheories.d

Several attempts have been made to bridge the gaps between some of thesedifferent theories, and to develop a unified, or at least, a preferable theory for mem-ory and the hippocampus [47,49,66,115,160,169,173,174,177,178]. However, theseattempts according to Holscher [90], are flawed two fold [90] (i) in the first place,each of them leaves out or ignores any data that are at variance with its logic, and(ii) isolates the hippocampus from the larger system — of which it is an integralpart — and ascribes special functions to every anatomical regions of the brain,regardless of the extensive evidence in favor of them being parts of one functionalsystem.

Under these circumstances, any effort to resolve the problem of the role played bythe hippocampus in memory function is bound to run into an impasse, mainly due tomultiple interpretations of the same data, as pointed out in [115]. This impasse in ouropinion is contrary to the general belief that may not be overcome without furtheramassing of experimental data, and without using a unified neural net model to solvethe main question on memory in the hippocampus. This paper at first will carefullydwell on the main assumptions, supporting data, predictions, and problems of eachof the four major theories on the hippocampal role in memory, and then present aunified model and explain their characteristic effects. In hindsight, we are comingto the conclusion that it is the only one of these theories that is capable, in somesense, of reconciling all of them, and coherently resolving the above six questions.These issues in preliminary form have been presented at the above internationalsymposium [95], and in the resulting short review [88].

2. The Cognitive Map Theory

According to this theory, “there exists at least one neural system which providesthe basis for an integrated model of the environment. This system underlies thenotion of absolute unitary space, which is a non-centerd stationary frameworkthrough which the organism and its egocentric spaces move. We shall call the sys-tem which generates this absolute space a cognitive map, and will identify it with

dFor example, Marr’s [145] archicortical theory is incorporated into a Standard Consolidation Theory; Teylerand DiScenna’s [252] “indexing theory” is considered in [176] as a particular case of Multiple Trace Theory;Gray and McNaughton’s [70] septo-hippocampal theory is rooted in the Theta-Regulated Attention Theorywhere the idea of the hippocampus as a comparator was admittedly borrowed by them from [259, 260]; formore about this priority question see [157, pp. 241–242]. For the earlier theories of hippocampus see [96].

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the hippocampus . . . It permits an animal to locate itself in a familiar environmentwithout reference to any specific sensory input . . . . The left hippocampus in humansfunctions in semantic mapping, while the right hippocampus retains the spatial map-ping function seen in infra-humans . . . The hippocampus is integral to the long-termstorage of locale information, which gives this structure a central role in memorymechanisms” [194, p. 1–3, 377].

A vast number of experiments have been carried out based on the assumptionsand predictions of this theory, and extensive modeling work has been done in anattempt to understand the main spatial effects associated with this theory and itslatest modifications. We shall refer to merely two characteristic effects which haveto be explained by any neural model describing the hippocampus functions, and itscontribution to the formation of long-term memory.

2.1. The effect of the place cell [194]

The hippocampus of a rat has locale-specific cells which become vigorously activepredominantly when a rat enters a certain enclosed space referred to as the placefield. Activation of place cells outside this field is a rare occurrence. These cells arecharacterized by the following general properties:

Non-directivity. In cylinder-shaped apparatuses, place cell firing depends only onthe position of the rat’s head, and is virtually independent of the direction in whichthe head is pointing [179].

Remapping. With a change of environment or internal conditions, place cells arecapable of simultaneous alteration of their firing patterns. The place fields of thosecells that are active in both the original and changed environment are generallyunrelated to each other [179]. There is no topological relation between the anatomicallocation of the cells within the hippocampus, and the place fields of these cells in anenvironment [196]. Some animals can do spatial tasks, despite complete place cellremapping [97].

Stability. A place field is normally stable for at least a half of an hour, even in dark-ness, and its long-term stability required for successful spatial tasks of performanceis correlated with the degree of attentional demands, defined as the relative timeduring which the animal pays more attention to spatial cues than to other aspectsof its sensory experience [109,111].

Dual code. The firing rate and the place cell spiking time, related to the concurrentcycle of the hippocampus theta rhythm of electroencephalogram (EEG), will varyas the rat moves through the place field, with the former showing a non-monotonicchange and accounting more for the speed of the animal’s movement, and the lattershowing a monotonic decrease of the phase precessing being indicative primarily ofthe current location of the animal in the place field [94]. Both codes, however, canoccur in both spatial and non-spatial behaviors of the rat [79], and can be highly

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correlated [79, 162], as well as independent [193]. Theta phase precession persistsafter the transient intrahippocampal perturbation [279], and is also found in theprefrontal cortex [101] as well as phase-locking [233].

Directionality. A place field is asymmetrical, and depends on the ambient conditionsand direction of the rat’s movement. It will rotate in synchrony with the rotation ofthe key environmental inputs (cues) [208], or to be more precise, spatial rotationsof the cues give rise to roughly equal rotations of the associated space-dischargecorrelations [179]. The fields recorded in the brain of a rat running along a lineartrack will get longer with experience, and extending in the backward direction oppo-site to the animal’s movement [161]. In contrast, the forward shifting of the firingfields of spatial representations towards prospective reward location occur graduallywithin a recording session, during which there were no changes in task demands orenvironmental cues [127]. No directionality will arise in case of free behavior of a ratin an open field [207, p. 108–109].

Multimodality. Under certain conditions, place cells respond to sensor inputs ofvarious modalities. Thus, upon fear conditioning, place cells will respond to acousticconditional signals, but will do so only when the rat is within the place field of thesecells [169]. However, a conditional signal may induce remapping, even when theenvironment itself remains unchanged [170].

2.2. The effect of viewpoint [112]

Bilateral hippocampal pathology (in the case of Jon) caused massive impairment ofthe ability to recognize objects when tests were performed from a shifted viewpoint,as compared to a mild impairment with testing from the same viewpoint. With theviewpoint unchanged, the patient showed moderate recognition impairment, whichwas dependent on the length of the list of objects to be recognized. In the absenceof pathology, recognition latency was small, and a linear function of the angulardistance between the test view and the study view [41].

2.3. Reservations

Originally, the theory was centerd on the assumption that the hippocampal placecells were the neural substrate for the cognitive map. A later statement made aweaker point to the effect that the hippocampus stores allocentrice representationof spatial locations [21], or of “where” of episodic memory [109], or even that it is notthe hippocampus proper, but the whole hippocampal system in the medial temporallobe (MTL) that stores the spatio-temporal context of events [112, 182, 186]. Thediscovery of the entorhinal grid cells [74] as an essential part of spatial representationstrongly suggests that the cognitive map is distributed across at least two, and likelymany more different structures [116, 193]. “The place cells code not place per se,

eRepresented in world-based coordinates rather than in body-centred, or egocentric coordinates.

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but rather a more elaborate conjunction of cues (both spatial and non-spatial),which . . . may form the substrate for episodic memory. This then leaves the questionof whether there is a region of the brain which truly houses a “cognitive map” inthe O’Keefe and Nadel sense of the word, or whether the spatial representation isdistributed across so many structures that it cannot really be called a “map” atall” [97, pp. 35–36]. “The extreme cognitive map hypothesis of a unitary, purelyspatial, hard-wired Cartesian map restricted to a navigational system seems to havedied the death of a thousand cuts: e.g., it is not unitary, sensory firing correlatesclearly can occur both with and without regard to location, and place cells appearto encode routes more than a map . . . ” [109, p. 752].

As to the storage of spatial information in the hippocampus itself, at least aspart of an episodic context, one of the authors of the Cognitive Map Theory hasrecently admitted: “It remains unclear whether this contextual trace is stored inthe hippocampus itself, as O’Keefe and Nadel originally supposed, or is it insteadstored in parahippocampal regions, as some recent data might suggest” [186]. Thisrecent data suggesting the absence of context storage in the hippocampus is foundin Hayes et al. [83]: it is the parahippocampal region, rather than the hippocampusthat is primarily involved in the processing and retrieval of locale information. Theabsence of a spatial map in the hippocampus is confirmed by Maviel et al. [149].As maintained in that paper, the hippocampus is but temporarily involved in theformation of a spatial map in the prefrontal and cingulate cortices. So, it still remainsprobable that the hippocampus may store spatial or context information for sometime, until the memory consolidation in the neocortex is complete. To assess it as apossibility, we shall examine in some details two major theories of long-term memoryconsolidation in next two sections.

3. The Standard Consolidation Theory

Unlike the previous one, this theory maintains that the hippocampus is involvedin the formation of both spatial and non-spatial declarative memory, but it is notthe ultimate memory store; together with the neighboring structures of the MTL,it performs the functions of interim buffer storage [1,243], which supposedly settlesthe well known theoretical problem of connectionism, referred to as the problem ofcatastrophic interference.f As assumed by the Standard Consolidation Theory, thehippocampus and the adjacent structures are free from this shortcoming; they takein new information in an online mode and transfer it gradually to the neocortex,presumably during sleep, or else are involved in the fairly long restructuring of theneocortical network, and with time, will eliminate the need for the hippocampus.The process of information transfer from the hippocampus to the neocortex, or the

fThe latter lies in the following: the associative neural network with modifiable synaptic links, formingmemory cells (attractors) in the neocortex, proves incapable of quick learning, and suffers catastrophicdeterioration when new information comes shortly after the initial learning. Rapid alterations of the synapticweights have the effect of eliminating the information previously stored in the neocortex [153].

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associated memory restructuring, is referred to as consolidation in this theory. Tobe more precise, the key assumptions of this theory were worded as follows [1]:

(1) The critical event for the formation, maintenance, and retrieval of long-termdeclarative memory is an interaction between multiple geographically separatedareas of neocortex, and the structures of the MTL, including the hippocampus,and the adjacent regions.

(2) Within the neocortex, the key event in consolidation is the gradual bindingg

together of the multiple geographically disparate cortical regions, that together,store the representation of a whole event. This gradual linking is the biologicalsubstrate of consolidation.

(3) The MTL learns quickly, but has a limited capacity. The neocortex learns slowly(i.e., disparate regions become bound together slowly), and has a large capacity.In both cases, learning proceeds according to the same simple (Hebbian) rulesfor changing the synaptic strength.

(4) Consolidation occurs when neural activity within the MTL coactivates separateregions of neocortex. These areas of neocortex are initially linked only weakly,but become more strongly connected as a function of repeatedly being acti-vated simultaneously by the MTL, and gradually become independent of thehippocampus.

From these assumptions follows the main prediction that the hippocampus,together with the adjacent MTL regions, are involved in the formation and replay oflong-term memory for a relatively short period of time after learning, until consoli-dation is completed, and that the hippocampus is not needed for retrieval of remotememory. While findings in several cases of amnesic patients support this hypothe-sis [9], it is not always consistent with experimental data for rats [31, 32, 243] andhealthy humans (refer, e.g., to the effect of age independence in Sec. 4.1). Nev-ertheless, this theory purports to explain the following, most puzzling, effect ofmemory [240,242].

3.1. The effect of retrograde amnesia (RA)

A lesion in the human hippocampal system, and its associated neocortical structures,caused by injury, surgery, neural degradation, or use of amnestic agents results in aloss of memory of the events that preceded such damage. In such a case, the memoryloss with time, which is established by special tests, has one of the following patterns:

The RA gradient arises in a large number of RA cases, and is characterizedby a greater loss of the traces immediately preceding the hippocampus lesion, as

gBinding is one of the outstanding, still unresolved, problems in neurosciences. In a restricted sense, thebinding is the phenomenon, or process, in which representational elements fuse into a coherent internalrepresentation. Synaptic binding, as stated here, is a particular case of this general definition. Anotherimportant particular case is the dynamic binding through local synchronization of cortical oscillations. Stillanother case of global binding-synchronization will be described in Secs. 6.2 and 7.3. Their merits andlimitations are described by Theophan [86] in the context of sensory integration.

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compared to the earlier traces [3, 10, 18, 28, 59, 181, 240, 242], and in rats this is alsotrue in the event of complete hippocampal lesions [30,270].

The reverse RA gradient occurs in cases of semantic dementia, and is charac-terized by the fact that the recent personal memory remains relatively intact, whilethe earlier memories of one’s life are lost [68,118,189,199].

Flat RA arises in the event of large lesions in the hippocampus, when the inabilityto recall the pre-injury information spans almost the whole life of the patient [29,59, 239]. Similar findings resulted from experiments with rats, [148] and referencestherein) even for partial lesions.

Reminder RA arises as follows. Application of amnesic agents (for animals, e.g.,an electric shock, hypothermia, inhibition of protein synthesis, selective hippocampallesion) shortly after reactivation of old traces by giving a “reminder” of the trainingsituation results in RA of these traces, regardless of their age, notably, no RA willarise without such a reminder [164,165,210].

3.2. Reservations

The Standard Consolidation Theory accounts for all these cases, except flat RA andreminder RA, by the fact that patients were affected by amnestic agents either beforeor after the consolidation was completed, which means that it is the interruption ofconsolidation at different stages that is responsible for various degrees of memoryimpairment. One of the fundamental problems with such an explanation lies in thefact that the existence of extensive RA, sometimes covering decades [18,59], stronglysuggests that physiological consolidation is also a very long process [118]. This, inturn, raises the difficult question of Nadel and Moscovitch [183] as to “why suchprocesses should take 25 years”, i.e., the question of biological significance for suchprolonged consolidation.

Another problem arises from interpretation of flat RA [3, 59, 181], as this caseappears to suggest that the hippocampus is needed to recover the traces for as longas they exist. On the other hand, the Standard Consolidation Theory predicts thatthe hippocampus is involved in consolidation for only a limited time, and makesa shot at explaining the flat RA phenomenon by possible lesions, either in theparahippocampus or in other structures outside the MTL. Thorough investigationshave testified against this possibility. So, Cipolotti et al. [29], and Chan et al. [28]demonstrate that flat RA occurs in the case of isolated lesions in the hippocampus,with the neocortical structures left totally intact. In fact, the phenomenon of flatRA falsifies the Standard Consolidation Theory [160].

Furthermore, this theory predicts that damage to the hippocampus results inequivalent damage to episodic and semantic memory in RA [241, 243], which issupported by some evidence [144], whereas many other findings run counter to thisassertion (refer to the effect of dissociation discussed in Sec. 4.2).

Finally, the most serious difficulty, in our opinion, lies in the fact that in var-ious cases, the learning dynamics in the hippocampus and neocortex, contrary to

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assumption 3, have similar, rather than different time scales [35, 149,278], and hip-pocampal activity sometimes is delayed relative to the neocortical one [75,99]. Thisevidence is a formidable challenge to the idea of buffer memory in the hippocampus.

We believe that all of these problems result from the oversimplified model ofthe consolidation process in this theory which identifies it with the binding process,whereby the cortical memory gradually acquires independence from the hippocam-pus through Hebbian modification of synaptic strength [240]. In fact, the consoli-dation process is far more complicated, as may be inferred from following data nothaving, as yet, a model explanation.

3.3. The consolidation effect

Frugality/Robustness

The recent memory is frugal i.e., it can be disrupted when superimposed with newinformation, or when electric shock or other amnestic agents are applied after theinitial learning, but it becomes more robust with an increase in the time before newtraining, or before an amnestic manipulation. The activation of the amygdala andother structures involved in emotional arousal play a modulatory role in consoli-dation, whereas the hippocampus and the central cholinergic system are of crucialimportance for this process [81,155,202].

Selectivity

Mutant mice with NMDA (N-methyl-D-aspartic acid) receptor deletion restricted tothe hippocampal field CA3 pyramidal cells have enlarged CA1 hippocampal placefields in a novel environment (their spatial selectivity being impaired), as comparedto those of control mice. In a familiar environment, their place fields are of normalsize. But enlarged CA1 hippocampal place field becoming of normal size, and suchrecovery takes one day with the improvement of spatial representation achievedwithout a continuous supply of external cues [188].

Graduality

The majority of hippocampal CA1 place cells in normal mice running for food rewardin a highly familiar track generated spike discharges in phase with the positive peaksof hippocampal theta rhythm (in fact there is phase precession of the spike withrespect theta), but reversed their mean phase of activity by almost 180 degreesfrom the wakeful state to the subsequent rapid eye movement (REM) sleep. Whenan animal was subjected to repeated experiences in the familiar and novel portionsof the track for seven days, the phase of activity in REM sleep was reduced toa much larger extent, as compared to wakefulness showing gradual phase changesfrom near-zero to almost 180 degrees [201]. Takashima et al. [248] also found that bychanging familiar and new portions of input information evidence for rapid systemconsolidation of declarative memory in humans that lasts three months.

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Association

If a conditioned stimulus (CS, a sound of certain frequency) paired with an uncondi-tioned stimulus (US, electric shock or stimulation of nucleus basalis) is applied to aguinea pig, its conditioned reflex (a change in heartbeat rate or respiratory rhythm),in the absence of additional training, becomes stronger through consolidation. “Therate of consolidation was directly related to the pre-training frequency distance (themagnitude of difference between the CS and best frequencies) and to the strengthof response to the CS; cells that were tuned closer to the CS, and therefore weremore responsive to it, completed their tuning changes within one hour, whereas cellsthat were tuned to more distant frequencies, and so were less responsive to the CS,required three days to complete their tuning shifts. These findings seem to be thefirst direct observation of long-term neural consolidation in memory” [267, p. 281].

4. The Multiple Traces Theory

This theory is based on the following key assumptions [59,183].

(1) Any information committed to memory and consciously perceived will quicklyand automatically set up distributed binding codes in the hippocampus, whichwill be employed for feature integration in the neocortex.

(2) All these binding codes, together with traces distributed over associative regions,form a memory trace of specific events.

(3) Binding codes in the hippocampus serve as pointers, or indexes, to the neocor-tical elements used to encode the detailed content of the experience.

(4) Every time memory is reactivated in the process of retrieval, a newly encodedtrace will be automatically set up in the hippocampus in a new neural andexperimental context.

(5) The inputs will be either recovered and enhanced on by repetition, or will be lostgiven infrequent repetition. The older the memory, the more codes will be storedin the hippocampus and the associative cortical region, and the less susceptibleto damage they will be.

This theory was developed as an alternative to the Standard Consolidation The-ory to eliminate primarily two of its shortcomings [183]: (1) the biologically implausi-ble protracted period of time required for memory consolidation, and (2) its makingno distinction for the purposes of consolidation between episodic and semantic mem-ory, nor between retrograde amnesia (RA) and anterograde amnesia (AA). The firstshortcoming is dealt with theoretically by postulating that the cortical-hippocampalcomplex can bind together any memory elements within a short period of consoli-dation, typically lasting seconds or minutes, but not more than a few days [59,175].The RA gradient is accounted for by the fact that the old traces extensively rep-resented in the hippocampus show greater resistance to damage than the morerecent ones [181]. Flat RA, i.e., gradient-free RA, is interpreted by this theory as a

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consequence of complete damage to the hippocampal complex [59, 183], which wasactually confirmed by subsequent experiments [29].

The second shortcoming seems to be eliminated as well on account of the aboveassumptions (1–5), and due to the naturally low rate of occurrence of episodic infor-mation as compared with semantic information, which leads according to Rosen-baum et al. [217], to greater stability of semantic traces in cases of hippocampaldamage in comparison with episodic traces, and on the other hand, to a continuousneed for the hippocampus to record and replay past episodic information. The latterwas repeatedly checked and confirmed by means of functional magnetic resonanceimaging (fMRI), which is a fact that will be viewed below in Sec. 4.1 as an essentialprediction of this theory.

4.1. The effect of age independence

With healthy normal people, the extent of fMRI activation of the hippocampusshown by scanning with simultaneous recollection of past episodic and autobiograph-ical events, is independent of how remote the recalled events may be, even if theyoccurred 25 to 40 years prior to scanning [11,42,62,140,151,185,198,219,244,245].At the same time, there are instances of both a decreased activation [76, 191, 195]and a increased activation [200,209], and we even know of a case when the right hip-pocampus showed activity increase with the memory age, while the left hippocampuswas invariably active throughout the lifespan [137]. A similar phenomenon is alsodescribed by in [42].

Independence of the hippocampal activity from the memory age is interpreted bythe authors of Multiple Memory Traces Theory as evidence in favor of the assump-tion that binding codes of long-term episodic memory are accumulated and stored inthe hippocampus, or at least in the hippocampal complex, and serve the purpose ofreproducing this memory in the associative cortical regions [175,181,184]. As regardsthe site of semantic memory storage, it is usually assumed to be found outside ofthe hippocampus in different regions of the brain, depending on the type of informa-tion [138], mostly in the left temporal lobe [119, 146, 189, 224]. In their discussions,the advocates of this theory often argue that semantic information can be repro-duced without the aid of the hippocampus (see, e.g., [139]) which, however, may berequired, but only for recording this information [167]. In fact, the situation is morecomplicated, as may be seen from the effect of episodic and semantic dissociation.

4.2. The effect of E/S dissociation

Hippocampal damage in humans affects both episodic (E) and semantic (S) memory[7, 8, 89, 144, 241]. But, episodic memory is affected more frequently and to a largerextent in the event of bilateral damage to the hippocampus [166, 239], as well asin cases of Alzheimer’s disease [27] in healthy aged people as well [130, 198]. Atthe same time, there is some evidence of selective damage caused either to episodic

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memory [129,141,156,216,246,255,256], or when the left hemisphere is affected, tosemantic memory [69,71,180].

4.3. Reservations

The first to be mentioned among them is the fact that complete lesions of the hip-pocampus — contrary to the assertions of the theory — may give rise to RA gradient(refer, e.g., to [270]). For this reason alone the theory in question, according to someanalysts (e.g., [160]), is falsified, and it should be abandoned. In testimony to thesame is the absence of correlation between the hippocampus volume and the degreeof memory loss [120], although such a correlation exists for the entire MTL vol-ume [63]. We think that unless the assumption of memory storage in the hippocam-pus is given up, this theory will not be reconciled with the Standard ConsolidationTheory, as they both should be rejected, and some researchers have already done soon the strength of their findings (refer, e.g., to [51] and [120]), although the synthesisof their ideas are continuing, e.g., [174], [173], [35].

Secondly it is important to note that the failure to explain the dissociation ofepisodic and semantic memory by the different extent to which the correspondingtraces are accumulated in the hippocampus: in the process of consolidation, seman-tic memory should be independent from the hippocampus [185], and at the sametime, due to frequent repetition, its binding codes are overwhelmingly more numer-ous there, than those of episodic memory. Even if it is assumed that such semanticinformation can somehow transform itself in the neocortex to be free from context,it is yet to be demonstrated why the continued accumulation of old semantic tracesin hippocampus will not interfere with accumulation and consolidation of new, espe-cially episodic, traces; numerical estimates [272, p. 645] show that the hippocampalstorage capacity, in terms of the number of its pyramidal neurons, is very limitedand overloading is inevitable. An attempt by the authors of the Multiple TracesTheory to get around this difficulty by introducing ad-hoc assumption concerningthe limited number of the oldest traces [185] is actually an assumption about thelimited time for the reactivation of traces in the hippocampus, which may be viewedas an admission of the theory’s failure in its key proposition. Indeed, as remarkedwith good reason in Meeter and Murre [160, p. 851], the previous question of “Whyconsolidation processes should take 25 years” has now changed to “Why shouldreactivation take 25 years?”.h

Third in significance is the theory’s failure to explain the co-existence of strongAA with short-term or mild RA [119], especially mild RA for semantic information[152], and of extensive RA with weak AA [59], let alone other important cases,

hThe recent modification of the Multiple Trace Theory [176,177] assumes two types of semantic memories,with only one of them being hippocampus-depended, thus it seems to be relaxing the above criticism. Thismodification, although supports new data, it is another ad hoc assumption of the Multiple Trace Theory.

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discussed below, without which it is difficult to understand the mechanism of long-term memory.i

4.4. The effect of AA/RA dissociation

Bilateral hippocampal lesions, caused by injury or surgery, in most cases lead to AA.The latter phenomenon is essentially a total inability to retain new information, withshort-term memory and attention seem remaining intact, which means an almostcomplete loss of memory of the any facts and events occurring after such damage.In this case, memory of all the pre-injury events is partly lost (RA, see Sec. 3.1). Adescription of the following specific cases of AA and RA correlations may be foundin the following literature.

Positive correlation

The stronger is AA, the more extensive is RA [30,240].

Disproportion

Strong AA is accompanied by short-term or mild RA [118,119,152,183]; new associa-tions are disproportionally impaired as compared to the memory of single items [64].

Focal RA (FRA)

Extensive RA co-exists with relatively mild AA [51, 59, 118, 142, 229, 246, 268] Mostcommonly, episodic RA is more extensive than semantic RA, but “pure” cases havealso been observed [268].

Transient General Amnesia (TGA)

After a minor injury or emotional stress, AA disappears quickly while RA persists,but it will not take long (a day to several months) before both are gone [234]. Thereverse situation is also observed: RA is the first to disappear followed by AA slowlypassing off [72, 103]. In this case, episodic memory suffers the most, while semanticmemory is recovered earlier.

5. The Theta-Regulated Attention Theory

On the strength of analysis of multisensor data from hippocampal and other relevantstructures in animals, Vinogradova [260] came to the following conclusions whichwe take as the key assumptions of the Theta-Regulated Attention Theory.

iNotably, the above three major flaws of the Multiple Traces Theory are also found in many other modifica-tions of the Standard Consolidation Theory, which rely on the premise that the hippocampus is a permanentor intermediate storage place for memory traces (e.g., [35, 173,174,231,271]).

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(1) The hippocampus is actively involved in the processes of two morpho-functionalcircular limbic subsystems: the regulatory (CA3 field-based) and informational(CA1 field-based) subsystems, which jointly perform the functions of attentionand initial fixation of memory traces.

(2) The CA3 field is responsible for the relatively simple functions of determining thematch/mismatch of signals appearing at its two — reticulo-septal and cortical —inputs, and of sending the mismatch signals to the brain-stem structures whichgovern arousal.j In a constant environment CA3, keeps the arousal system underinhibitory control.

(3) Given an input mismatch, when this inhibitory control is released, the first to beformed is the orienting reaction, an adaptive form of behavior providing optimalconditions for perception, followed by selective attention to a novel stimulus, andfinally by the initial fixation of information on this stimulus.

(4) With the mismatch between the two inputs gone, i.e., when the initially absentcortical signal appears as the hippocampal input with a certain time lag relativeto the reticuloseptal input, the high arousal caused by the reticular formationdeclines to the background level, and the whole system reverts to its originalcondition in anticipation of a new stimulus.

(5) Every new stimulus which is capable of triggering theta-rhythmic activity of themedial septum (Sm) evokes tonic inhibition in most pyramidal neurons of theCA3 field (the so-called inhibitory reset), thereby releasing reticular formationfrom inhibitory control. The state of novelty associated with the arrival of thetheta-modulated signal at the reticuloseptal input of the CA3 field will last untila signal comes from the cortex, upon a certain delay, to confirm that fixation oftraces have been completed.

(6) Once the theta-rhythm is triggered by a stimulus, no other signals will reset theongoing rhythmic process, nor will they gain access to the processing mecha-nisms of the hippocampus. If a familiar stimulus appears after some time, theinitial process involving the responses of CA3 neurons, arousal and orientingreaction, may occur again. However, it will be stopped immediately, as the cor-responding cortical signal will have been already shaped and rapidly appear atthe system’s input.

(7) The CA1-based information subsystem serves as an integrator and a delay linepreventing rigid fixation of spurious, irrelevant, and low-probability signals. Theresponses in the output parts of this subsystem may be regarded as an ultimatesignal for recording information in the multiple areas of the neocortex. The CA1field itself serves as an AND-gate for cortical inputs during the state of novelty,and is under the shunting or inhibitory control of the CA3 field.k

jA general excitation of the brain resulting in optimal condition for orienting and information processing.kThis assumptions unlike the previous ones are presented as a neuronal implementation rather than postu-lates of theory just to stress that our model as described in Sec. 8 is mainly a mathematical description ofVinogradova’s [258,260] theory and implementation.

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Thus, the hippocampus, as a part of the septo-hippocampal system, triggers, reg-ulates, and then terminates the process of locking the neocortex and hippocampusin synchrony but as it follows from the above assumption, it will not accommodatelong-, intermediate-, or short-term memory, thus serving merely as a structure essen-tial for the formation of such memory. The main prediction, or rather consequence,of this theory lies in the following: the hippocampal system is indispensable forarrangement of selective perception and suppression of irrelevant information, forhabituation to invariant signals, and for the detection of novel or significant changeswhich should be recorded in memory [260, p. 596]. Two major effects central to thistheory are described below.

5.1. The effect of novelty

Practically any stimulus, provided it is a novel one, will result in a prolonged tonicresponse of the hippocampal neurons in the CA3 field. The signal will first appearat the reticuloseptal input and will take some time before it appears at the neo-cortical input to the hippocampus, whereupon it will lose its quality of novelty.When exposed to a new stimulus, most pyramidal neurons of the CA3 field show aninhibitory reaction timed with the initiation of theta oscillations in the medial sep-tum [260]. The critical role of CA3 field in novelty detection was recently confirmedby Lee et al. [126] (but see [80] and [133]). The following aspects of effect of noveltyare described in the literature.

Distribution

Apart from the hippocampus, neurons that are responsive to novelty are also foundin structures of the limbic system and associative cortex [73,117,277].

Colocalization

The novelty-sensitive prefrontal and temporal regions predict (according to fMRI)whether an event would be subsequently remembered, which suggests the colocal-ization of novelty and memory mechanisms in these cortical structures [114].

Separability

Two large-scale non-overlapping neural networks defined in terms of the coherentactivity of their components come into action to process separately a new and afamiliar stimulus, respectively. The hippocampus is involved in the operation ofboth networks, as it is their only shared structure [73].

5.2. The effect of habituation

On recurrence of new stimuli, the pyramidal neurons of the CA3 field get graduallyhabituated to these inputs, easing the inhibitory responses and regaining the orig-inal high background activity. Integrity of both hippocampal inputs (cortical and

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reticulo-septal) are essential for gradual habituation to sensory responses. Recur-rence of a stimulus or stimulation of the fascia dentata causes sustainable (for 12hours or more) long-term potentiation (LTP) of responses from pyramidal neuronsin a certain area of the CA3 field, which blocks the neural reaction to novel inputs.Outside this area, the normal reaction to sensory signals is retained [16,260,262].

Dehabituation

The habituated responses are recovered with any changes in the parameters of signalor electric stimulation of the reticular formation [16,260,262].

Colocalization

Besides the hippocampus, as shown by fMRI data, habituation occurs in the samebrain regions where responses to novel inputs and memorizing processes take place(in the medial and inferotemporal cortex bilaterally, in the right amygdala andprefrontal cortex) [57,277].

Specificity

When a stimulus is repeated, responses will persist for a long time in the core systemof the stimulus, e.g., in the fusiform and cingulated cortex with attentive perceptionof geometrical figures or human faces [82,277].

Rapid habituation

Prefrontal and hippocampal responses to novel stimuli, unlike those in other brainregions, are rather rapidly habituated with the time course of this habituation beingroughly similar both with attended and unattended novel stimuli [277]. The latter,in the opinion of the authors, supports the view that prefrontal and hippocampalregions are key elements in rapid automatic detection of unexpected environmentalevents.

Desynchronization

Successful retention of information in learning is accompanied by initial enhance-ment of gamma synchronization between the hippocampus and the entorhinal cor-tex, followed by desynchronization [55]. Similar initial synchronization and laterdesynchronization during object recognition in the neocortical gamma-rhythmregion were reported by Rodriguez et al. [213]. The same phenomenon in the theta-rhythm range was described by Raghavachari et al. [203].

5.3. Reservations

The main objection against the Theta-Regulated Attention Theory, or more cor-rectly, against absence of memory in hippocampus is that “some explanation must

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be offered for why the hippocampus is critical in memory retrieval, and hence per-formance, even though the memory trace is always stored elsewhere” [181, p. 57].Another objection is that novelty is computed in the CA3 hippocampal region“based on a comparison between the inputs from the dentate guris and the inputsfrom the medial septal nucleus. This hypothesis, however, poses a difficulty; evenVinogradova claims that septal responses are usually polimodal. If this is correct,then a CA3 comparator could not use septal information to decide whether incominginformation is novel or not” [134, p. 37].

Still another difficulty is that the principal author of the Theta-Regulated Atten-tion Theory is also a co-author of an oscillatory model of novelty detection [15], whichassumes that the hippocampus is a temporary store of memory. We cannot explainthe resulting discrepancy between the Theta-Regulated Attention Theory and thatmodel. Nor can we use alternative oscillatory models (e.g., [13]) for uniform expla-nation of the effect of novelty and other memory effects because all such models aredeterministic, and either place the memory into the hippocampus, use the Hebbianlearning algorithm, or both.

However, the greatest difficulty of the Theta-Regulated Attention Theory liesin the way it might be used for explaining the main effects of long-term memorydescribed in Secs. 2–5. Without such explanation, the comparator function of thehippocampus in long-term memory would be another hippocampal theory on thestack of already so many. This issue is described at greater length in Sec. 9.

6. Attention as Basis for Reconciliation of Concurrent Theories

6.1. The logical ground for possible reconciliation

Figure 1(a) shows the main reason for mutual conflict between the four major the-ories, as different demands on hippocampus memory capacity needed: for limitedtime, forever, and never. But these conflicts, as will be shown below, cannot beresolved by assuming that all of the theories are only partially true, and beingcomplementary to each other. Reconciliation in the strict sense as union or amalga-mation of the theories is impossible, but in a wider sense, if at all, it is possible onlyin their common validity region. Since different types of memories are forming hier-archy, i.e., declarative ≥ spatial ≥ indexing ≥ comparator, that is a ≥ b ≥ c ≥ d = 0in notation from Fig. 1(a), then all considered theories can be reconciled in a widesense if a = b = c = d = 0, and the theory corresponding to the case d = 0can explain all of the major memory effects of each theory. The latter conditionwill be proved in Sec. 9, but the whole situation can now be cleared up by thefollowing analogy. Let us remember that the Standard Consolidation Theory main-tains that the hippocampus is essential to quick retention of information, but is notrequired for reproduction of old traces. Then it may be likened (following [230])to a photographic camera (which is not required indeed for picture reproduction).On the other hand, the Multiple Traces Theory allows comparing the hippocampus

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(following [66]) to a video camera, with the latter, unlike the former, being indeedindispensable for replay of episodic events, and their index sequence being fixed asin the hippocampus. It may be justly argued that photographic and video cameraswill only record the things “egocentrically” covered or viewed by the lens, whileaccording to the Cognitive Map Theory it is necessary to get and retain the “allo-centric” information [193] that is irrespective of the lens direction. Such informa-tion, as a locale-specific context, allows subsequent recovery of the memory of theepisodes, which suggests the priority and more profound nature of the Cognitive MapTheory.

In fact, there exists the view that the above theories are true, but incomplete[137], and should be regarded as mutually complementary concepts [66], much asa video camera cannot completely replace a professional photo-camera. The Theta-Regulated Attention Theory may counter this by pointing out that the above opticalanalogies, though fairly reasonable, appear to neglect one very important biologicalfact that without selective attention is possible to miss certain vital new informationwhich is critical for survival in a rapidly changing environment [205]. Therefore,simple integration of the theories would be a useless effort — we should look for anew, more flexible solution, which could give answers to all of the above problems,while making a better allowance for the trait of living organisms to crave for novelinformation, to attend to the environment, and to become habituated to anythingof frequent occurrence or minor importance. In other words, a more generic solutionshould reflect in a better way to the common attention mechanism involvement usedin the process of memory formation. Perhaps, the closest engineering analogy is notphoto or a video-camera, but rather a radar system for detection and automatictracking of moving targets, which is described in detail in Sec. 8.1, and capable ofdetecting and memorizing new and vital information.

So, the proposed interrelation between the different theories discussed can beschematically shown by using a Venn diagraml as in Fig. 1(b). The main point madeby this diagram lies in the fact that, owing to functional integration of various brainstructures through attention, the Theta-Regulated Attention Theory may prove tobe capable of accounting for the main effects covered by all four of the theoriesof long-term memory, with allowance made for their individual contributions, andhence, of reconciling them in a common framework.

6.2. Global binding as common ground for possible reconciliation

Besides engineering analogies, what specific neurobiological grounds are there forall of the effects discussed in Secs. 2–5 to be explained by the Theta-RegulatedAttention Theory? The answer to this question is not simple; it requires mathe-matical modelling with the use of the theory of dynamic systems. Therefore, we

lA diagram using circles to represent sets, with the position and overlap of circles indicating the relationshipsbetween sets.

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(a) (b)

Fig. 1. The logical ground for reconciliation. (a) Different requirement for hippocampal memorycapacity. (b) Schematic representation (Venn diagram) of the relation between explanatory powerof different memory theories, showing attention as their common psychophysiological basis, theirirreducibility to each other, and the scope for reconciling them in a unified theory. ATTN — atten-tion; CMT — Cognitive Map Theory; SCT — Standard Consolidation Theory; MTT — MultipleTraces Theory; TRAT — Theta-Regulated Attention Theory.

shall first give a brief qualitative explanation for general reader, which at a laterpoint will be supported by relevant details. It will be recalled, first of all, thatthe hypothesis of synaptic binding is common to the three theories [174]. TheTheta-Regulated Attention Theory, instead, puts forward the hypothesis of atten-tion being based on theta-rhythm synchronization of all cortical storage placesby one global septal pacemaker. By integrating the spatially distributed oscilla-tors into functional groups and configurations through their locking in rhythm, thelatter provides the conditions essential for retention of these groups, and the sub-sequent reproduction of such configurations. This becomes possible with the addi-tional proposition, referred to as Isolability Assumption [122], that different naturalfrequencies of the cortical oscillators, synchronized in such a functional group, aregradually equalized and can be restored, even after quenching of oscillations. Owingto the attention and synchronization mechanism, the Theta-Regulated AttentionTheory can not only explain this restoration of the original configurations upon reac-tivation, but also account for the main effects of rival theories. Let us explain this indue order.

First, the dynamic process of bringing oscillators with different natural frequen-cies to share a common frequency is similar to the gradual binding in the StandardConsolidation Theory, while the gradual equalization and fixing of these frequenciescan represent the long term consolidation ([267] see end of Sec. 3.3). Thus, unlike theStandard Consolidation Theory with its postulated slow synaptic binding and verylong consolidation, the Theta-Regulated Attention Theory views the hippocampus

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as being involved in relatively quick trace integration through the synchronizationof original cortical oscillators and fast recruiting new ones, thus strengthening theoriginal representation. That is why the Theta-Regulated Attention Theory has notrouble giving a new explanation to the Standard Consolidation Theory effects,reservations including.

Second, the capability of the Theta-Regulated Attention Theory to explain theMultiple Traces Theory effects is due to the fact that both these theories use theassumption of multiple traces in the neocortex, and assert that the hippocampusserves for the recording of binding codes (see Sec. 4), and reproducing the tracesirrespective of their age. However, the former — in distinction to the latter — assertsthat the hippocampus does not store the binding codes, but as will be shown later,generates them anew in every instance, based on automatic regulation of thetarhythm frequencies by means of the well-known control mechanism of phase locking(see Sec. 8). For this reason, the Theta-Regulated Attention Theory is capable notonly of explaining all of the effects treated by the Multiple Traces Theory, includingvarious forms of amnesia as special cases of desynchronization and destruction ofbinding codes, but also of eliminating the shortcomings pointed out in Sec. 4.3.

Third, there is a specific relationship between the Theta-Regulated AttentionTheory and the Cognitive Map Theory, which lies in the fact that both these theoriesshare the idea about a special role of theta-rhytm in spatial information prosessing,this point is reflected in the name “Neurolocator” for the unified model as describedin Sec. 8. To be more specific, the CA3 field of the hippocampus — as will be shownin Sec. 8 — is a strip of parallel, almost independent, cross correlators of the twomain inputs of the hippocampus, spatial and non-spatial. If we take that spatialinformation is more closely related to the theta-rhythmic activity while non-spatialinformation is to the gamma-rhythmic cortical activity then the Theta-RegulatedAttention Theory can account not only for the characteristic effects of the CognitiveMap Theory, but also for all the data that are seen as contradictory to the lattertheory, such as multimodality, attention-dependence, etc.

Thus, by using a common mechanism of attention and synchronization, theTheta-Regulated Attention Theory is capable, in a sense, of reconciling the maincurrent theories of long-term memory. Admittedly, this will take a lot of effort inmodeling to explain both its own effects, and all of the other relevant phenomenadescribed.

6.3. Summary of proposed reconciliation

We shall explain in Sec. 9 all of the effects underlying the four major theories underconsideration, thus showing that the selective attention is indeed the key systemprocess essential to information storage, consolidation, and retrieval. The primaryfunction in this process belongs to the septal theta rhythm which synchronizesrepresentation of the spatial location of an object, and its non-spatial features,

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mostly in the gamma frequency range, with the gamma riding theta. More cor-rectly, the center of attention is placed on the theta-frequency of place or directionoscillators, while other object properties are represented in its n-fold harmonics thatare mainly in gamma-frequency band. Although the functional units upon which theattention operates may be cortical oscillators representing the objects or features,and may vary under different experimental conditions, there is psychological andneurobiological evidence for the essentially spatial nature of basic units in termsof the fundamental quality, domination, and primary role of the loci occupied byobjects.

Therefore, the assertion of the Cognitive Map Theory concerning the primaryand exclusive role of the hippocampus in spatial information processing is valid tosome extent, even if this theory is not entirely true, as shown in Sec. 2.3, there isnothing like a cognitive map in the hippocampus. Nor does the hippocampus storethe allocentric (independent of the viewpoint) representation of object location,though it will certainly be involved in its formation based on neocortical egocentricrepresentation.

From data and explanations presented in Secs. 3 (see also Sec. 9) it follows thatthe incomplete Standard Consolidation Theory nevertheless contains some featurescentral to the unifying theory, to the degree that: (a) it is the neocortex and notthe hippocampus that is responsible for the ultimate storage of long-term memory(LTM); (b) hippocampal processing of LTM is not divided into separate semanticand episodic memory; (c) the hippocampus is essential for the quick recording andconsolidation of information in the neocortex. But, contrary to this theory, thehippocampus is also needed for the retrieval of old memory, although consolidationof traces will not rely upon it for years, as such dependence is being a matter of atime interval within which the relevant stimuli and representations will still attractattention, mainly during postlearning rest, nap, or sleep.

As regarding the apparently most advanced Multiple Traces Theory, it is correctin the sense that multiple episodic traces scattered in the neocortex are indeed linkedtogether by binding codes with some aid from the hippocampus, regardless of thememory age (see Sec. 9.8). However, contrary to this theory, the codes themselves arenot stored in the hippocampus, but are created anew through interaction betweenthe neocortex and the hippocampal system in every act of attention, i.e., for everyobject to attract attention. A binding code is the theta rhythm frequency to lockin sync with all of the cortical oscillators jointly involved in recording. Given thecues, such a rhythm will automatically arise in act of attention, without any needfor recording this code in the hippocampus.

So each theory, despite a lot of reservations and shortcomings, significantly con-tributes to the common ground for the reconciliation in a wide sense. In fact, there isno need to construct a straw man out of each of four theories, and then knock themdown to build a unified theory. On the contrary, here we have the collaboration andsynthesis of ideas reflected schematically in Fig. 1(b).

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7. Three Basic Principles of Unified Model

Our model is essentially an oscillatory one. There already exists many oscillatorymodels of attention and memory [12, 13, 15, 104, 105, 106, 107, 276], with almost allof them admittedly being inspired by Kryukov’s [122] model. Nevertheless, theyare essentially deterministic, not account for the stochastic unit neuronal activity,and therefore do not use at least two of the following three principles that arequite necessary for our model which will be described in Sec. 8. The first prin-ciple deals with the psycho physiological basis of proposed attention and behav-ior mechanism, as opposed to Hebb’s principles of brain functioning [84, 159]. Thesecond principle deals with the physical and mathematical basis of the proposedunified memory mechanism, as opposed to multiple memory systems [22, 48, 61].The third principle gives a new structural dynamical system ground for the globalaspects of our model, as opposed to the “catastrophically” inadequate connectionistmodels.

7.1. The principle of dominantam

The principle of dominanta states the existence in the central nervous system (CNS)of focus of excitation that attracts to itself other subdominant excitations imping-ing on the nervous systems at the same time, and renders braking influence on theactivity of other nervous centres. “At the higher levels and in the cerebral cortex,the principle of the dominanta is the physiological basis of the act of attentionand subject thought” [253, p. 46]. In contemporary terminology it can be likenedto “the dominant focus of consciousness” [113], “resonant cell assembly” [254],“biased competition model” [40], and many other similar propositions that areapparently unaware of the earlier and more fundamental Ukhtomsky’s dominantaprinciple.n

In the following, we list the main properties of dominanta, which are necessaryfor understanding the ground basis of our model “Neurolocator”. The dominanta ischaracterized by the following global properties. At any point in time, the nervoussystem has only one active, dominating constellation of co-excited neuronal groupsor centers characterized by a common rhythm and common action (behavior). Thesame individual centers or groups of neurons can be included in different dominantaconstellations; the involvement in one constellation, or disassociation from it, isdetermined by the ability or inability of these groups or centers to acquire the sametempo and rhythm of activity. Traces of the previous dominantas persist over longperiods in the higher levels of the nervous system, and with complete or partial

mThere exists in Russian neurophysiology extensive classical data on which the dominata concept is devel-oped, but we will cite only those that are most closely associated with our model of attention and memory.nOne important exception is the memory theory by E.R. John, partly based on the Ukhtomsky’s dominanta(see [100, p. 182]).

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recovery of the initial conditions, they can completely or partially reappear [253,pp. 55, 217, 221].

On the other hand, the dominanta is characterized by the following five localproperties.

Increased excitability : for a group of stimuli to be included in the dominanta, thethreshold of excitability of the dominanta must be lower than the intensity of theincoming stimulation.

Stability of excitation: for excitation to produce any marked behavioral effect, itmust not undergo rapid changes over time.

Excitation summation: the ability to accumulate excitation not only from specific,but also from non-specific stimuli.

Inertia, i.e., the ability to retain the state of excitation once the initial stimulus hasceased.

Conjugate inhibition, i.e., the ability to exclude from the dominanta those centerswhose activity is functionally incompatible with the activity of the dominanta con-stellation [253, pp. 43, 75–76].

Along with propagating spike excitation of the “all or nothing” type, the nervoussystem experiences gradual local stationary excitations. These can be produced bynormal stimulation, local cooling, or with local stimulation by electrical currents orvarious chemical substances. The resulting state of altered loci may be determined bythe functional parameter of physiological lability. This corresponds to the maximumstimulation frequency above which transformation of rhythm takes place in the nervetissue, such as frequency division [67].o

Apart from the optimum frequency and strength of stimulation, there is opti-mum lability and optimum depolarization at which local stationary excitation ismost easily transformed into local rhythmic activity which can propagate beyondthe boundaries of the initial locus. At the optimum levels of lability and depolariza-tion, the phenomenon of rhythm assimilation arises, whereby the rhythmic activitydeveloping in synchrony with the rhythm of the incoming stimulation persists forsome time after the incoming stimulation ceases [67].

Transition from local stationary excitation to propagating excitation is observedduring acquisition or extinction of conditioned reflexes. Transmission of excita-tion from the centers of the signal to the centers of the effectors is accompaniedby the synchronization of biopotentials in these centers, so that propagation of

oLability is the key parameter of the dominanta. In the usual sense it means transient, and can be definedquantitatively as inverse mean time of transition of some stochastic system from a given initial state to oneof its stationary states [124, pp. 302–303]. It is applicable both to the aperiodic as well as the oscillatorysystem. In the latter case, it may mean the natural or resonance frequency of oscillators. The effect offrequency division allows estimating the upper limit of physiological lability, because the frequency division(a well known nonlinear effect of oscillator’s synchronization when response frequency at the output cannot one-to-one follow the input frequency, mainly due to the low natural resonance frequency of the givenoscillator), results in abnormal behavior, e.g., tachycardia.

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excitation becomes easier as the surface that is involved in synchronous coherentactivity, and the coefficient of mutual correlation of “linked” centers increases. Forsome animals, such as rabbits, the synchronicity and coherence occur at the fre-quency of the theta rhythm. Extinctive inhibition (“fading” or “quenching” of oscil-lators) is accompanied by divergence of the frequencies of the linked centers, withdrops in the synchronicity of slow biopotentials and decreasing lability in thesecenters [136].

7.2. The principle of phase transition and metastability

In an attempt to understand the nature of local and global properties of the domi-nanta and its corresponding inertial and persistent memory traces, it is necessary tobuild a Basic Neuronal Model (as submodule of the “Neurolocator”), which wouldbe similar to some physical model expressing a memory trace in terms of a longrelaxation time and phase transition.

Such a physical model, namely classical kinetic Ising model of ferromagnets,p

shows the so called critical slowdown of its kinetics resulting in persistent statesand inertia at the temperature near the point of phase transition. However, threeimportant factor of the nervous system make it difficult for phase transition in thebrain to occur. Namely, the stochastic spike nature of neuronal activity, the time-varying threshold of firing and fast exponential decay of the membrane potential.Our Basic Neuronal Model is a two-dimensional Ising-like neuronal analogue thattakes into account the above three factors. We are not going into the technicaldetails given elsewhere, but only list the necessary main results of the studies onthis model obtained by means of new mathematical tools of Markov InteractionProcessesq [121,124] along with new data supporting them:

The existence of phase transitions in the form of long range order, i.e., sig-nificant correlations between the activities of very distant neurons without timelags was proved under certain conditions. Later on, similar results have been foundexperimentally: Roelfsema et al. [214] and Rodriguez et al. [213] under specific taskconditions had discovered the neuronal synchronization with zero phase difference,despite a significant distance between neurons. Recently, the long range synchroniza-tion of active (UP) and silent (DOWN) states have been discovered in neocorticalneurons during slow wave sleep [264], along with unusually large fluctuations at thetransition between them, which is highly characteristic of physical phase transition.Fujisawa et al. [60] in vivo demonstrate that a single neuron stimulation can induce

pOne of the simplest solvable models in statistical physics with spin states s = ±1, which is completelydescribed by the bilinear interaction potential. There is a one-to-one correspondence between kinetic Isingmodel and a network of formal neurons with its nearest neighbor synaptic connections resulting in theexistence of a persistent states and phase transitions [135]. The famous Hopfield’s [91] model superficiallyresembling Ising model is of no use here, since phase transition in it means destruction of its micro attractors.qThe latter represent a generalization of the usual Markov processes with multiple components to the caseof locally interacting components or Markov Random Fields.

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phase transitions and metastability in the neocortex (like a spot persistence effect,see below).

The existence of metastable statesr was predicted and confirmed by the simula-tion of the Basic Neuronal Model as an effect of spot persistence. A two-dimensionalcomputer simulation network of 30× 30 integrate-and-fire neurons with fixed near-est neighbor synaptic connections of identical strength starts with a spot of units ofzero background taken as the initial state, and evolves as follows. The net activitydwindles to the DOWN state if the synaptic strength is small, so that the configura-tion consisting mainly of zeros settles as shown in Fig. 2(a). On the contrary, if thesynaptic strength is large enough, the spot spreads out, thus forming the UP stateas shown in Fig. 2(c). A network with critical parameter values, however, is capableof remaining for a long time in a state close to the initial one, or spot persistence, asshown in Fig. 2(b). Lately, new simulations of the same Basic Neuronal Model havebeen carried out with different initial configurations confirming the existence of thecritical regime, UP and DOWN states, and anomalous fluctuations in-between [14].

A model of a cortical microcolumn oscillator based on the metastability effectwith the unusual property of very slow oscillations was proposed and investigated. Itis obtained by introducing into the above Basic Neuronal Model a single inhibitoryneuron which receives positive connections of identical strength from all neurons,and sends negative connections of identical strength to all other neurons. As a result,the network becomes capable producing oscillations of very long periods, with smallperiod’s variance; the wide range of linear frequency regulation (in gamma-theta-delta range) is realized by the varying threshold of the excitatory neurons. Suchoscillators, locally connected to each other, can hold the spots of activity for avery long time, even after quenching of oscillations which can explain the enigmaticpersistence of memory traces. The mathematical theory of such metastable statesshows [124, p. 250] that their lifetime depends essentially on the number of elementsin the spot, and can be very long in the case of optimal number, like physicalmetastability phenomena. The very slow oscillations, within and beyond the classicaldelta band (0.5–4Hz) were described in neocortex by Amzica and Steriade [2] andin hippocampus by Wolansky et al. [274]. The slow oscillations is proved to serve asynchronizing role in neocorticohippocampal interplay [171].

Theoretical prediction was made that during active perception of external stimulidifferent neuronal constellations work near points of an unstable equilibrium resem-bling the physical phenomenon of phase transition and metastability, and appearingas the neuronal substrate of Ukhtomsky’s dominanta. Similar predictions especiallyfor the sensorimotor cortex can be found in [77] and [108]. Now this prediction isgradually becoming the working principle of the CNS with unusual, but significantconsequences, such as described later in this work.

rUnstable and transient, but a relatively long-living state of a physical system, as with a supersaturatedsolution or supercooled liquid.

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(a) (b) (c)

Fig. 2. The effect of spot persistence. Each column corresponds to different interneuronal connec-tion strength: (a) subcritical, (b) critical, and (c) supercritical.

These results have been applied for consistent interpretation of the above fivelocal properties of the dominanta, and identification of micro foci (clusters, domains)of local excitation in neocortical columns as possible sites of long-term memory. Inparticular, the existence of long-lived micro foci of local excitation predicts the

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The Role of the Hippocampus in LTM 143

following relationship between long- and short-term memories. While short-termmemory is associated with the activity of the cortical oscillators, and long-termmemory with stationary local spot excitation in micro foci in the cortical layers, thetransition from one type of memory to the other must be identified with the well-studied phenomenon of transition at optimal lability of local stationary excitation toexcitation propagating beyond the limits of the micro focus (see Sec. 7.1). Ukhtom-sky’s dominanta, as a constellation of microcolumn oscillations coexcited at the oneand the same frequency, is a means of “reviving” inactive long-lived traces, pro-viding easy and rapid selection of only those traces which were at some time prior“recorded” in a similar situation (i.e., at the same arousal and frequency of oscilla-tions), and combining different modalities into a single integral representation; thelatter by the same mechanism then can be returned to the inactive form of localstationary excitation, and thus be protected from external and internal interfer-ences. This prediction relates to both the sensory system and the motor system. Itsconnection with the memory persistence problem is discussed in Sec. 11. The aboveprediction of relations between long- and short-term memory is consistent with muchof the data reviewed by Harris et al. [78], Ruchkin et al. [218], and Ranganath andBlumenfeld [204], especially on the collocation of both types of memory found invarious brain structures, so that there is no need to propose neurally distinct storesfor short and long-term retention; learning and memory involve the storage of infor-mation within the same cortical regions responsible for online processing of thatinformation.

7.3. The principle of central oscillator

This principle can best be understood from the proposed architecture which is dif-ferent from the common connectionist one on five counts as set forth below.

The basic processing element is not an individual neuron, but an elementary cor-tical oscillator (e.g., microcolumn), i.e., a relatively small network of synapticallyconnected integrate-and-fire excitatory neurons supplemented by one inhibitoryinterneuron as described in Sec. 7.2.

Information is recorded not in synaptic weights, but in a large system of origi-nally independent elementary cortical oscillators, whose optimal lability or “natural”frequencies are modified (see below) in the process of learning and consolidation toproduce encoding by ensembles of isolabile (i.e., isodirectional, isochromic, isolumi-nant etc.) oscillators. This modification is conditioned by rhythm assimilation, andis supported by new protein synthesis or some other biophysical mechanism to fix anew lability.

A simplified new architecture of the N processing element with the central oscil-lator is represented not by a layered neuronal structure with usual all-to-all N2

connections within a layer, but a star-like system consisting of a group of originallyindependent peripheral cortical oscillators and one central oscillator, which has only2N connections to each of its peripheral counterparts (Fig. 3).

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Fig. 3. Simplified architecture with central oscillator. SO, septal oscillator; CO, cortical oscillator.

The top-down versus bottom-up structural problems is resolved by the intro-duction of the central oscillator acting as a global pacemaker, or an “orchestraconductor”; it can change the current frequency of mutual synchronization withincertain limits, and involve cortical oscillators in various multimodal ensembles onthe basis of direct and recurrent connections.

Attentional selection of particular representation for further detailed processingis associated not with some high-level (e.g., salience) map, but directly with thecortical oscillators of a different level working in parallel, with the primary zoneincluded. Attention is switched from one group of oscillators to another in successionby changing the frequency of the central oscillator. Thus, information treatment isof a parallel-serial type of processing.

To sum up, the new and the connectionist architectures have a basic qualitativedifference between them, much like the difference between broadcasting and wiretelegraph. The components (oscillators) in the new architecture have dynamic func-tional links with each other rather than synaptic ones. Therefore, it is free fromthe well known problems of connectionism, such as combinatory explosion (expo-nential growth of neurons with growing of feature dimension), overflow catastrophe(loss of memory after exceeding critical capacity 0,14 N), superposition catastro-phe (loss of separate object representations after their superposition, see [265]), andinterference catastrophe (loss of all memories in case of rapid learning, see [153]).Another major distinction lies in the above assumption that information is storednot in synaptic links, but in space-frequency isolabile configurations or oscillatorensembles with similar natural frequencies (see assumption 6 of Sec. 8.3), withtheir learning being centrally controlled rather than a local Hebbian process. There-fore, we can consider the net architecture with central oscillator as a new working

sIt arises due to a hierarchical structure of neuronal networks with different degrees of abstraction thatgreatly complicates the feedback connection from upper level to the lower ones. In particular, the problemof temporal tagging is that abstract output from converging zones should return to specific sensory cellswithout a firmly established mechanism of tagging [247].

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principle of global information processing in the brain. How it interacts with theprinciples of dominanta, phase transition, and metastability will be described in thenext section.

8. “Neurolocator” — A Unified Model of Attention and Memory

8.1. Radar analogy

The attention and memory model “Neurolocator”, described at length by Kryukovand colleagues [85, 122–124], is neuronal representation of the Theta-RegulatedAttention Theory, and in a sense, has much in common with a radar system. Thisanalogy will be clarified below. Radar is a device for detecting and tracking movingtargets by sending into space electromagnetic signals as a series of short recurrentpulses with the subsequent recording and analysis of the targets echo. The distanceto the target is proportional to the time of delay between sending of pulses andreception of echos. Similar to the radar system, the “Neurolocator” sends a series oftheta-modulated pulses to the neocortex, and than receives the “echo” to determinetheir phase relative to that of the central theta-oscillator. The difference betweenthese phases varies as the target moves, but the theta-oscillator — owing to thefeedback loop with the hippocampus — can automatically track such variations bychanging the theta rhythm frequency so that the latter becomes a continuous indexof the cortical places where this moving target is represented. Such a system is calleda Phase-Locked Loop (PLL) system.t Together with the global broadcasting of thetheta-rhythm, it forms the heart of radar analogy.

A key element of radar is the comparator (phase detector), which measuresthe phase difference between the incoming oscillations and the oscillations of the socalled Voltage Controlled Oscillator. Its neuronal analogue may appear as a detectorof the match/mismatch between two pulse sequences, which we locate — followingVinogradova [260] and Vinogradova and Dudaeva [262] — in the CA3 field of the hip-pocampus. An integral part of radar is the transmitter, which sends out interrogationpulses to the ambient space. Its neuronal analogue is the central theta-pacemaker,which we locate — following Vinogradova [259] and Vinogradova et al. [263] — inthe medial septum, considering that the septal effects are ubiquitous in the brain,and the frequency of its theta rhythm is regulated by an increase of afferent stimu-lation, and by stimulation of the reticular formation [263]. This enables the medialseptum to perform the functions of the above Voltage Controlled Oscillator, thecentral component of the frequency-phase tracking system, while the amplifier with

tA phase-locked, or phase-lock, loop (PLL) is an electronic control system that generates a signal that islocked to the phase of an input or “reference” signal. A phase-locked loop circuit responds to both thefrequency and the phase of the input signals, automatically raising or lowering the frequency of a controlledoscillator until it is matched to the reference in both frequency and phase. A phase-locked loop is an exampleof a control system using negative feedback. Phase-locked loops are widely used in radio, telecommunications,computers, neural nets modeling, and other applications to generate stable frequencies, or to recover a signalfrom a noisy communication channel.

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a low-pass filter being involved in its stabilisation is associated in our model withthe reticular formation. All of the above components are linked to form the PLLsystem, and act similar to an automatic tracking system which can select objectsand keep, as in radar, a close watch on several moving targets at a time.

8.2. Schematic diagram of “Neurolocator”

The PLL radar system, as shown in Fig. 4(a), comprises five standard control units:Voltage Controlled Oscillator (VCO), phase detector (PD), low-pass filter (LF),receiver (R), and summator (Σ). Its neural counterpart is sketched in Fig. 4(b). Inconstructing it, we relied on the well established functions of various parts of the lim-bic system [258,260]: the hippocampal fascia dentata (FD) is a mixer and integratorof specific inputs; the medial septum (Sm) is the central oscillator or synchroniser,not only for the hippocampal CA3 field, but also for many other brain structures;the lateral septum (Sl) is an output mixer for CA3 fields of individual lamellas, i.e.,concurrently operating sections of the hippocampal formation, almost independentfrom each other structurally and functionally [273], and corresponding to variousoriginally independent groups of cortical oscillators. All these structures, accordingto Vinogradova [258, 260] are interconnected, and form two closed loops, as shownin Fig. 4(c). The first loop deals with information; it includes the hippocampal fieldCA1, anterior thalamus (AT), neocortex (NC), and other structures which retain,even if partially, their signal-specific sensitivity. This loop is active during initialinformation memory formation in the neocortex, as well as during online informa-tion treatment providing, for example, long delays in recycling of signals for theworking memory. The second loop serves the regulating purposes and incorporatesthe CA3 field, medial septum (Sm), lateral septum (Sl), mesencephalic reticular for-mation (mRF), and some other structures such as the amygdala (Am), which areinvolved in emotional and volitional control (VC in Figs. 4(a) and 4(b)). This loop isresponsible for non-specific brain activation and regulation of arousal, and will alsoautomatically set the theta rhythm to an optimal frequency to fit the current task.Since it is known that the hippocampus has an inhibitive effect on the activatingreticular formation (by means of the medial raphe nucleus, see [261]), the secondloop serves, in fact, the function of negative feedback for regulation of both arousal inthe brain and the septal oscillator frequency. Both loops are essential for our model,but we shall focus on its minimal version as indicated by the shading in Fig. 4(c)to clarify the central role of the septo-hippocampal system as a function of thewhole brain. To this end, we extend Fig. 4(b) to include the lamellar version of the“Neurolocator” as shown in Fig. 4(d) with this schema working as follows. There issingle central oscillator (Sm). The individual cortical oscillators are connected to theseptal oscillator, but not to each other. There are multiple hippocampal phase com-parators, with one connected to each cortical oscillator. These n phase-comparatorsgive rise to n error signals, which by a local feedback connections are convertedto n cross-correlations and then mixed together, and thus being weighted by the

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(a)

(b)

(c)

(d)

Fig. 4. Schematic diagrams of (a) radar range tracking system, (b) the “Neurolocator”, (c) limbicsystem [258], and (d) the lamellar version of the “Neurolocator”.

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feature saliencies of the respective cortical oscillators. Finally, the mixed signal islow-pass filtered, and used to adjust the septal oscillation. The cortical oscillatorswith a significantly salient feature automatically involve into the dominanta group,and their resonance frequencies are modified in the process of learning and con-solidation towards the frequency of the most salient oscillator. Thus, the memorytraces are stored, consolidated, and replayed in the same neocortical place, whereasthe septo-hippocampal system is playing the role of an “orchestra conductor” thatorganizes various groups of isofrequency oscillators. To sum it up, we now restateand specify the main model assumptions.

8.3. The “Neurolocator” assumptions

These are largely the same as in our earlier version of “Neurolocator” [122,124]:

(1) The system model “Neurolocator” has six functional units [see Fig. 4(b)]. Eachunit is a minor modification of the Basic Neuronal Model, e.g., the corticaloscillator unit is obtained via recurrent inhibition as described in Sec. 7.2.

(2) Besides the non-specific inputs from mRF, all the cortical oscillators have sen-sory inputs of certain modality, and thus serve as analysers of stimulus features(form/shape, colour, brightness, etc.). Their natural oscillation frequencies areuniformly distributed over the theta-gamma frequency range, and in the absenceof specific inputs, non-specific inputs from mRF do not cause, as a rule, oscil-lations, but only contribute to their generation if appropriate stimuli providesufficient arousal.

(3) The phase detector of the CA3 field serves as a match-mismatch comparator(coincidence detector) for the two main inputs, septal, and neocortical. Theirmaximum joint effect on the CA3 field will be represented by coefficient A,expressing the magnitude of correlation between these inputs, whose dependenceon the shift in time interval τ between these inputs is designated as g(τ), andwill be referred to as cross-correlation or pulse cross-intensity.

(4) The low-pass filter mRF is characterized by the transfer function of the firstorder F (p) = K/(1 + Tp), where K is the loop gain and T is the time constantamounting to several hundreds of milliseconds, in keeping with the way inertiais defined in Secs. 7.1 and 7.2, and accounted for in [85] and [123].

(5) The key assumption of the model lies in the fact that attention may be describedas a global emergent property of the system (showing up promptly when arousalreaches a certain threshold), which corresponds to the transient phase lockingof multiple cortical oscillators at the septal oscillator frequency. The schematicdiagram of the system that takes into account the lamellar structure of thehippocampus is given in Fig. 4(d).u

uThis diagram is well known in communication theory (see Fig. 3.37 in [132]), and therefore it needs nosimulation to check its basic properties for the case Ni = 0.

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(6) Isolability Assumption: when the number of cortical oscillators locked in anensemble reaches the critical value, their labilities tend to be equalized, i.e., theoscillators that are gradually brought to a common rhythm in an ensemble willchange their natural frequencies towards the common one, thus implementingisolability coding of information. This change is rather slow, (hours, even daysdue to the consolidation and the possible synaptic protein synthesis) only start-ing after the initial signal retention supported by a less slow dominanta’s inertiaand rhythm assimilation as the initial condition.

8.4. Key features of the “Neurolocator”

Based on the theory of Markov Interaction Processes [121], the model is describedby the following system [124, Eq. (9.7)], of stochastic integro-differential equationsv:

dϕi

dt= Λ0i −

n∑

j=1

A0jgj(ϕj) + Nj(t)

F (p), (i = 1, . . . , n) (1)

where ϕi — mean phase difference of the septal and ith group of cortical oscillators;Λ0i — their frequency detuning; A0igi(ϕi) — non-linear output function of the phasecomparator in ith lamella representing the cross-correlation of its two major inputs;Ni(t) — “white” noise of the ith lamella; n — total number of lamellas; F (p) —transfer function of the low-pass mRF filter. Operator multiplication by F (p) onthe right-hand side of (1) means convolution with function f(t), for which F (p) isLaplace transform.

It should be noted that Eq. (1) is an analytical form of the structural diagramfrom Fig. 4(d). In particular, the summation in Eq. (1) corresponds to the septal (Sl)summator in Fig. 4(d), and that the cortical oscillators, while not connected to eachother, interact with each other through their mutual influence on the septal oscillator(Sm), and therefore dφ/dt depends on all the cortical oscillators, rather than simplythe i-th oscillator. Therefore, the system Eq. (1) will be used for explaining mostof the effects described earlier in this paper, but we shall make a start with avery simple particular case, disregarding the lammelar nature of the hippocampus(n = 1), the noise (Ni(t) = 0), and the filter (F (p) = K), with the system reducedto one non-linear ordinary differential equation:

dϕ

dt= Λ0 −AKg(ϕ), (2)

where parameter AK is proportional to the arousal, and g(ϕ) stands for the cross-correlation of the two major hippocampal inputs, and thus, it is not necessarily a

vIt can be viewed as a multidimensional diffusion of particles that tend to coalesce. For the numericalsimulations of Eq. (1) in deterministic case see [107]. In particular, depending on the network parameters,one can implement a content addressable memory, hysteresis, strange attractor, synchronization-instabilityinterchange, selection of oscillator groups, and many other interesting regimes and effects. For the applicationof Eq. (1) in the stochastic case see [122], in particular, for the explanation of the divided attention, one-shotlearning, Stroop effect, Erkes-Dodson Law, and some other effects.

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sinusoidal, but often can be proved to be S-shaped function [122,124], with gmin > 0corresponding to the absence of mutual dependence between the two processes. Ifwe take for simplicity that g(ϕ) > 0, then given stimulus will only catch attention,or equivalently, the septal oscillator will be “captured” by some cortical input if thefollowing inequality is met:

1gmax

<AK

Λ0<

1gmin

. (3)

This inequality corresponds to feature 1 of the “Neurolocator” as described below.Other features of this model loosely correspond to those of the well known standardfirst-order PLL system [85,123,132], and will be presented here for easier referencingin explanation of the attention and memory effects.

(1) Attentionw is impossible both when the arousal is too low (AK/Λ0 < 1/gmax)and when it is too high (AK/Λ0 > 1/gmin).

(2) Attention arises rapidly upon increase of arousal(AK/Λ0 > 1/gmax), and mani-fests itself in picking out a particular signal from the mix of external or internal(e.g., from memory) stimuli.

(3) Attention is controlled by varying the detuning (Λ0) either automatically or by avolitional effort. There are conditions under which the i-th lamella is functionallydisconnected from the system (e.g., automatically, with high A0iK).

(4) Attention is unitary, but with moderate arousal AK, it is divisible by the Miller[163] rule (7± 2) or by the Cowan [34] rule (4± 1). In other words, the systemcan synchronize simultaneously 4 to 7 originally independent cortical oscillators,which will jointly control the septal oscillator.

(5) Attention is unstable, or at most, metastable due to noise Ni(t),and nonlinearityof function g(ϕ). Breakdown of attention may be abrupt (due to noise or inter-ference action from another group of cortical oscillators, see Fig. 6) or gradual(due to a progressive change of the model parameters, for example, as in thecase of habituation, see Sec. 9.1). In both cases, the system of synchronizationis transient, and not in a stable state.

(6) Conjugate inhibition (that is the inhibition of all the stimuli found outside thefocus of attention) relies on two mechanisms: first, due to unlocking, and second,due to the decrease of arousal, which according to assumption 2 of Sec. 8.3 isonly effective for the signals coming into the focus of attention.

(7) Attention may exist not only with similar frequencies of the septal and corticaloscillators (1:1 locking), but also with different frequencies (locking of p : q

type). It can be demonstrated that given p = 1 and q > 1, the most stablelocking for the case of g(ϕ) = sinϕ occurs with q = 4 (e.g., locking of 10 Hz and40 Hz oscillations are not only possible, but can even become dominant).

wFrom now on by attention we mean the selective attention, that is a theta-regulated attention in accordancewith Vinogradova’s [260] theory.

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(8) It takes several theta-rhythm periods for voluntary attention to set in, with thisprocess having two stages: the first stage involves frequency locking (gradualsynchronization), and the second being phase locking. Involuntary attention ispractically instantaneous, as the septal oscillator triggered by a new stimuluscan immediately reset the stimulus-representing cortical oscillators [172,251].

In conclusion, it may be noted that model computational capabilities are verypromising: (i) virtually unlimited time of memory retention; (ii) virtually unlimitedcapacity of isolability coding scheme; (iii) high protection against interference thatis typical for PLL-systems; (iv) applicability to the episodic memory sequencingwithout the need to introduce additional components. Each of these capabilitiescertainly deserves a special treatment, but it is beyond the scope of this paper.

9. A Brief Unified Explanation of the Basic Effects

Our explanation of the effects described in Secs. 2–5 begins on establishing a moreclose correspondence between the “Neurolocator” and the Theta-Regulated Atten-tion Theory. The attention process starts with an orienting response and with asearch for the corresponding stimulus in the environment. The modeled search forthe stimulus, akin to searching for a target by a radar PLL system, has two stages:frequency synchronization or capture transient, and phase synchronization or phaselock [92, pp. 435–436]. At the first stage, the frequency of the theta rhythm of aseptal oscillator is quickly varied by the external setting of the task, or by chang-ing the emotional arousal until it matches the frequency of the major neocorticaloscillators of the target place, which are found in the prefrontal and parietal corti-cal regions. This stage is described by the first summand on the right-hand side ofEq. (2), and corresponds to the presence of a signal only at the reticulo-septal inputto the hippocampus with absence of signals at its cortical input. At the second stage,the septal oscillator frequency remains almost unchanged, but on the other hand, it“pulls” the frequencies of the neocortical feature oscillators of the searched targetto the common assembly frequency. This stage is defined by both summands on theright-hand side of Eq. (2), and hence, by signals at both inputs to the hippocampus,as required by the Theta-Regulated Attention Theory.

Thus, establishment of selective attention is a transient process of reciprocal syn-chronisation of the septal theta-oscillator with a relatively small subset of neocorticaltheta- and gamma-oscillators which represent the features of a given stimulus. Gen-erally speaking, it is possible without the hippocampus (e.g., in familiarity test), i.e.,without the second stage. However, without this stage, in the event of hippocam-pal damage, normal quick recording of new information neither is feasible, nor isdetailed recollection possible. To make it clear, we shall first take a closer look at theconditions at which a stimulus will normally catch attention, and shall then extendthem to pathological and lesion cases.

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9.1. The effects of novelty and habituation

As shown in Sec. 8.4, a necessary condition for catching attention is the fulfilment ofinequality (3), in which following the assumptions of the Theta-Regulated AttentionTheory, we set:

A = (A1 + A2)A3, (4)

where A1 corresponds to the action of the CA1-based information subsystem onthe regulatory subsystem; A2 reflects the action of the neocortex on the regulatorysubsystem; and A3 accounts for the structural changes in the CA3-based regulatorysubsystem due to LTP changing (see below). Immediately after the appearance of anew stimulus and reset, A1 = A2 = 0, and then A1 increases until A1K exceeds thelower threshold of synchronization, represented on the left-hand side of inequality(3). Afterwards, A1 remains nearly constant, while A2 shows a gradual increase uponrecurrence of the new stimulus, which is attributed to phase locking of the corticaloscillators. This situation will hold until the upper synchronization threshold isreached, as represented on the right-hand side of expression (3). The initial phasein information recording ends in desynchronization between the hippocampus andthe neocortex, where the theta rhythm is disrupted, and the system will await newsignals (see feature 5 of Sec. 8.4). If, afterwards, the sensory system receives an inputfrom the same or a familiar stimulus, it will quickly reach the upper threshold —owing to high A2 — and upon generating a short (phasic) response, will revert to theoriginal condition of waiting for a new stimulus. Given an input from a new stimulus,the whole process described above is repeated, accompanied by prolonged (tonic)reactions, both in the hippocampus and neocortex. The mutual interferences fromdifferent stimuli are eliminated, as per system (1), due to the fact that their signalscome to the hippocampus following different paths and arriving at different lamellas[273]. The long-term potentiation (LTP) within each lamella, which is accountedfor by multiplier A3 in expression (4), suppresses the neural response to novelty[16, 260, 262], and thereby enhances the faculty of disabling a lamella in case of afamiliar stimulus. Therefore, the potentiation of the cortical input is equivalent tothe familiarity of the stimulus [260].

It may be easily verified that the above mechanism can account for the effects ofnovelty and habituation in all their aspects. So, the most puzzling phenomenon ofdehabituation becomes less of an enigma if we see that a change in the signal param-eters leads to a change in its associated system of cortical oscillators. This meansthat dehabituation does not suggest recovery of the previous quenched reaction, butsignifies a new tonic response which corresponds to new signal, and involves actua-tion of a new lamella. The almost obvious phenomena of distribution, colocalization,separability, specificity and rapid habituation point to the fact that memory tracesare formed and fixed outside the hippocampus, with the latter binding these traces inone large-scale and internally coherent neural network [73], and then getting quicklydisconnected afterwards [277].

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The transient gamma phase synchronization is followed by desynchronizationof the entorhinal cortex and the hippocampus, as observed in a successful memoryformation [55], as well as similar processes in the gamma and theta range at recogni-tion [203,213]. It is a dynamic manifestation of the effects of novelty and habituationin their succession (see Secs. 5.1, 5.2 and 7.1). Simultaneous transient locking of var-ious cortical regions in the theta- and gamma-rhythm ranges is a particular case infeature 7 of Sec. 8.4. It was confirmed by using electroencephalography [39, 222],magnetoencephalography [197], and intracranial recordings during episodic mem-ory formation [25, 227]. We consider it the most important part of the declarativememory mechanism based on spatiotemporal coding.x A similar mechanism was alsosuggested by Fell et al. [54], Lisman [133], and Axmacher et al. [5], where the lock-ing at different frequencies is considered to be optimal for induction of LTP. Thedifference between spatiotemporal coding and usual LTP is discussed in Sec. 11.

It will be noted here that LTP, as accounted for by A3 in Eq. (4), does not actas a neural substrate for memory in the “Neurolocator”, but performs the supportfunction of disconnecting individual hippocampal lamellas (with high A3) from theneocortex for some time, until short-term neocortical memory (synchronous activityof isolabile oscillators) is converted to long-term memory, than becoming inactiveand a stable form of “quenched” oscillators. This is the solution to the problem ofprotection against interference, and of superposition of new traces on the old ones.Therefore, the normal short living LTP is ideally suits this function, unlike its role inthe Hebbian learning leading to unsolvable persistency problem discussed in Sec. 11.

It should be noted, that our explanation of novelty detection is almost indepen-dent of CA1 field activity, but critically depends on CA3 fields comparator and FDmixer and integrator [see Fig. 4(d)]. This prediction has been recently confirmedby Lee et al. [126]. It was found in neurotoxic lesions experiments on spatial nov-elty detection that from three different CA1, FD, and CA3 lesion groups of rats,the CA1 group was only mildly impaired in reexploration,while both FD and CA3groups were severely impaired in that task. In discussions of this result, authors citedfour times from Vinogradova [260] that predicted this result. The result immediatelyattracted the attention of Hasselmo [80], who wrote critical comments admitting theneed for more sophisticated computation models that are currently being used forthe explanation of novelty detection. In particular, he argued that this new datais not really incompatible with the “standard hypothesis” of the CA3 field mediat-ing the encoding and retrieval of associative memories. We agree on the conditionthat there is no memory in the hippocampus. We do not agree if the above “stan-dard hypothesis” implies a buffer or permanent memory in hippocampus, alike theStandard Consolidation Theory or Multiple Trace Theory, because in that case themodel realization of the“standard hypothesis” could not uniformly explain all thedata described in Secs. 3 and 4.

xThe abnormal synchronization at different frequencies is reported to be neuronal correlate of various neu-ropsychiatric diseases [225].

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Finally, since our explanation of novelty effects requires the CA3 comparatorneither to be modality specific, nor to be storing any memory traces, it allows forsolving the novelty detection problem uniformly, for all signal modalities. Thereby,we answer the “difficult” question of Lisman [134] raised in Sec. 5.3 as follows:The CA3 comparator using cortical and septal information could not decide alonewhether incoming information is novel or not, but the whole septo-hippocampo-cortical system can, because novelty detection is emerging property of the wholePLL system, not just any part of it.

9.2. The effect of retrograde amnesia

The “Neurolocator” explains the RA gradient not by consolidation of traces, but bygradual increasing in the number of cortical oscillators due to frequency pulling,y

i.e., by increase in parameter A with the memory age, as every retrieval of traces isaccompanied by their repeated recording under somewhat new conditions. This isonly possible when oscillators are more frequently reactivated in the same configu-ration rather than being involved in other configurations, hence, RA decreases withthe memory age, especially for frequently recurring semantic information. Other-wise, especially with rare episodic information, RA will grow with the memory age,which accounts for the reverse RA gradient.

Such treatment of the RA gradient looks similar to the way the Multiple TracesTheory explains it, referring to the accumulation of multiple duplicates of the samememory traces, but it has three significant distinctions. First, the cortical indexesof these traces need not be retained in the hippocampus, as automatic tuning ofthe theta rhythm frequency to the natural frequency of the dominanta group ofneocortical oscillators will restore the whole spatiotemporal configuration of thetrace, provided there are cues or other reminders to search for the previously learnedconfiguration. Second, the case of life-long flat RA may be accounted for not onlyby complete damage of the hippocampus, as in the Multiple Traces Theory, but byany other serious damage to the phase-frequency tracking system, for example, bytransection of the main inputs to the septo-hippocampal system. Third, the RAgradient is understandable in the event of complete hippocampus damage [270],since it is not the hippocampus, but the septal oscillator that induces frequencysynchronisation of cortical oscillators. True, vividness and quick automatic frequencytuning is hampered without the hippocampus, but there remains the possibility ofsearching (though less effective) for and retrieving old traces, e.g., by means of thefeedback from the neocortex to the septum, e.g., through amigdalaz [see Fig. 4(c)].Fourth, the reverse RA gradient should not be necessarily attributed to selectivedamage to the corresponding cortical structures, typical of, e.g., semantic dementia;it may also be explained by locking impairment due to a gradual steady shift in

yIt occurs under the condition of frequency nearness like |f − f0| < 0, 1f0.zCorresponding data on successful recollection of highly emotional memories in amnestic patient with dam-age to the hippocampus are presented by Buchanan et al. [19].

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the current arousal (AK) during natural aging, for instance, which makes remotememory, and especially its episodic variety, increasingly inaccessible because of thegradually developing dissociation in arousal level. This assertion is in agreementwith many cases of age-induced dissociation described, e.g., in [130].

The same explanation by locking impairment may be extended to the reminderphenomenon. But here, the dissociation in arousal, as the main causa for RA, willnot develop in a gradual manner, but will occur immediately as a result of a specialamnestic treatment of the preactivated old traces. In consequence, these traces arerecorded again in a new context. On the account of dissociation of their states,they will not be retrieved under the restored normal conditions, and will show everysymptom of RA. Retrograde amnesia will not arise unless old traces are preactivatedfrom their passive state.

Thus, the “Neurolocator” provides an explanation for the unusual, and is onlyrecently “legitimised”, even if long known in literature, the phenomenon of reminder,which is not infrequently, though without good reason, referred to as reconsolidation[187,220]. Our explanation of this phenomenon is rather similar to the one offered bythe retrieval-based theory [165,210] which requires similarity, or congruity betweenthe contexts of acquisition and retrieval. However, it differs from the latter in offeringa specific oscillatory neural mechanism, instead of the simple constraints imposedon neurobiological interpretation.

9.3. The effect of consolidation

Consolidation is crucial to the understanding of memory, and especially its featureof association. The latter, as described in Sec. 3.3, demonstrates a new type of plas-ticity in acquiring and stabilising the stored sensory information for some time afterlearning. This new type of plasticity manifests itself as a gradual change in the nat-ural frequency of oscillators in the auditory cortex on repetition of a conditionedacoustic signal, but is also generally applicable to a conditioned stimulus of anymodality. The relevant data [266, 267] pointing to the specificity, quick retention,consolidation, and being unlimited in time retention of traces is strong experimen-tal evidence in favour of the “Neurolocator” assumption 6 of Sec. 8.3. This is sobecause when the number of cortical oscillators locked in synchrony, as an ensem-ble exceeds the critical extent, the optimal labilities of these oscillators will tendto reach equality, i.e., the oscillators that assimilate common rhythm gradually willchange their natural frequency towards a common frequency over a certain period oftime (hours, days). The latter frequency, or to be more precise, its associated labil-ity persists even after suppression of oscillations in the inactive long-term memory,and will be recovered during retrieval when these oscillators return to activity inresponse to external stimulation or increased arousal. The above is consistent withthe recent result: “The ensemble that plays together, stays together” [36].

The retrieval of information is in fact the restoration of the isolabile configurationthat existed at the time of the acquisition. In the case of inactive oscillators, i.e., with

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the associated oscillations suppressed, such memory traces are stabilized againstdisturbance and interference, against superimposition of new information traces, andagainst damage by electric shock, etc. The term “consolidation” originally meanttransition from the fragile and initially vulnerable post-learning condition of memoryto a state of the above-mentioned stability [155]. Later on, its meaning was extendedto include enhancement, i.e., time-dependent increase in memory strength. In thisnew sense, consolidation implies the off-line involvement of the hippocampal system,without additional external learning. The “Neurolocator” explains it as follows.

Let us assume that after initial learning the parameter K in Eq. (3) has decreasedto K ′ < K as a result of diminished arousal after rest or sleep. Then, given a partialreminder of one of the formerly memorised configurations, the previous conditionfor disconnection of the hippocampus from the neocortex, AK/Λ0 > 1/gmin, is nolonger fulfilled, and the system comes to a condition of activity similar to PLL track-ing. Therefore, with the cortical oscillators locked in synchrony and new oscillatorsrecruited, parameter grows as high as A′ whereby the inequality A′K ′/Λ0 > 1/gmin

becomes valid, followed by habituation and disconnection of the hippocampus fromthe neocortex. In consequence, without any additional learning, the memory tracebecomes stronger in terms of both amplitude (A′ > A) and frequency selectivity,with the latter being the very reason for the amplitude increase A′ owing to theequalizing of the natural frequencies of the oscillators. The time required for suchincrease is roughly K/K ′ times longer than the period of initial learning, so consol-idation may take hours, or even weeks, but certainly not decades, as maintained inthe Standard Consolidation Theory.

The processes of attention and memory in sleep deserve special discussion. But,here it will be merely pointed out that the most likely reason for a change in parame-ter K is the variation of physiological arousal and theta rhythm amplitude, which —according to Vinogradova [259] — is caused by variation of the acetylcholine level inthe medial septum. Therefore, the above mechanism of trace strengthening withoutadditional learning provides a very simple explanation for the following seeminglyparadoxical finding [81]: high acetylcholine levels set the network dynamics to atten-tion, encoding, and novelty processing [205] while low levels switch it to consolidationand retrievalaa [26,206]. The same neuronal mechanism explains such consolidationfeatures as selectivity and graduality as follows.

If the model parameter K is decreased before learning to simulate deletion ofNMDA-receptors from the CA3 field cells in mutant mice [188], then the initialparameter AK/Λ0 decrease, which is equivalent to increase of Λ0, that is the decreaseof the frequency selectivity of cortical oscillators, and hence their spatial selectiv-ity will be impaired. Then, the system will have its parameter A self-adjusted to

aaIt is interesting to note that spontaneous retrieval of the event sequences is possible not only during sleepor rest but also in an awake state of low acetylcholine level, and more interestingly in direct as well asin backward time direction, depending on the sign of Λ0i in Eq. (1). We believe this property of Eq. (1)explains the sequential replay in the rat hippocampus in a temporally reversed order [58].

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optimal value through the consolidation of memory traces in sleep, when the naturalfrequencies of local oscillators are brought to the common locking frequency, similarto the way it was described for the case of consolidation in normal mice duringsleep. As a result, the spatial selectivity will improve without any additional supplyof external cues.

The graduality of consolidation, which is difficult to detect in a wakeful state[201], is easily found by comparing phases in conditions of REM sleep and wakeful-ness. Gradual learning in an unfamiliar part of the track causes the natural frequen-cies of cortical oscillators to change towards the constant theta rhythm frequencyin sleep, as well as in other conditions, owing to which their average phase declinesrelative to the theta rhythm phase, with this decline becoming more perceptibleat the REM stage than in a wakeful state. The latter is evident from the formulaϕ = g−1(Λ0/AK), derived by setting the right-hand side of Eq. (2) to zero, whereg−1 is a function inverse to g; its gradient in sleep is much higher, since the g gradientin sleep decreases due to the changing activity of the cholinergic system [81,188].

9.4. The effect of AA/RA dissociation

This effect with all its specific cases has the following inherently consistent expla-nation. The complete AA, that is a total failure to retain new information resultingfrom hippocampal lesion, as per “Neurolocator”, occurs when inequality (3) provesinvalid with any values of AK and Λ0. This is only possible if, upon damage tothe hippocampus, gmax decreases to g′max

∼= g′min, thus reducing to zero the phaselocking range of the parameter AK/Λ0 values, and virtually eliminating the oper-ating volume of the hippocampus. In reality, AA may be partial, corresponding notto disappearance, but only to narrowing of the locking range, and thus suggestingthis narrowing as a model measure of AA. In fact, it was found [52] that the extentof anterograde memory of visual material showed a relationship to hippocampalvolumes rather than to regional cortical white matter volumes, while retrogradevisual memory was related to posterior cortical white matter volumes, but not tohippocampal volumes. It was also discovered [3,17] that the degree of injury to thecortex was a better predictor of remote context memory deficit than hippocam-pal damage, whereas losses of recent episodic autobiographic memory, according toSchmidtke and Vollmer [223], are exclusively related to the damage suffered by thehippocampus. These data support the following model explanation of AA, and arehelpful in establishing a partially common mechanism for AA and RA.

In terms of the “Neurolocator”, hippocampal damage corresponds to changesof function g(ϕ), and respectively to a reduction in the locking range of AK/Λ0

values, for which inequality (3) is true (see Figs. 5(a) and 5(b), the grey areas HPand NC), while neocortical damage is associated simply with changing parameter A

by a fixed value, or equivalently, with a shift of the range parameter AK/Λ0 by thisfixed value (see Figs. 5(c) and 5(d)) to the right (hyperactivity, hyperexcitation) orto the left (hypometabolims, hypothermia, etc.). With these two types of variations

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in inequality (3) combined, we may explain all the AA-RA correlations presentedschematically in Fig. 5 in the following way.

Positive correlation results from the narrowing of the phase locking range: thenarrower it is, i.e., the larger the AA, the more extensive is the RA.

(a)

(b)

(c)

(d)

Fig. 5. The effect of AA/RA dissociation. (a) intact hippocampus and intact neocortex, no AA,no RA; (b) damaged hippocampus, intact neocortex (left — relational information; right — non-relational information); (c) intact hippocampus and damaged neocortex; (d) transiently damagedhippocampus and neocortex; arrows indicate memory restoration with time. RAs means semanticretrograde amnesia; AAE means episodic anterograde amnesia.

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Disproportionality is also a consequence of the locking range narrowing resultingin extensive AA, but in this case with mild RA only being in the non-relational infor-mation. In this case, a phase locking is of little importance, and retrieval may onlyrely on frequency synchronization (see feature 8 of Sec. 8.4), i.e., making direct useof the septum reset signal without involving the hippocampus. The above is consis-tent with the evidence that in normal humans fMRI activation of the hippocampusis greater, the more retrieval depends on relational processing [65], and that amnesicpatients show a deficit of associative recognition which is disproportionately greaterthan that of recognising single items [64]. Our model explains involvement of thehippocampus, both in relational and in item-based treatment of information, butthis involvement as shown by Davachi and Wagner [37] will be greater in the firstcase, due to a greater role of phase locking.

Focal RA is a case of a shift without narrowing (RA without AA). Transientgeneral amnesia (TGA) involves various combinations of temporary shift and tem-porary narrowing, with elimination of shift and narrowing progressing at differentrates. Subsequent discussion of the effect of E/S dissociation (see Secs. 4.2 and 9.5)will make it clear why episodic memory is affected more frequently and to a greaterextent, and is restored slower than semantic memory.

On the whole, our explanation of the effect of AA/RA dissociation is in agreementwith the existing hypothesis about the combination of two impairment mechanisms:hippocampal-anterograde and neocortical-recording/retrieval [223]. However, it cov-ers a far broader spectrum of data and provides the systematic explanation in termsof neural networks.

9.5. The effect of E/S dissociation

Episodic memory is affected by hippocampal lesion to a greater extent than is seman-tic memory, which is explained by the fact that, in accordance with Feature 8 ofSec. 8.4, it takes two treatment stages to record and replay episodic information,whereas with the less structured semantic memory, the same may be achieved inmany cases within the first stage. The first stage in a reduced form is possible with-out to hippocampal involvement. Our model can account for the case of selectivedamage to episodic memory with semantic memory being left intact, whereas selec-tive impairment of semantic memory, with preservation of episodic memory, is ruledout in our model, except for the case of extensive lesion of the cerebral cortex in thedominant left hemisphere (where semantic memory is known to suffer more damage,while lesion of the non-dominant right hemisphere leads to greater impairment ofepisodic memory [119]). Hence, it follows that the hippocampus is critical to therecording and replay of primarily episodic information, but not to the storage ofboth types of information.

The episodic memory will be affected to a greater extent, not only for the reasonthat there are more traces of semantic memory in the neocortex due to its morefrequent reactivation, but also because phase capture, which is absolutely necessary

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for episodic memory retrieval, cease to exist in the event of hippocampal damage.Selective impairment of episodic or semantic memory is accounted for (similar to thecase of focal RA) by the fact that brain damage may be followed either by a decreaseor increase of arousal, due to hypometabolism or hyperactivation, respectively. Thisis consistent with the existing evidence showing that semantic memory is affectedmore in the event of damage to the left hemisphere, which will function normallyunder a higher arousal as compared with the right hemisphere, while episodic mem-ory will suffer greater impairment if the right hemisphere is damaged [119]. Thus, ourmodel in contrast to the Multiple Traces Theory can provide a unified explanationof processing in hippocampus, for both episodic and semantic information.

9.6. The effect of place cell

According to the Theta-Regulated Attention Theory, the CA3 field registers thematch/mismatch of signals from the two major inputs irrespective of modality,because this field registers the coincidence of these two signals. It is therefore rea-sonable to regard the activity of a CA3 place cell as a microscopic analogue of thecross-correlation function of the two inputs, i.e., as an individual neural contributionto function Ag(ϕ) in Eq. (2), whence almost all the features of the place cell effectare derived, considering that the CA1 field will also register co-occurrence of activ-ity from the CA3 and neocortical inputs, and will enhance their spatial specificity;according to Muller [179], the CA3 and CA1 place cells are almost identical in thisproperty of co-occurrence, though their other properties are quite different [126].

Non-directivity implies independence of Ag(ϕ) from the direction in which theanimal’s head is pointing in the case of a cylindrical apparatus, which is similar tothe way the cross-correlation function of a stationary stochastic processes dependsonly on the temporal shift in τ = t− (t− τ), and is independent of the current timet, or in our case — the current head direction.

Remapping is an abrupt change in Ag(ϕ) upon variation of the theta rhythmfrequency caused by changes in the internal or external conditions, or following achange of the conditioned stimulus [170]. In this case, the isolabile configurationof cortical oscillators synchronized by a new theta-rhythm will undergo an unpre-dictable alteration, and the topological relations between the fields of various placecells will no longer be retained, which points to the absence of topological corre-spondence between the anatomical location of place cells in the hippocampus andthe spatial location of place fields.

Stability firing of place cells is the stability of correlations Aigi(ϕi), and reflectsthe stable or steady theta-rhythm under a condition of predominant attention toany stimulus [111], as well as more long-term stabilization of place fields as a resultof cortical episodic memory consolidation, as suggested also by Kentros [109].

Dual code is pair: activity Ag(ϕt) and phase ϕt connected by Eq. (2). The firstcomponent, due to a strong dependence of A and gmin on arousal, is found to berelated to the movement speed of the rat, in as much as the latter is also highly

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dependent on arousal. Furthermore, it first increases and then decreases along thetrack as cross correlation of two inputs. The second component, depending on detun-ing Λ0 as per Eq. (2), accounts for the change of the rat’s position from the placefield center, whereΛ0 = 0, and changes monotonically away from it, assuming thatvarious natural frequencies of cortical place oscillators correspond to different loci.Both codes according to Eq. (2) are highly correlated during phase-locking, andindependent otherwise. The data of Zugaro et al. [279] prove that the hippocampusdoes not contain place theta oscillators. This accords with data obtained by Jonesand Wilson [101], and Siapas et al. [233] as described in Sec. 2.1.

Directionality results from the progressive recruitment of new cortical oscillatorsin formation of a place field (passive in backward shift and learned in forward shift)with repeated rat’s movement in the same direction.

Multimodality is an almost obvious feature, as Ag(ϕt) defines the cross-correlations between spatial information and a signal of any modality in the CA3field, while additional spatial selection in the CA1 field enhances the spatial featuresand preserve multimodal representation of an object found in the place field of agiven cell. Multimodality is a basis for allocentric representation of the object (thatis representation in object-centered coordinates) since it is only possible in the caseof synchrony of spatial and feature oscillators.

9.7. The effect of viewpoint

It is accounted for by the following: a patient with bilateral hippocampal lesion iscapable of recognizing a familiar object from an unchanged viewpoint owing to thefact that the theta rhythm frequency, relying on the feedback from the neocortex tothe septum, will be roughly the same as during learning, provided that the learningprocess was sufficiently long. In the absence of pathology, the near-independence ofthe recognition time from the shift angle is explained by the fact that the attentionsystem, making a search in the long-term memory, will quickly and automaticallytune the theta rhythm frequency to that of involved in the learning process, whichmanifests itself as a sharp increase in coefficient A at this frequency.

9.8. The effect of age independence

It is explained by two special features of the “Neurolocator”. First, the extent offMRI activation of the hippocampus during scanning with simultaneous recollectionof past events is determined not only by the activated area of hippocampus, but alsoby the time of activation of a particular memory trace. Second, although the timeof activation of an old trace due to noise N(t) in the system Eq. (1) is a randomvariable, as time of attention catching is dependent on the degree of learning andretention of information, and on the sophistication of the retrieval task, the expectedvalues of this time in many cases may nevertheless be only slightly dependent onthe memory age. In fact, the analyses and computational estimates of this time,

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Fig. 6. Transient attention: mean time (tϕ) to the first breakdown of attention as a function ofarousal (AK/Λ0) and initial phase(ϕ0). Adopted with permission from Kryukov et al. [124]. Eachcurve of tϕ is obtained as a numerical solution for the probabilistic mean first passage time ofbilateral boundary for the stochastic diffusion process described by Eq. (1) in a particular case:n = 1, F (p) = K, the diffusion coefficient D = 1/30 and nonlinear sigmoid function g(ϕ) =αϕ− [1 + exp(−ϕ + 3)]−1, α = 0.2.

presented in Fig. 6, indicate that the expected duration of attention, i.e., the timeduring which phase-locking of neocortical oscillators and septal theta-generator takeplace, as a function of parameter AK/Λ0, at fixed ϕ0, has a plateau, and hence, willnot depend on the age in a certain region of this parameter, despite the fact thatthis parameter, and especially A, may vary and be distinctly age-dependent. It is tothe existence of this plateau that we attribute the most frequently reported indepen-dence of the fMRI activation magnitude from the age of memory traces. In general,hippocampal activation as follows from Fig. 6 may show various patterns depend-ing on the arousal, the initial conditions, and the adopted registration method. Inparticular, the unusual data on the different character of activation in the left andright parts of the hippocampus [137] is accounted for by the difference in time thatis required for the activation of traces in the left and right hemispheres, due to theirdifferent arousal.

This explanation is consistent with some reported information [219] to the effectthat under similar conditions, the fMRI activation will peak within two secondsin the left hippocampus and within 6–8 s in the right one. A similar explanationof the same data of Maguire and Frith [137] is provided in [62], with the onlydifference being that our explanation covers uniformly all of the other reported casesof dependence on age, and discloses the cause (plateau) for prevalence of cases, wherethe age of memory traces are irrelevant.

10. Predictions and Supporting Results

Having explained all the effects underlying the four major theories under considera-tion without assumption on hippocampal memory, we can make specific predictions

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which simultaneously provide the answer to questions 1–6 in the Introduction, viz.

(1) Spatial information may be regarded as having precedence over other types ofinformation about an object, not only in rats, but also in humans, becauseof the output regions of the dorsal tract (“Where?”) operate mainly at thetheta-rhythm frequency of the attention system, and have greater weight, evenin the case of non-spatial problems, whereas the ventral tract (“What?”) usesmainly gamma-rhythm frequencies, which may have less influence on septo-hippocampal control of attention. This prediction is partially supported bynew data from Kumaran and Maguire [125], and Duzel et al. [46], showing ahippocampal preference or bias toward the processing of spatial information.Also we predict that view-independent (allocentric) representation of placesand objects is only possible with interaction of these two channels in thehippocampus.

(2) Spatial and non-spatial information about the same object nonlinearly inter-act in the hippocampus along its longitudinal axis by means of joint con-trol of the septal theta rhythm frequency, with each lamella correspond-ing to maximal activation will have grater control over theta frequency, andprovide better object memory than its spatial or non-spatial component inisolation. This prediction was confirmed by Small [235], Small et al. [236],demonstrating nonlinear fMRI activationab along longitudinal axis with great-est fMRI activation in the body of the hippocampus during pairing faceswith names. A similar activation pattern was observed when names wererecalled cued with faces. However, we further predict that the actual associ-ation of these two types of information is not localized within the hippocam-pus, but is distributed among all the major brain structures locked in thetaand gamma rhythm frequencies, which is possible to a certain degree evenwith severe hippocampal lesions, e.g., as reported in [270]. Manns and Eichen-baum [143] state that a fundamental function of the mammalian hippocam-pus is to combine incoming information about spatial context and nonspacialitems, suggesting the echolocation system in bats as a suitable experimentalmodel. We predict that the adequate neuronal model for it will be the“Neurolocator”.

(3) Besides synaptic plasticity, the neocortex has a neuronal ensemble plasticity.In model terms, it was formulated as Isolability Assumption [122], resultingin a new learning scheme, which is potentially able to provide infinite LTMcapacity due to combinatorics of topographic ensemble code. A similar type ofplasticity has been recently described in the somato-sensory cortex as “map plas-ticity” [53], in the hippocampus and primary sensory cortex as “neural cliqueassemblies” [131], in the visual cortex as “effective connectivity” [275], and in

abAs for the fMRI activation connected with the presence of oscillatory brain processing see [190] and [228],and many other, demonstrating close correlation between hemodynamic responses and neuronal synchro-nization.

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the auditory cortex as “receptive field plasticity” [266]. The auditory memorywith such plasticity has all the attributes of associative memory, including con-solidation and cognitive/behavioral correlates. By Isolability Assumption, thisnew type of plasticity may serve in other sensory modality as a neurobiologicalsubstrate for LTM being free from the well known limitations of the memorybuilt upon synaptic plasticity, though closely related to it. This prediction isimplicitly expressed in [267], and [131], and it is in agreement with the resultsof Buonomano and Merzenich [20] that cortical map plasticity cannot be fullyaccounted for by synaptic plasticity.

(4) There is no clear-cut demarcation line between the treatment of the episodic andsemantic memory systems, in the sense that the two-stage hippocampal process-ing is required for episodic, as well as semantic information. The difference inthis respect lies in the degree of hippocampal involvement into the synchroniza-tion process (from almost complete noninvolvement in the case of well learnedsemantic information via partial involvement for semantic information withepisodic elements, to complete involvement in phase lock stages for episodicinformation). This prediction is supported by Snowden and Neary [237], Snow-den et al. [238], Howard et al. [93], all supplying data sufficient for rejecting theview that episodic and semantic memory are separate memory systems. Thesame is true with respect of data from McCarthy et al. [152].

(5) The following prediction was originally formulated in Dudai [43, p. 211]: “It isnot the active state of LTM that persists throughout the lifetime of memory.Rather, what persists is the capacity to reactivate, or reconstruct, the originalor a similar representation by the process of retrieval”. Indeed, the retrievalin “Neurolocator” is actually restoration, or rather reconstruction, of isolabile(i.e., isofrequency, isodirectional, isofeatural, etc.) configuration, or a similarone, which existed at the time of acquisition. This configuration, in a stateof inattention, persists in the dormant state of locally active persistent spots.The persistence of local spots refers to the prolonged lifetime of microcolomnactivity, due to the assumption that the functional element of the neocortex isnot a single neuron, but small local neuronal ensemble capable of generatingthe cooperative effect of spot persistence, as shown in Fig. 2. The object codingby the combination of active spots in both optical and extracellular recordingswas recently discovered in the visual cortex [249], which is strong support forour spatiotemporal code through Isolability Assumption, as well as for our spotpersistence effect. As for the hippocampal LTP, it is not obligatory for thisspecific type of coding, but as predicted by Martin and Morris [147], has a lessspecific supporting role that accompanies memory formation, namely in our case,it prevents the overwriting of preexisting information. This is in accord with therecent findings of [154], and earlier findings from [110,221] saying that NMDA-receptor blockade impairs post-training consolidation, but is not essential forthe processes necessary to learn or retain spatial information in the short term.

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(6) The hippocampus is involved in two different functional systems, and performsdissimilar, but mutually coordinated functions, which ensure a normal atten-tion process and fixation of memory traces in the neocortex. However, itis not the locus for either long-term, intermediate-term, or even short-termstorage of memory traces. It is indispensable for the arrangement of selec-tive perception and suppression of irrelevant information, for habituation toinvariant signals, and for detection of novel or significant changes whichshould be recorded in neocortical memory. This prediction was formulated byVinogradova [260], and was experimentally supported by two of the most impor-tant findings: first, the CA3 field is critical for novelty detection [126], second,episodic retrieval and visual attention are similarly activate in almost the samebrain regions [24]. Also, there is a lot of new data in support of the predic-tion that oscillatory neuronal synchrony serves as a mechanism of attention[50,56,226,250], mechanism of memory [6, 158, 197, 226, 228] and mechanism ofcognition [102,275].

11. Discussion

This paper contains results directly bearing on the controversial issues of the natureof memory traces in the brain, their acquisition, consolidation, persistence, retriev-ability, and the role of hippocampus therein. Recent debates concerning these issueshave shown that it is impossible today to reconcile the existing theories of long-termmemory on purely experimental grounds for the following reasons. Firstly, these the-ories usually tend to ignore, or suitably reinterpret, certain data which will not fitin with their logic, and secondly, they rely too much on the localization of varioustypes of memory in different brain structures, and endow the hippocampus withthe properties of storing memory traces of various types — from spatial to episodicmemory.

The “Neurolocator” model is free from the above shortcomings, as it takesinto account the most important data of the four major theories in the globalaspect of long-term memory beyond the hippocampus. However, it is essentiallyat variance with the customary aspects of connectionists models, e.g., with theassumptions on the auto-associative function of hippocampal field CA3, or on thefunction of LTP as a storage medium for specific memory in the hippocampus andneocortex.

In our attempt to offer an alternative to the connectionist model, we find itnecessary to reveal and criticize the shortcomings of the current neurobiologicaltheories, and we show a way for reconciling them within one, more flexible andadequate, theoretical framework. Admittedly, this approach is in contradiction withthe spirit of the current theoretical trends. So, for instance, many scientists mayfind it hard to accept the idea of a global synchronization system in the brain, as itinvalidates the concept of multiple memory systems. Objections may be also raised

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against the idea about a new type of cortical plasticity, as it practically negatesthe commonly accepted hypothesis of Hebb’s modification. Yet another challengeis the assumption that the CA3 field of hippocampus primarily serves the simplefunction of a comparator and does not store memory traces, which undermines thefoundations of almost all of the existing long-term memory theories.

The new approach based on Ukhtomsky’s dominanta principle offers among otherthings, a fresh and fruitful insight, not only into the memory and attention processes,but also into the general cognitive/behavioral function of the brain, including itsrelation to the phenomena of consciousness and mind, the problems of personal-ity, and social psychology. To this end, however, it is necessary first to identifyexplicitly the contradictory trends, and to reconcile them in the context of thenumerous data they are based upon by using the dominanta model of memory andattention.

The strength of our approach can be demonstrated in the following discussion ofthe long standing memory persistence problem, namely, what it is that physicallypersists in long-term memory. It involves, two issues [44], p. 190. First, why is itthat, in spite of the short lived individual components of the cellular material inwhich the trace is registered, the engram endures sometimes for a lifetime? This isthe “endurance issue”. Second, how do memory traces persist over periods in whichthey are not expressed? This is the “dormancy issue”. Let’s turn to the “enduranceissue” first. Dudai [44] considers it both at the molecular level and the synapticto circuit levels, but we restrict discussion to the circuit level, since all the dataconsidered in previous Sections are from this level.

Most neuroscientists believe that hippocampal LTP is the core mechanism oflearning and memory. But they usually do not take into account that: (a) there is noevidence that LTP changes encode the memory itself, that is specific engram [147],and (b) LTP rapidly decays due to destabilising processes such as the metabolicturnover of synaptic receptors [231]. It is the strength of the Standard Consoli-dation Theory that it took the “endurance issue” seriously, and depicts the twosystem processes that are engaged to overcome the brief life span of proteins dueto their molecular turnover at the synaptic level to the circuit level. The main ideais that despite the short life time of hippocampal LTP, it may need only last longenough to permit the completion of a slower neocortical consolidation process [147]simply by shifting fast learned information from the hippocampus to the neocor-tex. Unfortunately, the cortical traces are also subject to the same destabilisingforces due to the five-days lifespan of synaptic NMDA-receptors [231, 271], so thatit is questionable whether many synapses, that had been modified from their orig-inal consolidation, survive to the time of retrieval, months or even years later [45].There exist three main proposals to solve this more general system-level persistencyproblem.

The first proposal assumes that the cortical reactivated traces may be retrievedback to the hippocampus for further association with the initial hippocampal trace

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[38, 272], with simultaneous periodic strengthening of them through the so called“synaptic reentry reinforcement”, i.e., repeated post learning reinforcement “at thesame set of synapses or neurons that were involved in creating the major mem-ory traces in the network” [232, p. 755a]. Unfortunately, this proposition involvedanother still unsolved problem, that of temporal tagging [168,174,247,257,269] beingneeded to temporarily mark memory traces, and to make sure that the correct reac-tivation at the same original set of synapses occurs during cortical consolidation,even after repeated trace retrieval back to hippocampus.

The second proposal is virtually contained in the Multiple Traces Theory assump-tions, and it seems as near to the goal as the first, since here for trace reinforcementto happen, there is no need to transfer the specific information from the hippocam-pus to the neocortex and back again, but only to increase the number of traces inthe neocortex and hippocampus in each memory retrieval. Unfortunately, the pro-posal requires long term hippocampal storage of binding codes that can saturate thesmall hippocampal capacity [173, 272]. Besides, it involves some other reservationsas described in Sec. 4.3.

The third proposal described in Dudai [44, 45] is the most radical of them all,and seems to be free from the above problems, but at the same time is the mostdifficult to accept since it comes against Zeitgeist.ac Memories, according to thisproposal, are encoded not by hippocampal LTP, but by spatiotemporal patternsof neural population activity. These memories may still involve synaptic plasticity,but their synapses should not necessarily be original ones, and may be degrade:“What is retained over time is not the actual internal representation, but ratherthe capacity to generate it. The information is stored in “hardware” alternations inthe circuit that is capable of expressing that specific representation. For a memoryto be retrieved, certain cues are required to engage the circuit and generate therelevant activity pattern anew. In other words, memories are not retained “as is”,but reconstructed; what persists after learning is the changes in the system thatleads to their reconstruction in a certain way, but not another . . . ” [44, p. 191].This is a new tentative solution to the “endurance issue” through cell assemblycoding by nonpersistent elements. As for the “dormancy issue”, it is resolved in thisproposal by transition of the memory system, or some part of it, into an inactivestate. “We know that physical systems, like neural networks, could endure for a longtime in semistable energy minima and still show much dynamics and flux” [45, p.78]. Long term traces persist in such a dormant inactive representational state untilreactivation in retrieval occurs.

Concerning the neural realization of this theoretical proposition, the “Neu-rolocator” may be considered as the model implementation of it. Indeed, here

acThe fourth proposal by Arshavsky [4] to solve the persistence problem by applying genomic hypothesisis also radical and against zeitgeist, but we will not discuss it here because it does not as yet involve thehippocampal function.

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memories are encoded by spatiotemporal configurations of globally synchronizedcortical microcolumns oscillators, whose natural frequency could be modified andpreserved according to Isolability Assumption by synaptic protein synthesis, or someother biophysical mechanism to fix a new natural frequency. By means of PLL action,the “Neurolocator” is capable to generate or reconstruct various learned patterns ofcortical activity anew, with theta-rhythm being a binding code for cortical featureoscillators. This is the model solution to the “endurance issue”. As for the “dor-mancy issue”, it is resolved here by automatic lowering of the parameter of arousalduring rest or sleep, leading to the transition of the whole system, or some part of it,into the state of desynchronization and inactivity, resulting in local effect of persis-tent spots. By returning to normal arousal, the system will automatically revive theglobal active state with a specific cortical configuration defined by system dynamicsand specific cues. Thus, the “Neurolocator” provides a radically new solution to thetrace persistence in the memory system composed of nonpersistent elements. How-ever, the previous attempts in this direction are not discarded altogether, but bybeing suitably adapted, they can be incorporated into a more general framework. Forexample, Vertes [257] proposed hippocampal theta-rhythm as a tag for short termmemory by driving hippocampal neurons to the threshold of activation of NMDAreceptors in LTP. This proposal obviously can not solve the problems discussed, butnevertheless move it close to our solution. Similarly, Mizuhara et al. [168] proposeda beta-rhythm as an index for cortical networks for functional integration of widelydistributed neural activity. Both propositions are in agreement with feature 7 ofSec. 8.4.

12. Conclusions

Our model makes explicit use of the following ideas which we believe to be crucialfor the understanding of long-term memory: (i) The main functional element is acomparatively small assembly, a group of neurons which, appearing in slightly differ-ent versions and combinations, serves as a unified submodule for the system modelof attention and memory; (ii) During active perception of external stimuli, individ-ual submodules and the whole system work near points of an unstable equilibriumresembling the physical phase transitions; (iii) The key principle of integrating sub-modules into a system is dominanta principle, which defines the main propertiesof attention and memory, especially system inertia and trace persistence. We asso-ciate it definitely with phase transitions, low-frequency EEG oscillations, and phaselocking of these oscillations. At the highest level, the brain has a phase-frequencytracking system of automatic regulation which controls attention and memory inhumans, and operates in the theta-gamma frequency band with the function ofits key component, i.e., comparator, fulfilled by the hippocampus. If so, we havegood grounds for reconciling all the major theories on the role of the hippocampusin long-term memory within one theory, namely, the Theta-Regulated AttentionTheory developed by O. S. Vinogradova; (iv) The basic difference of our approach

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from current connectionist modeling is a strong unifying neurobiological orienta-tion and essential usage of new mathematical tools, such as the theory of MarkovInteraction Processes and the related dynamic control system called phase-lockedloop (PLL). In particular, the model postulates a new type of cortical plasticitywhich does not use Hebbian hypothesis of synaptic modification to store the spe-cific memory in the neocortex. All these ideas are realized in our system-level modelwhich allows explaining, from a unified point of view, a large body of experimentaleffects as a common ground for reconciliation of rival theories, with due regardsfor their individual significant contributions to the general theory of long-termmemory.

Several attempts have been made to reconcile a number of concurrent theorieson the role of the hippocampus in long-term memory. Those attempts have not beencompletely satisfactory, as they fail to take into account the specific contribution ofrival theories into one general theory. On the contrary, Vinogradova’s [260] theory,as supported by the “Neurolocator”, takes into account the individual contributionsof all the major theories, and is rejecting the main cause of disagreement — commonhypothesis that the hippocampus is a memory store of various type — can reconcileall of them in the following sense. It is like the Cognitive Map Theory in thathippocampal processing of spatial information is playing a primary and central rolein LTM. It is like the Standard Consolidation Theory, in that declarative memoryis a unified system that need not be divided into separate episodic and semanticmemory, and that its final store is the neocortex, and not the hippocampus. It islike the Multiple Traces Theory, in that the hippocampus is critical for retrieval ofepisodic-like information, whatever its age.

Considering that the “Neurolocator” is able to answer a number of fundamen-tal questions on long term memory and attention, it seems safe to maintain that:(a) phase transitions in the brain are not a theoretical provision which is only usefulfor a unified explanation of numerous facts, but are real brain phenomena existingat the various levels of neuronal organization; (b) the principle of phase-frequencysynchronization, or more generally, the dominanta principle as a local and systemmanifestation of phase transitions in the nervous system is probably the main prin-ciple of brain functioning; (c) the brain contains a phase-locked loop tracking systemautomatically controlling attention and memory in humans, and is functioning inthe theta-gamma frequency band, in which the hippocampus has the multifunctionalrole of a key element, critically depending on the CA3 field comparator.

So, the theory by Vinogradova [260] explains far more phenomena than othertheories; it is simultaneously coherent with the information and theories in differentbranches of science: neurobiology, neuropsychology,engineering, statistical physicsand mathematics. Therefore, according to the philosophical orientation of Conant[33] it potentially can overthrow the theories that living memories are stored in hip-pocampus. Thus, “we are [not] far away from understanding how the hippocampusfunctions as part of an integrated brain system. Indeed, such understanding may[not] be beyond comprehension” [96, p. 104].

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Acknowledgement

We would like to thank Jakov Kazanovich, Vladimir Arhipov, and five anonymousreferees for critical comments on our earlier draft of this manuscript, HegumenInnokentiy, Anna Scherbakova and Ludmila Melnikova for technical assistance, andJohn Reynolds for editorial assistance.

Note Added in Proof

There appeared a series of new data in support of the comparator model. Seee.g., Kumaran D, Maguire EA, Which computational mechanisms operate in thehippocampus during novelty detection? Hippocampus 17:735–748, 2007.

References

[1] Alvarez P, Squire LR, Memory consolidation and the medial temporal lobe: A simplenetwork model, Proc Natl Acad Sci USA 91:7041–7045, 1994.

[2] Amzica F, Steriade M, The K-complex: Its slow (< 1-Hz) rhythmicity and relation todelta waves, Neurology 49:952–959, 1997.

[3] Anagnostaras SG, Gale GD, Fanselow MS, The hippocampus and Pavlovian fearconditioning: Reply to Bast et al., Hippocampus 12:561–565, 2002.

[4] Arshavsky YI, The seven sins of the Hebbian synapse: Can the hypothesis of synapticplasticity explain long-term memory consolidation? Prog Neurobiol 80:99–113, 2006.

[5] Axmacher N, Mormann F, Fernandez G, Elger CE, Fell J, Memory formation byneuronal synchronization, Brain Res Brain Res Rev 52:170–182, 2006.

[6] Bastiaansen M, Hagoort P, Event-induced theta responses as a window on the dynam-ics of memory, Cortex 39:967–992, 2003.

[7] Bayley PJ, Squire LR, Medial temporal lobe amnesia: Gradual acquisition of factualinformation by nondeclarative memory, J Neurosci 22:5741–5748, 2002.

[8] Bayley PJ, Squire LR, Failure to acquire new semantic knowledge in patients withlarge medial temporal lobe lesions, Hippocampus 15:273–280, 2005.

[9] Bayley PJ, Hopkins RO, Squire LR, Successful recollection of remote autobiographicalmemories by amnesic patients with medial temporal lobe lesions, Neuron 38:135–144,2003.

[10] Bayley PJ, Gold JJ, Hopkins RO, Squire LR, The neuroanatomy of remote memory,Neuron 46:799–810, 2005.

[11] Bernard FA, Bullmore ET, Graham KS, Thompson SA, Hodges JR, Fletcher PC, Thehippocampal region is involved in successful recognition of both remote and recentfamous faces, Neuroimage 22:1704–1714, 2004.

[12] Borisyuk RM, Kazanovich YB, Oscillatory neural network model of attention focusformation and control, Biosystems 71:29–38, 2003.

[13] Borisyuk RM, Kazanovich YB, Oscillatory model of attention-guided object selectionand novelty detection, Neural Netw 17:899–915, 2004.

[14] Borisyuk R, Cooke T, Metastable states, phase transitions, and persistent neuralactivity, Biosystems 89:30–37, 2007.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 171

[15] Borisyuk R, Denham M, Hoppensteadt F, Kazanovich Y, Vinogradova O, Oscillatorymodel of novelty detection, Network: Comput Neural Syst 12:1–20, 2001.

[16] Bragin AG, Vinogradova OS, Emelianov VV, Influence of the dentate fascia on thesensory responses of neurons in hippocampal field CA3, Zh Vyssh Nerv Deiat Im I PPavlova 26:605–611, 1976.

[17] Bright P, Buckman J, Fradera A, Yoshimasu H, Colchester AC, Kopelman MD, Ret-rograde amnesia in patients with hippocampal, medial temporal, temporal lobe, orfrontal pathology, Learn Mem 13:545–557, 2006.

[18] Brown AS, Consolidation theory and retrograde amnesia in humans, Psychon BullRev 9:403–425, 2002.

[19] Buchanan TW, Tranel D, Adolphs R, Emotional autobiographical memories inamnesic patients with medial temporal lobe damage, J Neurosci 25:3151–3160, 2005.

[20] Buonomano DV, Merzenich MM, Cortical plasticity: From synapses to maps, AnnuRev Neurosci 21:149–186, 1998.

[21] Burgess N, Becker S, King JA, O’Keefe J, Memory for events and their spatial context:Models and experiments, Philos Trans R Soc Lond B Biol Sci 356:1493–1503, 2001.

[22] Bussey TJ, Multiple memory systems: Fact or fiction? Q J Exp Psychol 57:89–94,2004.

[23] Buzsaki G, Rhythms of the Brain, Oxford University Press, 2006.[24] Cabeza R, Dolcos F, Prince SE, Rice HJ, Weissman DH, Nyberg L, Attention-related

activity during episodic memory retrieval: A cross-function fMRI study, Neuropsy-chologia 41:390–399, 2003.

[25] Canolty RT, Edwards E, Dalal SS, Soltani M, Nagarajan SS, Kirsch HE, Berger MS,Barbaro NM, Knight RT, High gamma power is phase-locked to theta oscillations inhuman neocortex, Science 313:1626–1628, 2006.

[26] Cartwright RD, The role of sleep in changing our minds: A psychologist’s discussionof papers on memory reactivation and consolidation in sleep, Learn Mem 11:660–663,2004.

[27] Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM,Stevens JM, Cipolotti L, Rossor MN, Patterns of temporal lobe atrophy in semanticdementia and Alzheimer’s disease, Ann Neurol 49:433–442, 2001.

[28] Chan D, Revesz T, Rudge P, Hippocampal, but not parahippocampal, damage ina case of dense retrograde amnesia: A pathological study, Neurosci Lett 329:61–64,2002.

[29] Cipolotti L, Shallice T, Chan D, Fox N, Scahill R, Harrison G, Stevens J, Rudge P,Long-term retrograde amnesia . . . the crucial role of the hippocampus, Neuropsycholo-gia 39:151–172, 2001.

[30] Clark RE, Broadbent NJ, Zola SM, Squire LR, Anterograde amnesia and temporallygraded retrograde amnesia for a nonspatial memory task after lesions of hippocampusand subiculum, J Neurosci 22:4663–4669, 2002.

[31] Clark RE, Broadbent NJ, Squire LR, Hippocampus and remote spatial memory inrats, Hippocampus 15:260–272, 2005.

[32] Clark RE, Broadbent NJ, Squire LR, Impaired remote spatial memory after hippocam-pal lesions despite extensive training beginning early in life, Hippocampus 15:340–346,2005.

[33] Conant JB, Science and common sense, Yale University Press, New Haven, 1951.

April 1, 2008 10:56 WSPC/179-JIN 00171

172 Kryukov

[34] Cowan N, The magical number 4 in short-term memory: A reconsideration of mentalstorage capacity, Behav Brain Sci 24:87–114, 2001.

[35] Dash PK, Hebert AE, Runyan JD, A unified theory for systems and cellular memoryconsolidation, Brain Res Brain Res Rev 45:30–37, 2004.

[36] Davachi L, The ensemble that plays together, stays together, Hippocampus 14:1–3,2004.

[37] Davachi L, Wagner AD, Hippocampal contributions to episodic encoding: Insightsfrom relational and item-based learning, J Neurophysiol 88:982–990, 2002.

[38] Day M, Morris RG, Memory consolidation and NMDA receptors: Discrepancy betweengenetic and pharmacological approaches, Science 293:755, 2001.

[39] Demiralp T, Bayraktaroglu Z, Lenz D, Junge S, Busch NA, Maess B, Ergen M,Herrmann CS, Gamma amplitudes are coupled to theta phase in human EEG duringvisual perception, Int J Psychophysiol 64:24–30, 2007.

[40] Desimone R, Visual attention mediated by biased competition in extrastriate visualcortex, Philos Trans R Soc Lond B Biol Sci 353:1245–1255, 1998.

[41] Diwadkar VA, McNamara TP, Viewpoint dependence in scene recognition, PsycholSci 8:302–307, 1997.

[42] Douville K, Woodard JL, Seidenberg M, Miller SK, Leveroni CL, Nielson KA,Franczak M, Antuono P, Rao SM, Medial temporal lobe activity for recognition ofrecent and remote famous names: An event-related fMRI study, Neuropsychologia43:693–703, 2005.

[43] Dudai Y, Molecular bases of long-term memories: A question of persistence, CurrOpin Neurobiol 12:211–216, 2002.

[44] Dudai Y, Memory from A to Z. Keywords, Concepts, and Beyond, Oxford UniversityPress, 2004.

[45] Dudai Y, The neurobiology of consolidations, or, how stable is the engram? Annu RevPsychol 55:51–86, 2004.

[46] Duzel E, Habib R, Rotte M, Guderian S, Tulving E, Heinze HJ, Human hippocampaland parahippocampal activity during visual associative recognition memory for spatialand nonspatial stimulus configurations, J Neurosci 23:9439–9444, 2003.

[47] Eichenbaum H, Hippocampus: mapping or memory? Curr Biol 10:R785–R787, 2000.[48] Eichenbaum H, Cohen NJ, From Conditioning to Conscious Recollection, Oxford

University Press, Oxford, 2001.[49] Eichenbaum H, Dudchenko P, Wood E, Shapiro M, Tanila H, The hippocampus,

memory, and place cells: Is it spatial memory or a memory space? Neuron 23:209–226, 1999.

[50] Ekstrom AD, Caplan JB, Ho E, Shattuck K, Fried I, Kahana MJ, Human hippocampaltheta activity during virtual navigation, Hippocampus 15:881–889, 2005.

[51] Evans JJ, Graham KS, Pratt KH, Hodges JR, The impact of disrupted cortico-corticoconnectivity: A long-term follow-up of a case of focal retrograde amnesia, Cortex39:767–790, 2003.

[52] Fama R, Marsh L, Sullivan EV, Dissociation of remote and anterograde memoryimpairment and neural correlates in alcoholic Korsakoff syndrome, J Int NeuropsycholSoc 10:427–441, 2004.

[53] Feldman DE, Brecht M, Map plasticity in somatosensory cortex, Science 310:810–815,2005.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 173

[54] Fell J, Fernandez G, Klaver P, Elger CE, Fries P, Is synchronized neuronal gammaactivity relevant for selective attention? Brain Res Brain Res Rev 42:265–272, 2003.

[55] Fell J, Klaver P, Lehnertz K, Grunwald T, Schaller C, Elger CE, Fernandez G, Humanmemory formation is accompanied by rhinal-hippocampal coupling and decoupling,Nat Neurosci 4:1259–1264, 2001.

[56] Fell J, Klaver P, Elfadil H, Schaller C, Elger CE, Fernandez G, Rhinal-hippocampaltheta coherence during declarative memory formation: Interaction with gamma syn-chronization? Eur J Neurosci 17:1082–1088, 2003.

[57] Fischer H, Wright CI, Whalen PJ, McInerney SC, Shin LM, Rauch SL, Brain habitu-ation during repeated exposure to fearful and neutral faces: A functional MRI study,Brain Res Bull 59:387–392, 2003.

[58] Foster DJ, Wilson MA, Reverse replay of behavioural sequences in hippocampal placecells during the awake state, Nature 440:680–683, 2006.

[59] Fujii T, Moscovitch M, Nade L, Memory consolidation, retrograde amnesia, and thetemporal lobe, in Boller F, Grafman J (eds.), Handbook of Neuropsychology, 2nd (edn),2:223–250, Elsevier Press, Amsterdam, Netherlands, 2000.

[60] Fujisawa S, Matsuki N, Ikegaya Y, Single neurons can induce phase transitions ofcortical recurrent networks with multiple internal states, Cereb Cortex 16:639–654,2006.

[61] Gaffan D, Against memory systems, Philos Trans R Soc Lond B Biol Sci 357:1111–1121, 2002.

[62] Gilboa A, Winocur G, Grady CL, Hevenor SJ, Moscovitch M, Remembering our past:Functional neuroanatomy of recollection of recent and very remote personal events,Cereb Cortex 14:1214–1225, 2004.

[63] Gilboa A, Ramirez J, Kohler S, Westmacott R, Black SE, Moscovitch M, Retrievalof autobiographical memory in Alzheimer’s disease: Relation to volumes of medialtemporal lobe and other structures, Hippocampus 15:535–550, 2005.

[64] Giovanello KS, Verfaellie M, Keane MM, Disproportionate deficit in associative recog-nition relative to item recognition in global amnesia, Cogn Affect Behav Neurosci3:186–194, 2003.

[65] Giovanello KS, Schnyer DM, Verfaellie M, A critical role for the anterior hippocampusin relational memory: Evidence from an fMRI study comparing associative and itemrecognition, Hippocampus 14:5–8, 2004.

[66] Gluck MA, Meeter M, Myers CE, Computational models of the hippocampal region:Linking incremental learning and episodic memory, Trends Cogn Sci 7:269–276, 2003.

[67] Golikov NV, The question of local and disseminated excitation in contemporary neu-rophysiology, in Vereschagin SM, Golikov NV (eds.), Mechanisms of local reactionsand propagating excitation, pp. 5–12. Nauka: Leningrad, 1970.

[68] Graham KS, Hodges JR, Differentiating the roles of the hippocampal complex andthe neocortex in long-term memory storage: Evidence from the study of semanticdementia and Alzheimer’s disease, Neuropsychology 11:77–89, 1997.

[69] Graham KS, Simons JS, Pratt KH, Patterson K, Hodges JR, Insights from semanticdementia on the relationship between episodic and semantic memory, Neuropsycholo-gia 38:313–324, 2000.

[70] Gray JA, McNaughton N, The Neuropsychology of anxiety: An enquiry into the func-tion of the septo-hippocampal system, Oxford University Press, 2000.

April 1, 2008 10:56 WSPC/179-JIN 00171

174 Kryukov

[71] Grossi D, Trojano L, Grasso A, Orsini A, Selective “semantic amnesia” after closed-head injury. A case report, Cortex 24:457–464, 1988.

[72] Guillery-Girard B, Desgranges B, Urban C, Piolino P, de la Sayette V, Eustache F,The dynamic time course of memory recovery in transient global amnesia, J NeurolNeurosurg Psychiatry 75:1532–1540, 2004.

[73] Habib R, McIntosh AR, Wheeler MA, Tulving E, Memory encoding andhippocampally-based novelty/familiarity discrimination networks, Neuropsychologia41:271–279, 2003.

[74] Hafting T, Fyhn M, Molden S, Moser MB, Moser EI, Microstructure of a spatial mapin the entorhinal cortex, Nature 436:801–806, 2005.

[75] Hahn TT, Sakmann B, Mehta MR, Phase-locking of hippocampal interneurons’ mem-brane potential to neocortical up-down states, Nat Neurosci 9:1359–1361, 2006.

[76] Haist F, Bowden Gore J, Mao H, Consolidation of human memory over decadesrevealed by functional magnetic resonance imaging, Nat Neurosci 4:1139–1145,2001.

[77] Haken H, Principles of Brain Functioning: A Synergetic Approach to Brain Activity,Behavior, and Cognition, Springer, Berlin, New York, 1996.

[78] Harris JA, Petersen RS, Diamond ME, The cortical distribution of sensory memories,Neuron 30:315–318, 2001.

[79] Harris KD, Henze DA, Hirase H, Leinekugel X, Dragoi G, Czurko A, Buzsaki G, Spiketrain dynamics predicts theta-related phase precession in hippocampal pyramidal cells,Nature 417:738–741, 2002.

[80] Hasselmo ME, The role of hippocampal regions CA3 and CA1 in matching entorhinalinput with retrieval of associations between objects and context: Theoretical commenton Lee et al., Behav Neurosci 119:342–345, 2005.

[81] Hasselmo ME, McGaughy J, High acetylcholine levels set circuit dynamics for atten-tion and encoding and low acetylcholine levels set dynamics for consolidation, ProgBrain Res 145:207–231, 2004.

[82] Haxby JV, Hoffman EA, Gobbini MI, The distributed human neural system for faceperception, Trends Cogn Sci 4:223–233, 2000.

[83] Hayes SM, Ryan L, Schnyer DM, Nadel L, An fMRI study of episodic memory:Retrieval of object, spatial, and temporal information, Behav Neurosci 118:885–896,2004.

[84] Hebb D, The Organization of Behavior, Wiley, New York, 1949.[85] Hegumen Theophan (Kryukov), Attention and memory model based on the principle

of dominanta and comparator function of hippocampus, Zh Vyssh Nerv Deiat Im I PPavlova 54:10–29, 2004.

[86] Hegumen Theophan (Kryukov), Sensory integration: Hierarchy and synchronization,Zh Vyssh Nerv Deiat Im I P Pavlova 55:163–169, 2005.

[87] Hegumen Theophan (Kryukov), Attention, memory, and the hippocampus: Anattempt to reconcile concurrent theories, in International Symposium “Hippocampusand memory”, The Symposium devoted to the memory of professor Olga S Vino-gradova, Pushchino, Russia, June 25–29, pp. 32, 2006.

[88] Hegumen Theophan (Kryukov), The role of hippocampus in long-term memory:Dynamic system approach, Zh Vyssh Nerv Deiat Im I P Pavlova 57:261–278, 2007.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 175

[89] Holdstock JS, Mayes AR, Isaac CL, Gong Q, Roberts N, Differential involvementof the hippocampus and temporal lobe cortices in rapid and slow learning of newsemantic information, Neuropsychologia 40:748–768, 2002.

[90] Holscher C, Time, space and hippocampal functions, Rev Neurosci 14:253–284, 2003.[91] Hopfield JJ, Neural networks and physical systems with emergent collective compu-

tational abilities, Proc Natl Acad Sci USA 79:2554–2558, 1982.[92] Horowitz P, Hill W, The Art of Electronics, Cambridge University Press, 1980.[93] Howard MW, Addis KM, Jing B, Kahana MJ, Semantic structure and episodic mem-

ory, in Landauer T, McNamara DS, Dennis S, Kintsch W (eds.), LSA: A road tomeaning, pp. 121–141, Erlbaum, Mahwah NJ, 2006.

[94] Huxter J, Burgess N, O’Keefe J, Independent rate and temporal coding in hippocam-pal pyramidal cells, Nature 425:828–832, 2003.

[95] International Symposium “Hippocampus and memory”. The Symposium devotedto the memory of professor Olga S Vinogradova, Pushchino, Russia, June 25–29,http://www.hippo2006.psn.ru/, 2006.

[96] Isaacson RL, Unsolved Mysteries: The Hippocampus, Behav Cogn Neurosci Rev 1:87–107, 2002.

[97] Jeffery KJ, Gilbert A, Burton S, Strudwick A, Preserved performance in ahippocampal-dependent spatial task despite complete place cell remapping, Hippocam-pus 13:175–189, 2003.

[98] Jensen O, Kaiser J, Lachaux JP, Human gamma-frequency oscillations associated withattention and memory, Trends Neurosci 30:317–324, 2007.

[99] Ji D, Wilson MA, Coordinated memory replay in the visual cortex and hippocampusduring sleep, Nat Neurosci 10:100–107, 2007.

[100] John ER, Mechanisms of Memory, Academic Press, New York, 1967.[101] Jones MW, Wilson MA, Phase precession of medial prefrontal cortical activity relative

to the hippocampal theta rhythm, Hippocampus 15:867–873, 2005.[102] Kahana MJ, The cognitive correlates of human brain oscillations, J Neurosci 26:1669–

1672, 2006.[103] Kapur N, Millar J, Abbott P, Carter M, Recovery of function processes in human

amnesia: Evidence from transient global amnesia, Neuropsychologia 36:99–107, 1998.[104] Kazanovich YB, Borisyuk RM, Dynamics of neural networks with a central element,

Neural Netw 12:441–454, 1999.[105] Kazanovich Y, Borisyuk R, Synchronization in oscillator systems with a central ele-

ment and phase shifts, Progress of Theoretical Physics 110:1047–1057, 2003.[106] Kazanovich YB, Borisyuk R, An oscillatory neural model of multiple object tracking,

Neural Computation 18:1413–1440, 2006.[107] Kazanovich YaB, Kryukov VI, Lyuzyanina TB, Synchronization and phase locking

in oscillatory models of neural networks, in Holden AV, KryukovNeurocomputers VI(eds.), Neurocomputers and Attention. I. Neurobiology, Synchronization and Chaos,pp. 319–351, Manchester Press, Manchester, 1991.

[108] Kelso JAS, Dynamic patterns: The Self-Organization of Brain and Behavior, MITPress, Cambridge, 1995.

[109] Kentros C, Hippocampal place cells: The “where” of episodic memory? Hippocampus16:743–754, 2006.

April 1, 2008 10:56 WSPC/179-JIN 00171

176 Kryukov

[110] Kentros C, Hargreaves E, Hawkins RD, Kandel ER, Shapiro M, Muller RV, Aboli-tion of long-term stability of new hippocampal place cell maps by NMDA receptorblockade, Science 280:2121–2126, 1998.

[111] Kentros CG, Agnihotri NT, Streater S, Hawkins RD, Kandel ER, Increased attentionto spatial context increases both place field stability and spatial memory, Neuron42:283–295, 2004.

[112] King JA, Burgess N, Hartley T, Vargha-Khadem F, O’Keefe J, Human hippocampusand viewpoint dependence in spatial memory, Hippocampus 12:811–820, 2002.

[113] Kinsbourne M, Integrated cortical field model of consciousness, Ciba Found Symp174:43–50, 1993.

[114] Kirchhoff BA, Wagner AD, Maril A, Stern CE, Prefrontal-temporal circuitry forepisodic encoding and subsequent memory, J Neurosci 20:6173–6180, 2000.

[115] Knierim JJ, Hippocampus and memory, Can we have our place and fear it too? Neuron37:372–374, 2003.

[116] Knierim JJ, Neural representations of location outside the hippocampus, Learn Mem13:405–415, 2006.

[117] Knight RT, Contribution of human hippocampal region to novelty detection, Nature383:256–259, 1996.

[118] Kopelman MD, Disorders of memory, Brain 125:2152–2190, 2002.[119] Kopelman MD, Kapur N, The loss of episodic memories in retrograde amnesia: Single-

case and group studies, Philos Trans R Soc Lond B Biol Sci 356:1409–1421, 2001.[120] Kopelman MD, Lasserson D, Kingsley DR, Bello F, Rush C, Stanhope N, Stevens

TG, Goodman G, Buckman JR, Heilpern G, Kendall BE, Colchester AC, Retro-grade amnesia and the volume of critical brain structures, Hippocampus 13:879–891,2003.

[121] Kryukov VI, Markov interaction processes and neuronal activity, in Dobrushin RL,Kryukov VI, Toom AL (eds.), Locally Interacting Systems and Their Applications inBiology, pp. 122–139. Lecture notes in mathematics 653, Springer, Berlin, 1978.

[122] Kryukov VI, An attention model based on the principle of dominanta, in Holden AV,Kryukov VI (eds.), Neurocomputers and Attention. I. Neurobiology, Synchronizationand Chaos, pp. 319–351, Manchester Press, Manchester, 1991.

[123] Kryukov VI (Hegumen Theophan), A model of attention and memory based on theprinciple of the dominanta and the comparator function of the hippocampus, NeurosciBehav Physiol 35:235–252, 2005.

[124] Kryukov VI, Borisyuk GN, Borisyuk RM, Kirillov AB, Kovalenko YeI, Metastable andunstable states in the brain, in Dobrushin RL, Kryukov VI, Toom AL (eds.), Stochas-tic Cellular Systems: Ergodicity, Memory, Morphogenesis, pp. 225–357, ManchesterUniversity Press, Manchester, New York, 1990.

[125] Kumaran D, Maguire EA, The human hippocampus: Cognitive maps or relationalmemory? J Neurosci 25:7254–7259, 2005.

[126] Lee I, Hunsaker MR, Kesner RP, The role of hippocampal subregions in detectingspatial novelty, Behav Neurosci 119:145–153, 2005.

[127] Lee I, Griffin AL, Zilli EA, Eichenbaum H, Hasselmo ME, Gradual translocation ofspatial correlates of neuronal firing in the hippocampus toward prospective rewardlocations, Neuron 51:639–650, 2006.

[128] Leutgeb S, Leutgeb JK, Moser MB, Moser EI, Place cells, spatial maps and thepopulation code for memory, Curr Opin Neurobiol 15:738–746, 2005.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 177

[129] Levine B, Black SE, Cabeza R, Sinden M, Mcintosh AR, Toth JP, Tulving E, StussDT, Episodic memory and the self in a case of isolated retrograde amnesia, Brain121:1951–1973, 1998.

[130] Levine B, Svoboda E, Hay JF, Winocur G, Moscovitch M, Aging and autobiographicalmemory: Dissociating episodic from semantic retrieval, Psychol Aging 17:677–689,2002.

[131] Lin L, Osan R, Tsien JZ, Organizing principles of real-time memory encoding: Neuralclique assemblies and universal neural codes, Trends Neurosci 29:48–57, 2006.

[132] Lindsey WC, Synchronization System in Communication and Control, Prentice Hall,Englewood Cliffs, NJ, 1972.

[133] Lisman J, The theta/gamma discrete phase code occuring during the hippocampalphase precession may be a more general brain coding scheme, Hippocampus 15:913–922, 2005.

[134] Lisman J, The mechanism of novelty computation according to Vinogradova andothers, in International Symposium “Hippocampus and Memory”, The Symposiumdevoted to the memory of professor Olga S. Vinogradova. Pushchino, Russia, June25–29, p. 37, 2006.

[135] Little WA, The Existence of Persistent States in the Brain, Math Biosci 19:101–120,1974.

[136] Livanov MN, Neuronal mechanisms of memory, Usp Fiziol Nauk 6:66–89, (in Russian)1975.

[137] Maguire EA, Frith CD, Aging affects the engagement of the hippocampus duringautobiographical memory retrieval, Brain 126:1511–1523, 2003.

[138] Maguire EA, Frith CD, The brain network associated with acquiring semantic knowl-edge, Neuroimage 22:171–178, 2004.

[139] Maguire EA, Mummery CJ, Buchel C, Patterns of hippocampal-cortical interactiondissociate temporal lobe memory subsystems, Hippocampus 10:475–482, 2000.

[140] Maguire EA, Henson RN, Mummery CJ, Frith CD, Activity in prefrontal cortex,not hippocampus, varies parametrically with the increasing remoteness of memories,Neuroreport 12:441–444, 2001.

[141] Maguire EA, Frith CD, Rudge P, Cipolotti L, The effect of adult-acquired hippocam-pal damage on memory retrieval: An fMRI study, Neuroimage 27:146–152, 2005.

[142] Manning L, Focal retrograde amnesia documented with matching anterograde andretrograde procedures, Neuropsychologia 40:28–38, 2002.

[143] Manns JR, Eichenbaum H, Evolution of declarative memory, Hippocampus 16:795–808, 2006.

[144] Manns JR, Hopkins RO, Squire LR, Semantic memory and the human hippocampus,Neuron 38:127–133, 2003.

[145] Marr D, Simple memory: A theory for archicortex, Philos Trans R Soc Lond B BiolSci 262:23–81, 1971.

[146] Martin A, Chao LL, Semantic memory and the brain: Structure and processes, CurrOpin Neurobiol 11:194–201, 2001.

[147] Martin SJ, Morris RG, New life in an old idea: The synaptic plasticity and memoryhypothesis revisited, Hippocampus 12:609–636, 2002.

[148] Martin SJ, de Hoz L, Morris RG, Retrograde amnesia: Neither partial nor completehippocampal lesions in rats result in preferential sparing of remote spatial memory,even after reminding, Neuropsychologia 43:609–624, 2005.

April 1, 2008 10:56 WSPC/179-JIN 00171

178 Kryukov

[149] Maviel T, Durkin TP, Menzaghi F, Bontempi B, Sites of neocortical reorganizationcritical for remote spatial memory, Science 305:96–99, 2004.

[150] Mayes AR, Roberts N, Theories of episodic memory, Philos Trans R Soc Lond B BiolSci 356:1395–1408, 2001.

[151] Mayes AR, Mackay CE, Montaldi D, Downes JJ, Gong QY, Singh KD, Roberts N,Does retrieving decades-old spatial memories activate the medial temporal lobes lessthan retrieving recently acquired spatial memories? Neuroimage 11: S421 2000.

[152] McCarthy RA, Kopelman MD, Warrington EK, Remembering and forgetting ofsemantic knowledge in amnesia: A 16-year follow-up investigation of RFR, Neuropsy-chologia 43:356–372, 2005.

[153] McClelland JL, McNaughton BL, O’Reilly RC, Why there are complementary learningsystems in the hippocampus and neocortex: Insights from the successes and failuresof connectionist models of learning and memory, Psychol Rev 102:419–457, 1995.

[154] McDonald RJ, Hong NS, Craig LA, Holahan MR, Louis M, Muller RU, NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquiredspatial representation in rat hippocampus, Eur J Neurosci 22:1201–1213, 2005.

[155] McGaugh JL, Memory — A century of consolidation, Science 287:248–251, 2000.[156] McKenna P, Gerhand S, Preserved semantic learning in an amnesic patient, Cortex

38:37–58, 2002.[157] McNaughton N, The role of the subiculum within the behavioural inhibition system,

Behav Brain Res 174:232–250, 2006.[158] McNaughton N, Ruan M, Woodnorth MA, Restoring theta-like rhythmicity in rats

restores initial learning in the Morris water maze, Hippocampus 16:1102–1110, 2006.[159] McNaughton N, Wickens J, Hebb, pandemonium and catastrophic hypermnesia: The

hippocampus as a suppressor of inappropriate associations, Cortex 39:1139–1163,2003.

[160] Meeter M, Murre JM, Consolidation of long-term memory: Evidence and alternatives,Psychol Bull 130:843–857, 2004.

[161] Mehta MR, Quirk MC, Wilson MA, Experience-dependent asymmetric shape of hip-pocampal receptive fields, Neuron 25:707–715, 2000.

[162] Mehta MR, Lee AK, Wilson MA, Role of experience and oscillations in transforminga rate code into a temporal code, Nature 417:741–746, 2002.

[163] Miller GA, The magical number seven plus or minus two: Some limits on our capacityfor processing information, Psychol Rev 63:81–97, 1956.

[164] Miller RR, Matzel LD, Memory involves far more than “consolidation”, Nat Rev Neu-rosci 1:214–216, 2000.

[165] Millin PM, Moody EW, Riccio DC, Interpretations of retrograde amnesia: Old prob-lems redux, Nat Rev Neurosci 2:68–70, 2001.

[166] Mishkin M, Suzuki WA, Gadian DG, Vargha-Khadem F, Hierarchical organization ofcognitive memory, Philos Trans R Soc Lond B Biol Sci 352:1461–1467, 1997.

[167] Miyashita Y, Cognitive memory: Cellular and network machineries and their top-downcontrol, Science 306:435–440, 2004.

[168] Mizuhara H, Wang LQ, Kobayashi K, Yamaguchi Y, Long-range EEG phase synchro-nization during an arithmetic task indexes a coherent cortical network simultaneouslymeasured by fMRI, Neuroimage 27:553–563, 2005.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 179

[169] Moita MA, Rosis S, Zhou Y, LeDoux JE, Blair HT, Hippocampal place cells acquirelocation-specific responses to the conditioned stimulus during auditory fear condition-ing, Neuron 37:485–497, 2003.

[170] Moita MA, Rosis S, Zhou Y, LeDoux JE, Blair HT, Putting fear in its place: Remap-ping of hippocampal place cells during fear conditioning, J Neurosci 24:7015–7023,2004.

[171] Molle M, Yeshenko O, Marshall L, Sara SJ, Born J, Hippocampal sharp wave-rippleslinked to slow oscillations in rat slow-wave sleep, J Neurophysiol 96:62–70, 2006.

[172] Mormann F, Fell J, Axmacher N, Weber B, Lehnertz K, Elger CE, Fernandez G,Phase/amplitude reset and theta-gamma interaction in the human medial temporallobe during a continuous word recognition memory task, Hippocampus 15:890–900,2005.

[173] Morris RG, Elements of a neurobiological theory of hippocampal function: The roleof synaptic plasticity, synaptic tagging and schemas, Eur J Neurosci 23:2829–2846,2006.

[174] Morris RG, Moser EI, Riedel G, Martin SJ, Sandin J, Day M, O’Carroll C, Ele-ments of a neurobiological theory of the hippocampus: The role of activity-dependentsynaptic plasticity in memory, Philos Trans R Soc Lond B Biol Sci 358:773–786,2003.

[175] Moscovitch M, Nadel L, Consolidation and the hippocampal complex revisited: Indefense of the multiple-trace model, Curr Opin Neurobiol 8:297–300, 1998.

[176] Moscovitch M, Westmacott R, Gilboa A, Addis DA, Rosenbaum RS, Viskontas I,Priselac S, Svoboda E, Ziegler M, Black S, Gao F, Grady CL, Freedman M, KohlerS, Leach L, Levine B, McAndrews MP, Nadel L, Proulx G, Richards B, Ryan L,Stokes K, Winocur G, Hippocampal complex contribution to retention and retrievalof recent and remote episodic and semantic memories: Evidence from behavioral andneuroimaging studies of healthy and brain-damaged people, in Ohta N, MacLeodCM, Uttl B (eds.), Dynamic Cognitive Processes, pp. 333–380, Springer Verlag2005.

[177] Moscovitch M, Rosenbaum RS, Gilboa A, Addis DR, Westmacott R, Grady C, McAn-drews MP, Levine B, Black S, Winocur G, Nadel L, Functional neuroanatomy ofremote episodic, semantic and spatial memory: A unified account based on multipletrace theory, J Anat 207:35–66, 2005.

[178] Moscovitch M, Nadel L, Winocur G, Gilboa A, Rosenbaum RS, The cognitive neu-roscience of remote episodic, semantic and spatial memory, Curr Opin Neurobiol 16:179–190, 2006.

[179] Muller R, A quarter of a century of place cells, Neuron 17:979–990, 1996.[180] Murre JM, Graham KS, Hodges JR, Semantic dementia: Relevance to connectionist

models of long-term memory, Brain 124:647–675, 2001.[181] Nadel L, Bohbot V, Consolidation of memory, Hippocampus 11:56–60, 2001.[182] Nadel L, Hardt O, The spatial brain, Neuropsychology 18:473–476, 2004.[183] Nadel L, Moscovitch M, Memory consolidation, retrograde amnesia and the hippocam-

pal complex, Curr Opin Neurobiol 7:217–227, 1997.[184] Nadel L, Moscovitch M, The hippocampal complex and long-term memory revisited,

Trends Cogn Sci 5:228–230, 2001.

April 1, 2008 10:56 WSPC/179-JIN 00171

180 Kryukov

[185] Nadel L, Samsonovich A, Ryan L, Moscovitch M, Multiple trace theory of humanmemory: Computational, neuroimaging, and neuropsychological results, Hippocampus10:352–368, 2000.

[186] Nadel L, Ryan L, Hayes SM, Gilboa A, Moscovitch M, The role of the hippocam-pal complex in long-term episodic memory, in Cognition and emotion in the brain,International congress series, 1250:215–234, Elsevier, 2003.

[187] Nader K, Schafe GE, LeDoux JE, The labile nature of consolidation theory, Nat RevNeurosci 1:216–219, 2000.

[188] Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S, Hippocam-pal CA3 NMDA receptors are crucial for memory acquisition of one-time experience,Neuron 38:305–315, 2003.

[189] Nestor PJ, Graham KS, Bozeat S, Simons JS, Hodges JR, Memory consolidationand the hippocampus: Further evidence from studies of autobiographical memoryin semantic dementia and frontal variant frontotemporal dementia, Neuropsychologia40:633–654, 2002.

[190] Niessing J, Ebisch B, Schmidt KE, Niessing M, Singer W, Galuske RA, Hemodynamicsignals correlate tightly with synchronized gamma oscillations, Science 309:948–951,2005.

[191] Niki K, Luo J, An fMRI study on the time-limited role of the medial temporal lobe inlong-term topographical autobiographic memory, J Cogn Neurosci 14:500–507, 2002.

[192] O’Keefe J, Do hippocampal pyramidal cells signal non-spatial as well as spatial infor-mation? Hippocampus 9:352–364, 1999.

[193] O’Keefe J, Burgess N, Dual phase and rate coding in hippocampal place cells: Theo-retical significance and relationship to entorhinal grid cells, Hippocampus 15:853–866,2005.

[194] O’Keefe J, Nadel L, The Hippocampus as a Cognitive Map, Clarendon Press, OxfordUK, 1978.

[195] Piefke M, Weiss PH, Zilles K, Markowitsch HJ, Fink GR, Differential remoteness andemotional tone modulate the neural correlates of autobiographical memory, Brain126:650–668, 2003.

[196] O’Keefe J, Burgess N, Donnett JG, Jeffery KJ, Maguire EA, Place cells, naviga-tional accuracy, and the human hippocampus, Philos Trans R Soc Lond B Biol Sci353:1333–1340, 1998.

[197] Osipova D, Takashima A, Oostenveld R, Fernandez G, Maris E, Jensen O, Theta andgamma oscillations predict encoding and retrieval of declarative memory, J Neurosci26:7523–7531, 2006.

[198] Piolino P, Desgranges B, Benali K, Eustache F, Episodic and semantic remote auto-biographical memory in ageing, Memory 10:239–257, 2002.

[199] Piolino P, Desgranges B, Belliard S, Matuszewski V, Lalevee C, De la Sayette V,Eustache F, Autobiographical memory and autonoetic consciousness: Triple dissocia-tion in neurodegenerative diseases, Brain 126:2203–2219, 2003.

[200] Piolino P, Giffard-Quillon G, Desgranges B, Chetelat G, Baron JC, Eustache F, Re-experiencing old memories via hippocampus: A PET study of autobiographical mem-ory, Neuroimage 22:1371–1383, 2004.

[201] Poe GR, Nitz DA, McNaughton BL, Barnes CA, Experience-dependent phase-reversalof hippocampal neuron firing during REM sleep, Brain Res 855:176–180, 2000.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 181

[202] Power AE, Vazdarjanova A, McGaugh JL, Muscarinic cholinergic influences in mem-ory consolidation, Neurobiol Learn Mem 80:178–193, 2003.

[203] Raghavachari S, Kahana MJ, Rizzuto DS, Caplan JB, Kirschen MP, Bourgeois B,Madsen JR, Lisman JE, Gating of human theta oscillations by a working memorytask, J Neurosci 21:3175–3183, 2001.

[204] Ranganath C, Blumenfeld RS, Doubts about double dissociations between short- andlong-term memory, Trends Cogn Sci 9:374–380, 2005.

[205] Ranganath C, Rainer G, Neural mechanisms for detecting and remembering novelevents, Nat Rev Neurosci 4:193–202, 2003.

[206] Rasch BH, Born J, Gais S, Combined blockade of cholinergic receptors shifts the brainfrom stimulus encoding to memory consolidation, J Cogn Neurosci 18:793–802, 2006.

[207] Redish AD, Beyond the Cognitive Map: From Place Cells to Episodic Memory, MITPress, Cambridge MA, 1999.

[208] Redish AD, The hippocampal debate: Are we asking the right questions? Behav BrainRes 127:81–98, 2001.

[209] Rekkas PV, Constable RT, Evidence that autobiographic memory retrieval does notbecome independent of the hippocampus: An fMRI study contrasting very recent withremote events, J Cogn Neurosci 17:1950–1961, 2005.

[210] Riccio DC, Moody EW, Millin PM, Reconsolidation reconsidered, Integr PhysiolBehav Sci 37:245–253, 2002.

[211] Riccio DC, Millin PM, Gisquet-Verrier P, Retrograde amnesia: Forgetting back, CurrDir Psychol Sci 12:41–44, 2003.

[212] Riedel G, Micheau J, Function of the hippocampus in memory formation: Desperatelyseeking resolution, Prog Neuropsychopharmacol Biol Psychiatry 25:835–853, 2001.

[213] Rodriguez E, George N, Lachaux JP, Martinerie J, Renault B, Varela FJ, Perception’sshadow: Long-distance synchronization of human brain activity, Nature 397:430–433,1999.

[214] Roelfsema PR, Engel AK, Konig P, Singer W, Visuomotor integration is associatedwith zero time-lag synchronization among cortical areas, Nature 385:157–161, 1997.

[215] Rolls ET, Kesner RP, A computational theory of hippocampal function, and empiricaltests of the theory, Prog Neurobiol 79:1–48, 2006.

[216] Rosenbaum RS, Kohler S, Schacter DL, Moscovitch M, Westmacott R, Black SE,Gao F, Tulving E, The case of K, C.: Contributions of a memory-impaired person tomemory theory, Neuropsychologia 43:989–1021, 2005.

[217] Rosenbaum RS, Winocur G, Moscovitch M, New views on old memories: Re-evaluatingthe role of the hippocampal complex, Behav Brain Res 127:183–197, 2001.

[218] Ruchkin DS, Grafman J, Cameron K, Berndt RS, Working memory retention systems:A state of activated long-term memory, Behav Brain Sci 26:709–728, 2003.

[219] Ryan L, Nadel L, Keil K, Putnam K, Schnyer D, Trouard T, Moscovitch M, Hip-pocampal complex and retrieval of recent and very remote autobiographical memories:Evidence from functional magnetic resonance imaging in neurologically intact people,Hippocampus 11:707–714, 2001.

[220] Sara SJ, Strengthening the shaky trace through retrieval, Nat Rev Neurosci 1:212–213, 2000.

[221] Saucier D, Cain DP, Spatial learning without NMDA receptor-dependent long-termpotentiation, Nature 378:186–189, 1995.

April 1, 2008 10:56 WSPC/179-JIN 00171

182 Kryukov

[222] Schack B, Vath N, Petsche H, Geissler HG, Moller, E, Phase-coupling of theta-gammaEEG rhythms during short-term memory processing, Int J Psychophysiol 44:143–163,2002.

[223] Schmidtke K, Vollmer H, Retrograde amnesia: A study of its relation to anterogradeamnesia and semantic memory deficits, Neuropsychologia 35:505–518, 1997.

[224] Schmolck H, Kensinger EA, Corkin S, Squire LR, Semantic knowledge in patient H.M.and other patients with bilateral medial and lateral temporal lobe lesions, Hippocam-pus 12:520–533, 2002.

[225] Schnitzler A, Gross J, Normal and pathological oscillatory communication in the brain,Nat Rev Neurosci 6:285–296, 2005.

[226] Sederberg PB, Schulze-Banhage A, Madsen JR, Bromfield EB, McCarthy DC, BrandtA, Tully MS, Kahana MJ, Hippocampal and neocortical gamma oscillations predictmemory formation in humans, Cereb Cortex 17(5): 1190–1196, 2007.

[227] Sederberg PB, Gauthier LV, Terushkin V, Miller JF, Baranathan JA, KahanaMJ, Oscillatory correlates of the primary effect in episodic memory, Neuroimage32(3):1422–1431, 2006.

[228] Sederberg PB, Schulze-Bonhage A, Madsen JR, Bromfield EB, McCarthy DC, BrandtA, Tully MS, Kahana MJ, Hippocampal and neocortical gamma oscillations predictmemory formation in humans, Cereb Cortex 17:1190–1196, 2007.

[229] Sellal F, Manning L, Seegmuller C, Scheiber C, Schoenfelder F, Pure retrograde amne-sia following a mild head trauma: A neuropsychological and metabolic study, Cortex38:499–509, 2002.

[230] Shastri L, Episodic memory and cortico-hippocampal interactions, Trends Cogn Sci6:162–168, 2002.

[231] Shimizu E, Tang Y-P, Rampon C, Tsien JZ, NMDA receptor-dependent synapticreinforcement as a crucial process for memory consolidation, Science 290:1170–1174,2000.

[232] Shimizu E, Tang, Y-P, Rampon C, Feng R, Shrom D, Tsien JZ, Response on: Dayand Morris. Memory consolidation and NMDA receptors: Discrepancy between geneticand pharmacological approaches, Science 293:755a, 2001.

[233] Siapas AG, Lubenov EV, Wilson MA, Prefrontal phase locking to hippocampal thetaoscillations, Neuron 46:141–151, 2005.

[234] Simons JS, Hodges JR, Transient global amnesia: A review of the recent literature,Neurocase 6:211–230, 2000.

[235] Small SA, The longitudinal axis of the hippocampal formation: Its anatomy, circuitry,and role in cognitive function, Rev Neurosci 13:183–194, 2002.

[236] Small SA, Nava AS, Perera GM, DeLaPaz R, Mayeux R, Stern Y, Circuit mecha-nisms underlying memory encoding and retrieval in the long axis of the hippocampalformation, Nat Neurosci 4:442–449, 2001.

[237] Snowden JS, Neary D, Relearning of verbal labels in semantic dementia, Neuropsy-chologia 40:1715–1728, 2002.

[238] Snowden JS, Thompson JC, Neary D, Knowledge of famous faces and names in seman-tic dementia, Brain 127:860–872, 2004.

[239] Spiers HJ, Maguire EA, Burgess N, Hippocampal amnesia, Neurocase 7:357–382, 2001.[240] Squire LR, Alvarez P, Retrograde amnesia and memory consolidation: A neurobiolog-

ical perspective, Curr Opin Neurobiol 5:169–177, 1995.

April 1, 2008 10:56 WSPC/179-JIN 00171

The Role of the Hippocampus in LTM 183

[241] Squire LR, Zola SM, Episodic memory, semantic memory, and amnesia, Hippocampus8:205–211, 1998.

[242] Squire LR, Clark RE, Knowlton BJ, Retrograde amnesia, Hippocampus 11:50–55,2001.

[243] Squire LR, Stark CE, Clark RE, The medial temporal lobe, Annu Rev Neurosci27:279–306, 2004.

[244] Steinvorth S, Levine B, Corkin S, Medial temporal lobe structures are needed to re-experience remote autobiographical memories: Evidence from H.M. and W.R, Neu-ropsychologia 43:479–496, 2005.

[245] Steinvorth S, Corkin S, Halgren E, Ecphory of autobiographical memories: An fMRIstudy of recent and remote memory retrieval, Neuroimage 30:285–298, 2006.

[246] Stracciari A, Mattarozzi K, Fonti C, Guarino M, Functional focal retrograde amnesia:Lost access to abstract autobiographical knowledge? Memory 13:690–699, 2005.

[247] Suder K, Worgotter F, The control of low-level information flow in the visual system,Rev Neurosci 11:127–146, 2000.

[248] Takashima A, Petersson KM, Rutters F, Tendolkar I, Jensen O, Zwarts MJ,McNaughton BL, Fernandez G, Declarative memory consolidation in humans: Aprospective functional magnetic resonance imaging study, Proc Natl Acad Sci USA103:756–761, 2006.

[249] Tanifuji M, Tsunoda K, Yamane Y, Neural representation of object images in themacaque inferotemporal cortex, in Kanwisher S, Duncan J (eds.), Functional Neu-roimaging of Visual Cognition, Attention and performance XX, pp. 241–256, OxfordUniversity Press, 2004.

[250] Taylor K, Mandon S, Freiwald WA, Kreiter AK, Coherent oscillatory activity in mon-key area v4 predicts successful allocation of attention, Cereb Cortex 15:1424–1437,2005.

[251] Tesche CD, Karhu J, Theta oscillations index human hippocampal activation duringa working memory task, Proc Natl Acad Sci USA 97:919–924, 2000.

[252] Teyler TJ, DiScenna P, The hippocampal memory indexing theory, Behav Neurosci100:147–154, 1986.

[253] Ukhtomsky AA, The Dominanta, Piter, St Petersburg, (in Russian) 2002.[254] Varela FJ, Resonant cell assemblies: A new approach to cognitive functions and neu-

ronal synchrony, Biol Res 28:81–95, 1995.[255] Vargha-Khadem F, Gadian DG, Watkins KE, Connelly A, Van Paesschen W, Mishkin

M, Differential effects of early hippocampal pathology on episodic and semantic mem-ory, Science 277:376–380, 1997.

[256] Verfaellie M, Koseff P, Alexander MP, Acquisition of novel semantic information inamnesia: Effects of lesion location, Neuropsychologia 38:484–492, 2000.

[257] Vertes RP, Hippocampal theta rhythm: A tag for short-term memory, Hippocampus15:923–935, 2005.

[258] Vinogradova OS, The Hippocampus and Memory, Nauka, Moscow, 1975.[259] Vinogradova OS, Expression, control, and probable functional significance of the neu-

ronal theta-rhythm, Prog Neurobiol 45:523–583, 1995.[260] Vinogradova OS, Hippocampus as comparator: Role of the two input and two output

systems of the hippocampus in selection and registration of information, Hippocampus11:578–598, 2001.

April 1, 2008 10:56 WSPC/179-JIN 00171

184 Kryukov

[261] Vinogradova OS, Kitchigina VF, Kudina TA, Zenchenko KI, Spontaneous activityand sensory responses of hippocampal neurons during persistent theta-rhythm evokedby median raphe nucleus blockade in rabbit, Neuroscience 94:745–753, 1999.

[262] Vinogradova OS, Dudaeva KI, Comparator function of the hippocampus, Dokl AkadNauk SSSR 202:486–489 (in Russia), 1972.

[263] Vinogradova OS, Kitchigina VF, Zenchenko CI, Pacemaker neurons of the forebrainmedical septal area and theta rhythm of the hippocampus, Membr Cell Biol 11:715–725, 1998.

[264] Volgushev M, Chauvette S, Mukovski M, Timofeev I, Precise long-range synchroniza-tion of activity and silence in neocortical neurons during slow-wave sleep, J Neurosci26:5665–5672, 2006.

[265] von der Malsburg C, Binding in models of perception and brain function, Curr OpinNeurobiol 5:520–526, 1995.

[266] Weinberger NM, The nucleus basalis and memory codes: Auditory cortical plasticityand the induction of specific, associative behavioral memory, Neurobiol Learn Mem80:268–284, 2003.

[267] Weinberger NM, Specific long-term memory traces in primary auditory cortex, NatRev Neurosci 5:279–290, 2004.

[268] Wheeler MA, McMillan CT, Focal retrograde amnesia and the episodic-semantic dis-tinction, Cogn Affect Behav Neurosci 1:22–36, 2001.

[269] Wiltgen BJ, Brown RA, Talton LE, Silva AJ, New circuits for old memories: The roleof the neocortex in consolidation, Neuron 44:101–108, 2004.

[270] Winocur G, McDonald RM, Moscovitch M, Anterograde and retrograde amnesia inrats with large hippocampal lesions, Hippocampus 11:18–26, 2001.

[271] Wittenberg GM, Tsien JZ, An emerging molecular and cellular framework for memoryprocessing by the hippocampus, Trends Neurosci 25:501–505, 2002.

[272] Wittenberg GM, Sullivan MR, Tsien JZ, Synaptic reentry reinforcement based net-work model for long-term memory consolidation, Hippocampus 12:637–647, 2002.

[273] Witter MP, Wouterlood FG, Naber PA, Van Haeften T, Anatomical organization ofthe parahippocampal-hippocampal network, Ann NY Acad Sci 911:1–24, 2000.

[274] Wolansky T, Clement EA, Peters SR, Palczak MA, Dickson CT, Hippocampal slowoscillation: A novel EEG state and its coordination with ongoing neocortical activity,J Neurosci 26:6213–6229, 2006.

[275] Womelsdorf T, Schoffelen JM, Oostenveld R, Singer W, Desimone R, Engel AK, FriesP, Modulation of neuronal interactions through neuronal synchronization, Science316:1609–1612, 2007.

[276] Wu Z, Guo A, Selective visual attention in a neurocomputational model of phaseoscillators, Biol Cybern 80:205–214, 1999.

[277] Yamaguchi S, Hale LA, D’Esposito M, Knight RT, Rapid prefrontal-hippocampalhabituation to novel events, J Neurosci 24:5356–5363, 2004.

[278] Zeineh MM, Engel SA, Thompson PM, Bookheimer SY, Dynamics of the hippocampusduring encoding and retrieval of face-name pairs, Science 299:577–580, 2003.

[279] Zugaro MB, Monconduit L, Buzsaki G, Spike phase precession persists after transientintrahippocampal perturbation, Nat Neurosci 8:67–71, 2005.