mapping memory function in the medial temporal lobe with the immediate-early gene arc
TRANSCRIPT
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Behavioural Brain Research 254 (2013) 22– 33
Contents lists available at ScienceDirect
Behavioural Brain Research
jo u r n al hom epage: www.elsev ier .com/ l ocate /bbr
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apping memory function in the medial temporal lobe with themmediate-early gene Arc
agdalena M. Sauvage ∗, Nozomu H. Nakamura, Zachery Beerunctional Architecture of Memory unit, Mercator Research Group, Faculty of Medicine, Ruhr University Bochum, Bochum 44801, Germany1
i g h l i g h t s
We examined the functional segregation of the MTL by detecting Arc expression.The LEC, MEC and POR are equally recruited during spatial and non-spatial memory.The PrC is tuned to the type of stimulus used, not to the spatial demands of the task.CA1 is functionally segregated along the dorsoventral axis, not CA3.Proximal CA3 and distal CA1 process preferentially non-spatial information.
r t i c l e i n f o
rticle history:eceived 22 April 2013ccepted 27 April 2013vailable online 3 May 2013
eywords:roximal CA3istal CA1
hinal corticesemory
rc
a b s t r a c t
For the past two decades an increasing number of studies have underlined the crucial role of the imme-diate – early gene Arc in plasticity processes thought to sustain memory function. Because of the highspatial and temporal resolution of this technique, the detection of Arc products appears to have becomea new standard for the mapping of cognitive processes. To date, most Arc studies have focused on iden-tifying the contribution of the hippocampal subfields CA1 and CA3 to spatial processes. In contrast, fewhave investigated their role in non-spatial memory, or the role of other medial temporal lobe (MTL) areasin spatial and non-spatial memory. This short review describes recent studies focusing on these issues.After a brief overview of Arc’s functions, we report a set of studies that put to the test some well-acceptedtheories in recognition memory. First, we describe data indicating that the parahippocampal areas maynot be strictly segregated into spatial and non-spatial streams, as originally described. Second, we report
mmediate-early genes findings revealing a functional segregation along the dorsoventral axis in CA1, but not in CA3. Finally, webring evidence for a segregation of CA3 along the proximodistal axis and discuss the involvement of aproximal CA3-distal CA1 network during non-spatial memory. In summary, ‘Arc imaging’ appears to be apowerful tool to identify neural substrates of cognitive processes, not only in the hippocampus but alsoin the remaining of the MTL. Moreover, because of its fundamental role in synaptic processes, it offers arare and exciting opportunity to further bridge plasticity processes and memory function.
© 2013 Elsevier B.V. All rights reserved.
ontents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231.1. The medial temporal lobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231.2. Mapping MTL function with high resolution molecular imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2. A brief overview of Arc functions and mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242.1. Arc and synaptic/neuronal plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242.2. Arc and cognitive processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Revisiting the hypothesis of a segregation of the MTL in terms of spatial
3.1. The ‘two streams’ hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.2. Testing the predictions of the two-streams hypothesis . . . . . . . . . . .
∗ Corresponding author at: MRG1/FAM unit, Medicine Faculty, Universitaetstrasse 150E-mail addresses: [email protected], magdalena.sauvage@ruhr-uni-bochum
1 www.rub.de/fam.
166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.bbr.2013.04.048
and non-spatial information processing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
, 44 801 Bochum, Germany..de (M.M. Sauvage).
M.M. Sauvage et al. / Behavioural Brain Research 254 (2013) 22– 33 23
3.3. Departing from the ‘two-streams’ hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264. Information processing along the dorsoventral axis of CA1 and CA3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.1. Spatial information processing in the dorsal and ventral parts of the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274.2. Spatial and non-spatial information processing in dorsal CA1 and dorsal CA3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274.3. CA1 and CA3 are not segregated to the same extent along the dorsoventral axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5. Functional segregation of CA1 and CA3 along the proximodistal axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.1. Segregation of spatial and non-spatial information within CA1 and CA3? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.2. Testing the hypothesis of a functional segregation of CA3 and CA1 during non-spatial memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.3. A preferential involvement of proximal CA3 and distal CA1 in non-spatial recognition memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 . . . . . .
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Because the MTL is structurally and functionally well-conserved
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. Introduction
.1. The medial temporal lobe
The study of H.M brought clear evidence that the medial tem-oral lobe (MTL) of the brain is critical for memory function [foreviews see 1,2]. Since then, decades of investigations have furtherharacterized its contribution to spatial and non-spatial mem-ry in healthy subjects, aging as well as in pathological casesuch as Alzheimer’s Disease [for reviews see: 3–5]. The MTL ismpressively well-conserved across species [6] and comprises thearahippocampal region which includes the perirhinal cortex (PrC),he postrhinal (POR) cortex (parahippocampal cortex in humans;araHIP), the medial and the lateral entorhinal cortex (MEC andEC, respectively) and the hippocampus (HIP), which includes theA1 and CA3 hippocampal subfields (Fig. 1).
The hippocampus has received the most attention to date, with plethora of human and animal studies that have focused onssessing the role of CA1 and CA3 in memory function. Thosetudies have principally focused on the dorsal part of the hippocam-us using lesion, imaging, mutagenesis or electrophysiologicalpproaches [see for reviews: 7–11]. In comparison, much fewertudies have investigated the contribution of ventral CA1 and ven-ral CA3 to memory function [for a review see 12], and only aandful of them have studied the existence of a functional segrega-ion in CA1 or CA3 along the proximodistal axis [13–15]. Moreover,
ost studies have focused on the role of CA1 and CA3 in spatial pro-esses, while few have investigated their role in memory devoidf spatial components. However, recent studies suggest that CA1
s essential for non-spatial processes [16,17: for a review see 18].nother MTL area that has also received much attention is the PrC,rincipally for its role in object recognition memory [for reviewsee: 19–21].ig. 1. Regions of the medial temporal lobe A) in rodents and B) in humans.he medial temporal lobe is conserved across species. CA1: light blue; CA3, red; perirhinPOR/ParaHIP, respectively): dark green; lateral entorhinal cortex (LEC): orange; medial ehis figure legend, the reader is referred to the web version of the article.)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
In contrast, little is known about the contribution of the POR, theLEC and the MEC to memory function. Moreover, even though thePOR was originally described as primarily subserving spatial pro-cesses, conflicting results have recently emerged suggesting thatthe POR would mediate contextual associations, rather than solelyprocess spatial information [22; for reviews see 21,23]. Finally, eventhough the role of the LEC and MEC have been extensively stud-ied within the frame of spatial navigation and path integration,little is known about their contribution to processes (spatial or non-spatial) with a high memory load. A potential reason for this is thatattention has been drawn on these areas only since 2004 with thediscovery of the ‘grid cells’ in animals, which are thought to supportthe encoding of a metric representation of environments [24,25].Another possible reason is that the LEC and the MEC still remainlargely undifferentiated from the PrC and the parahippocampal cor-tex in humans, principally because of the limited spatial resolutionof standard MR techniques [for a review see 5; but 26]. Thus, theprecise role of the POR, the LEC and the MEC in recognition memory,the specific contribution of CA1 and CA3 in non-spatial memory,and whether those functions differ along the dorsoventral or prox-imodistal axis of the hippocampus still remains elusive. Given thoseareas are all adjacent, addressing those questions requires high spa-tial resolution techniques to precisely assess the source of activityoccurring within the MTL during behavioral memory tasks.
1.2. Mapping MTL function with high resolution molecularimaging
al cortex (PrC): light green; postrhinal cortex/parahippocampal cortex in humansntorhinal cortex (MEC): dark blue. (For interpretation of the references to color in
across species, a great deal of effort has been devoted for the pastdecades to develop molecular imaging tools in animals that allowfor a spatial resolution high enough to assess with precision the
24 M.M. Sauvage et al. / Behavioural Bra
Fig. 2. Example of Arc pre-mRNA signals in CA1.A representative picture of Arc expression (detection of pre-mRNAs) in CA1 follow-ing a delayed non-matching to sample task (see [157]). Cell nuclei are counterstaineditb
sapwtoilcaR(pdlftdaeAcasm2AansosfmIwam
n blue (DAPI). Arrows show examples of cells that have been activated during theask (presence of Arc pre-mRNAs). Arrow heads: examples of cells that have noteen recruited during the task. Scale bar, 20 �m.
ource of task-induced brain activity, even when brain regions aredjacent. One of these techniques is based on the detection of RNAroducts (mRNA or pre-mRNA) of immediate-early genes (IEGs),hich appears to have become a new standard to map brain func-
ion over the last decades [for reviews see 9,27,28]. RNA expressionf IEGs is a critical indicator of the initiation of molecular processesn individual cells, and has been interpreted as a reflection of cellu-ar activation. Hence, the detection of IEGs on brain sections in givenells is indicative of a functional relation between the stimuluspplied and the cell in which the IEG is expressed. Importantly, thisNA detection technique provides not only a high spatial resolutioneach cell activated can be identified; Fig. 2), but also a better tem-oral resolution compared to conventional immunohistochemicaletection since RNA expression peaks within minutes of stimu-
us delivery, instead of hours for the proteins which are detectedor immunohistochemistry. Another important advantage of thisechnique is that it allows for simultaneous evaluation of multipleistant brain sites (potentially the entire brain), which still remains
great challenge for other technical approaches, such as in vivolectrophysiology. Different types of IEGs such as c-fos, zif 268 andrc have been used to map plasticity and cognitively related pro-esses. What is known about their regulation, mechanisms of actionnd function, and how they compare to each other has been exten-ively summarized in a series of recent reviews, hence will not beentioned in the present study in any details [for reviews see 9,
7–34]. These reviews have all underlined a very strong tie betweenrc and plasticity processes, such as the long-term potentiationnd depression of synapses (LTP and LTD), postulated as a mecha-ism of memory formation [35]. In addition, dysregulation of Arc isuggested to be at the origin of plasticity and/or cognitive deficitsbserved in aging, drug addiction, Alzheimer’s Disease, Fragile Xyndrome, and is suspected to also play a role in ADHD [36–38,or reviews see 32,39]. Furthermore, Arc expression was found to
ore reflect the cognitive demands of behavioral tasks than other
EGs such as c-fos and zif 268 [40]. Hence, in the present review,e focus on describing recent Arc studies that aimed at teasingpart the role of the different MTL areas in spatial and non-spatialemory. Those studies scrutinized the functional segregation of
in Research 254 (2013) 22– 33
the MTL in terms of spatial and non-spatial information processing,both ‘between’ and ‘within’ MTL areas. The first study challengesthe well-accepted, yet not thoroughly tested, ‘two streams’ hypoth-esis, according to which the PrC and LEC preferentially processnon-spatial information while the POR and the MEC process spatialinformation, by showing that the MTL is not strictly segregated interms of spatial versus non-spatial information content. The secondstudy contributes to dissociate the functions of the dorsal and theventral parts of CA1 and CA3 by providing support for a strongerdorsoventral segregation within CA1 than CA3. Finally, the thirdstudy focuses on a timely topic centered on the functional seg-regation of the hippocampus along the proximodistal axis, as itbrings the first evidence of a functional segregation within CA3, andindicates that a proximal CA3-distal CA1 network could be pref-erentially recruited during non-spatial memory. Altogether, thesestudies bring new insights on the specific contribution of each MTLarea to spatial and non-spatial memory function through a complexpattern of functional segregations.
2. A brief overview of Arc functions and mechanisms ofaction
2.1. Arc and synaptic/neuronal plasticity
The IEG Arc (activity-regulated cytoskeleton-associated protein;also known as Arg3.1) is an ‘effector’ IEG, hence directly influencescellular structure and functions as opposed to regulatory transcrip-tion factor IEGs such as c-fos and zif 268 [41,42]. Arc was discoveredabout twenty years ago by two independent laboratories [43,44],and is enriched in postsynatic densities and mainly expressed inprincipal (glutamatergic) neurons [45: glial expression has notbeen systematically reported but see 46,47]. Arc expression wasoriginally described as being enriched in neuronal dendrites andinduced following LTP-inducing stimulations, which suggested alink between Arc and synaptic-and cell-wide plasticity processes[43,44]. In the hippocampal subfields CA1 and CA3 the expres-sion of Arc RNA peaks in the nucleus approximately six minutesfollowing (electrical or behavioral) stimulation, and is thereaftertranslocated to the cytoplasm, where its concentration is maximalapproximately thirty minutes after stimulation [48: for a reviewsee 28]
For the past decade, this precise kinetic has allowed researchersto investigate CA1 and CA3 functions in detail, by either detectingArc RNAs in the nucleus or the cytoplasm of neurons following dif-ferent types of cognitive stimuli. Of note, this kinetic is strikinglydifferent in the dentate gyrus, where Arc’s transcription is pro-longed and detectable up to 8 h following the stimulus [49,50]. Toour knowledge this is not the case for other MTL areas. Interestingly,Arc RNA has the characteristic to be transported to the dendritesand to accumulate at sites where synaptic plasticity has occurred,where it is believed to undergo local translation [51,52].
The mechanisms by which Arc is induced or exerts its actionare not fully understood yet. However, activation of voltage sensi-tive calcium channels or NMDA was reported to stimulate ‘de-novo’Arc transcription and translation, while Group1 mGluR activationinduces the local translation of Arc mRNAs that have accumulatedat the dendrites as a consequence of an earlier stimulation [53;for a review see 34]. At least two mechanisms by which Arc couldcontribute to synaptic/neuronal plasticity have been described.Arc can act on AMPA receptor (AMPAR) trafficking by increas-ing endocytosis, or can stabilize internal AMPAR pools so that
AMPAR levels at the cellular surface remain constant after plastic-ity has occurred. These mechanisms are thought to induce LTD andenable homeostatic plasticity [54,55: for reviews see 34,56]. Inter-estingly, AMPARs alone can downregulate Arc expression, hence
ral Bra
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ppear to create a negative feedback system between Arc andMPARs [57]. Moreover, Arc has also been reported to interactith microtubules to trigger dendritic modeling by interacting with
ytoskeletal proteins and increasing spine numbers, a mechanismhought to induce LTP [58,59; for more details on those mechanismsee reviews 30–32,34,56]. In summary, even though much remainso be known about the mechanisms by which Arc is induced, actsnd is regulated, the existing findings strongly suggest that Arcs a main player in both synaptic- and cell-wide plasticity pro-esses that could sustain learning and memory-related cognitiverocesses.
.2. Arc and cognitive processes
In vivo studies confirmed this hypothesis and brought furthervidence of a clear link between Arc expression and cognitiveerformance. Indeed, inhibiting Arc expression by infusing Arc anti-ense oligodeoxynucleotides in the hippocampus showed that Arcas critical for LTP maintenance in vivo [60,61]. In addition, a sim-
lar infusion was found to alter memory consolidation in a spatialater maze task, without affecting acquisition or short-term mem-
ry [60, for a review see 9]. In a similar vein, consolidation ofong-term (but not short-term) memory was impaired in a largeumber of implicit and explicit memory paradigms in Arc (−/−)ice, and so was late phase LTP in DG in vivo, and in CA1 slice prepa-
ations [62]. Also of interest, a recent in vivo study showed thatTP- and LTD-inducing stimulations led to changes in Arc mRNAevel in CA1, albeit in an opposite manner [63]. In addition, detec-ion of Arc mRNAs following exposure to new spatial environmentsed to results comparable to those obtained in place cell studies,urther reinforcing the relationship between Arc transcription andnformation processing in the hippocampus [64]. These findings,ogether with the fact that Arc expression was found to more reflecthe cognitive demands of behavioral tasks than other IEGs, maderc a very strong candidate for the mapping of plasticity-relatedctivity that occurs during specific cognitive processes in rodents40: for reviews see 9,28]. As a consequence, a growing numberf studies have used this ‘Arc mapping’ technique for the past tenears. For example: Arc expression was shown to reflect behavioralxperience in the hippocampus and the neocortex during spatialxploration [48,64,65], spatial water maze tasks [40,66–68], con-extual fear-conditioning [69–71], operant learning [72–74] and
passive avoidance task [75]. The vast majority of these studiesere geared toward the characterization of CA1 and CA3 func-
ions in spatial navigation and in contextual/spatial memory (usingisual cues), while very few have investigated non-spatial, yet stillippocampal-dependent memory, or the contribution of other MTLreas to these memory types. In the following sections, we report
set of three studies that do so by contrasting the patterns of Arcxpression induced in the MTL during spatial or non-spatial mem-ry tasks, using different types of stimuli (visual and olfactory), andifferent types of memory tasks (spontaneous recognition memoryask; delayed non-matching to sample task).
. Revisiting the hypothesis of a segregation of the MTL inerms of spatial and non-spatial information processing
.1. The ‘two streams’ hypothesis
A popular concept in recognition memory is the ‘two streams’ypothesis, according to which the perirhinal (PrC) and the lateral
ntorhinal (LEC) cortices principally process information relatedo item’s features (a ‘what’ stream), the postrhinal cortex (POR;arahippocampal cortex in humans) and the medial entorhinal cor-ex (MEC) spatial information (a ‘where’ stream), and ultimatelyin Research 254 (2013) 22– 33 25
both types of information are integrated in the hippocampus (HIP)(Fig. 3). This concept was first proposed by Mishkin and colleaguesin 1983, and has had a tremendous impact on the conceptualiza-tion of memory function since then. Indeed, this model is essentiallyanatomy-based, and relies mainly on the existence of preferentialinputs from the ventral visual stream to the PrC and from the PrC tothe LEC, as well as the existence of preferential inputs from the dor-sal visual stream to the POR, and from the POR to the MEC [76,77:for reviews see 78,79]
However, the only robust evidence available in the literaturefor a specific involvement of medial temporal areas in either theselective processing of item or spatial information concerns the PrCand the HIP, respectively [80–83: for reviews see 19,20,29,84]. Con-versely, whether the POR and the MEC are selectively involved inspatial processes, or whether the LEC preferentially deals with non-spatial information, had not been thoroughly tested. Moreover, atodds with the predictions of the ‘two streams’ model, conflictingresults emerged from the literature regarding the POR (paraHIP inhumans). Indeed, the POR, originally thought to principally sub-serve spatial processes in humans, was more recently suggested tocontribute more generally to the recollection process and to con-textual associations [22,85: for reviews see 5,21]. In addition, eventhough many studies have investigated LEC and MEC functions inspatial navigation/path integration, little is known about their spe-cific contribution to memory function (see: Section 1.1), and nostudy to date has tested directly whether the LEC was truly moresensitive to item information than spatial information, or whetherthe MEC was more recruited during spatial than non-spatial mem-ory. However, against the predictions of the model, recent lesionand electrophysiological studies showed that the LEC could processat least some type of spatial information and that the MEC couldalso be critical for some non-spatial memory processes [86–88],underlying the necessity of a more thorough evaluation of the roleof the LEC in a selective ‘what’ stream and that of the MEC in the‘where’ stream.
3.2. Testing the predictions of the two-streams hypothesis
To test which MTL areas were especially sensitive to item iden-tity or spatial demands, the patterns of expression of Arc pre-mRNA(detectable as a nuclear labeling) were compared in the LEC, theMEC, the PrC, and the POR during the recognition phase of fourdistinct memory tasks. These tasks shared the same experimentalconditions and vary only in terms of the type of stimulus used (odoror object) or spatial demands. In these spontaneous item recogni-tion memory paradigms, mice were exposed to two identical itemsduring a study phase (Fig. 4A,B) and, after a delay, exposed againto two items during a recognition phase (Fig. 4 C–F). When spatialmemory was studied, items presented during the recognition phasewere identical to those experienced during the study phase, but onewas displaced (Fig. 4C,E). When non-spatial memory was studied(item recognition memory), one of the two items presented duringthe study phase was replaced by a new one, while the locations ofthe items remained identical (Fig. 4D,F). Memory performance wasassessed by calculating the standard D2 ratio [89], and all groupsdiscriminated between ‘old’ and ‘new’ (item or location) to a com-parable level [90]. Arc pre-mRNAs were detected on non-adjacentsections that covered approximately 400 microns of each targetarea. According to the predictions of the ‘two streams’ hypothesisan area belonging to the ‘where’ stream was expected to be specif-ically sensitive to the spatial demands of the task (e.g. to be morerecruited during the spatial tasks than non-spatial ones, indepen-
dently of the type of stimulus used). Conversely, an area belongingto the ‘what’ stream was expected to be specifically sensitive to thetype of stimulus used (e.g. to be differentially recruited when odoror objects are used, and invariant to spatial demands).
26 M.M. Sauvage et al. / Behavioural Brain Research 254 (2013) 22– 33
Fig. 3. Depiction of the flow of information in the ‘two streams’ model.T ormatI ationM of the
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he ventral visual stream is thought to preferentially relay to the PrC and the LEC infn contrast, the dorsal visual stream is suggested to provide more contextual inform
EC. Both types of information are thought to be ultimately integrated at the level
Largely at odds with the predictions of the model, the LEC wasot especially sensitive to the type of stimulus used since it wasecruited to the same level for odor and object stimuli, indepen-ently of the spatial demand of the task [90]. Moreover, the MECnd the POR displayed similar levels of Arc expression across spa-ial and non-spatial tasks (and across stimulus-types), against thedea that those areas would preferentially process spatial informa-ion [90]. Conversely, the PrC was especially sensitive to the typef stimulus used (e.g. was differentially recruited when odors andbjects were used independently of the spatial demand of the task)ulfilling the predictions of the model [90].
.3. Departing from the ‘two-streams’ hypothesis
One of the key findings of this study is that the LEC was not dif-erentially activated when odors and objects were used as stimuli,uggesting that this region is not especially sensitive to stimuluseatures, hence does not appear to rightfully deserve its tagging as awhat’ stream region (of note, experimental conditions can unlikelyccount for the absence of a stimulus-type tuning here because such
tuning was found in the PrC on the same brain sections). Fur-hermore, this time in agreement with the model, the LEC was notuned to the spatial demands of the task, but was recruited to theame level for spatial and non-spatial tasks, which also confirmedecent studies showing that the LEC processes to a certain extentbject-related spatial information [87,88]. These results broughturther support to the theory that the LEC does not specificallyelay information content to the hippocampus, but rather sends
global signal indicative of the saliency/familiarity of the stimuli
hat have been attended [91]. This theory has also received muchupport from in vitro electrophysiological studies that showed thathe LEC is activated by PrC stimulation only when a concomitanttimulation of the amygdala has occurred, a stimulation which hasion related to the identity/features of stimuli attended (‘what’ type of information)., for example: spatial information (‘where’ type of information), to the POR and the
hippocampus.
been conceptualized as some type of a salience tag [92,93]. Alto-gether these results support the idea that the LEC would processthe saliency/familiarity levels of stimuli, rather than spatial or fea-ture information, a theory that has recently received strong supportfrom the literature in humans [for a review see 5].
Other intriguing findings in this study are that, against the pre-dictions of the ‘two streams’ model and the literature on spatialnavigation, the MEC was not tuned to spatial information duringrecognition memory tasks (e.g. was not more recruited during thespatial tasks than during the non-spatial ones), and was clearly lessactivated than any other MTL area during all tasks (approximately2%, albeit still significantly recruited). Hence, these findings suggestthat the MEC contributes to path integration and memory functionto a different extent (at least during the recognition phase of thetask). Moreover, in contrast to its role in spatial navigation, theMEC appears not to be exclusively dedicated to the processing ofspatial information in recognition memory, since it contributed tothe same extent to spatial and non-spatial information processingin the present tasks. In further support to this idea, a recent lesionstudy showed that MEC lesions impair performance on a delayednon-matching to odor memory task [86]. Importantly, the absenceof selective spatial tuning in the MEC and the low level of activityobserved at this level can unlikely stem from technical flaws sincea selective spatial tuning was found in CA3 with the same behav-ioral paradigm, in the same animals (see Section 4.3), and a hightask-induced Arc expression (6–9%) was found in the POR on thesame brain sections.
Finally, those data confirmed recent human findings suggestingthat the POR is critically involved in the processing of spatial and
non-spatial information, by reporting that the POR was recruitedto a similar level in all tasks independently of the type of stimulusused or the spatial demands of the tasks [22,85,94–98: for reviewssee 5,21].
M.M. Sauvage et al. / Behavioural Brain Research 254 (2013) 22– 33 27
Fig. 4. Spontaneous item recognition memory tasks.M ce wew l memp t locas
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ice explored two identical stimuli during a ‘study’ phase, and following a delay, miere used: odors mixed with sand in plastic cups (A,C,D) and objects (B,E,F). Spatiahase (C, E), and non-spatial memory was tested by introducing a novel stimulus (atimulus (or novel stimulus location) reflected successful recognition memory.
In conclusion, testing the predictions of the ‘two streams’ypothesis for the areas that had not been thoroughly investigatedo date revealed that the LEC did not especially belong to a selectivewhat’ stream of information processing, and that the POR and the
EC did not preferentially convey spatial information, at least dur-ng the recognition phase of memory tasks. Interestingly, activationf the anterior parahippocampal gyrus (which includes the PrC andhe LEC) is more correlated to familiarity responses, and the pos-erior parahippocampal gyrus (including the paraHIP/POR and the
EC) with recollection in humans. Hence, altogether, those dataring further support to a recent theory, according to which theunctional segregation of the medial temporal lobe could be betteronceptualized as a segregation between memory processes suchs recollection and familiarity, rather than in terms of spatial con-ent [for further details on this study see 90: for a review 5]. Furthernvestigations are still required to test this latter hypothesis.
. Information processing along the dorsoventral axis ofA1 and CA3
.1. Spatial information processing in the dorsal and ventral partsf the hippocampus
It is well-accepted that the dorsal and ventral parts of theippocampus subserve at least partially different functions [foreviews see 12,99]. The dorsal hippocampus is believed to prefer-ntially process spatiotemporal information [100–103], while the
re again exposed to two stimuli during the ‘recognition’ phase. Two types of stimuliory was tested by moving one stimulus to a novel location during the recognition
tion that had been already experienced; D, F). A higher exploration time for a novel
ventral part is thought to be more involved in emotional processes[104–106: for a review see 107]. However, this belief of a dorsoven-tral functional segregation was also strongly encouraged by the pat-tern of projections between cortical/subcortical areas and the dor-sal and ventral parts of the hippocampus. For example, the dorsalpole of the hippocampus receives more visual information, whilethe ventral part receives more limbic inputs [108–111: for a reviewsee 12]. Nevertheless, place cells were also found in the ventral partof the hippocampus, albeit with larger place fields [112,113]. More-over, some studies have shown that spatial memory performance isimpaired following lesions or inactivation of the ventral hippocam-pus in context-specific visual discrimination, spatial water mazeand working memory tasks, as well as during the retrieval of con-textual fear-conditioning, suggesting that the ventral hippocampusalso processes spatial information to a critical extent [114–117].Most of the aforementioned studies lesioned the entire hippocam-pus, which did not allow for the role of CA1 and CA3 in the dorsaland ventral parts of the hippocampus to be teased apart. Hence, tothis date, the extent to which CA1 and CA3 are functionally segre-gated along the dorsoventral axis of the hippocampus, and whetherthis segregation is comparable in CA1 and CA3, remains unclear.
4.2. Spatial and non-spatial information processing in dorsal CA1
and dorsal CA3Even though patterns have started to emerge within the dor-sal hippocampus, the specific contribution of the hippocampal
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ubfields CA1 and CA3 to memory function is still not thoroughlynderstood. What is known is that both CA1 and CA3 heavilyontribute to spatial memory. For example, place cells have beenescribed in both areas indicating a prominent role in spatial nav-
gation [113,118–120]. In addition, numerous reports have shownhat CA1 is crucial for the detection of novel spatial arrangements,nd that CA3 is critical for the memory of item-in-place, for con-extual fear-conditioning and for delayed non-matching-to-placer spatial Morris water maze tasks [121–128]. What CA1 andA3 appear to differ in is the extent to which they contributeo non-spatial memory. Indeed, recent electrophysiological andesion studies have shown that CA1 is critically involved in tem-oral encoding, as reflected by its involvement in the learning ofequences or pairs of stimuli separated by a short delay, whileA3 only participates to a limited extent to these processes16,17,129–132]. However, most of the knowledge that has accu-
ulated on CA1 and CA3 function comes from studies comparingorsal CA1 to dorsal CA3, while the contribution of ventral CA1nd ventral CA3 to memory function, and whether it differs fromorsal CA1 and dorsal CA3, has received much less attention andemains elusive. To clarify those issues, we describe below a studyhich has investigated CA1 and CA3’s patterns of Arc expression in
he dorsal and the ventral parts of the hippocampus during spatialnd non-spatial memory (see Fig. 4B, E, F; [133]).
.3. CA1 and CA3 are not segregated to the same extent along theorsoventral axis
As reported in the literature, dorsal CA1 was strongly recruiteduring the detection of novel locations, which confirmed our under-tanding of CA1 function [133]. More surprising was that dorsalA1 was recruited to a comparable level for the detection of novelbjects, reflecting the absence of a selective spatial tuning in dor-al CA1. This finding, however, added to the recent reports of
critical involvement of dorsal CA1 to the processing of otheron-spatial information (such as time) by showing that CA1 islso strongly involved in processing object information over time16,17]. The issue of a critical involvement of the hippocampusn the detection of novel objects is still under debate, given the
any studies reporting a negligible effect of hippocampal lesionsn object recognition memory [134: for a review see 135]. How-ver, other studies report severe memory impairments followingippocampal and/or amygdala lesions, and suggest that the reliancen the hippocampus could depend on the memory load or theelay applied to the task [136–140]. In addition, the finding of an
nvolvement of dorsal CA1 in the processing of object informa-ion is also supported by a new tract tracing study that reportshe existence of direct projections from the PrC to dorsal CA1, sug-esting that object information processing could occur at this level141].
Also, as expected, dorsal CA3’s ability to process spatial infor-ation was comparable to dorsal CA1’s, confirming the role of CA3
n the rapid encoding of new spatial information [133]. However,orsal CA3 was strikingly less recruited for the detection of novelbjects, underlying the existence of a specific spatial tuning in dor-al CA3. Of note, the PrC does not project to dorsal CA3 the way itoes to dorsal CA1 (while POR, LEC and MEC inputs are compara-le), which could at least partially explain why dorsal CA3 is lessecruited during object recognition memory than dorsal CA1 [141].
A similar spatial tuning could be observed in ventral CA3, as Arcxpression was comparable in ventral and dorsal CA3 for the spatialnd the non-spatial tasks, indicative of a robust and stable prefer-
ntial recruitment of CA3 along the dorsoventral axis during spatialecognition memory [133]. In striking contrast, patterns of activa-ion in dorsal and ventral CA1 were different [133]. Ventral CA1as clearly more activated for the detection of spatial novelty thanin Research 254 (2013) 22– 33
for object novelty, resulting in a selective spatial tuning similar tothat observed in ventral and dorsal CA3, but not dorsal CA1. Thefinding of a spatial tuning in ventral CA3 and CA1 are at odds withstudies that showed a preferential role of the ventral hippocampuswithin non-spatial domains. However, it brings support to otherstudies which report considerable spatial information processing inthe ventral hippocampus; for example: the existence of place cellsat this level and a critical involvement of ventral hippocampus incontext-specific visual discrimination, contextual fear condition-ing and spatial water maze and working memory tasks [113–117].Hence, the well-accepted concept of a lesser involvement of theventral hippocampus in spatial processes may need to be revisitedin further studies focusing on the role of the ventral hippocampuswithin the domain of spatial memory.
In summary, CA3 (dorsal and ventral parts) appears to be pre-dominantly involved in the detection of new locations (as opposedto that of objects), and its function to be rather homogenous alongthe dorsoventral axis of the hippocampus. In addition, the dor-sal and the ventral parts of CA1 and CA3 contribute to the sameextent to spatial recognition memory. In contrast, dorsal CA1 isrecruited to the same level for the detection of novel objects andnovel locations, revealing for CA1 a functional heterogeneity alongthe dorsoventral axis in the non-spatial domain, which seems to beabsent in CA3.
5. Functional segregation of CA1 and CA3 along theproximodistal axis
5.1. Segregation of spatial and non-spatial information withinCA1 and CA3?
As previously described in detail (see Sections 4.2 and 4.3),CA1 processes both spatial and non-spatial information. More-over, even though the role of CA3 has principally been studiedwithin the frame of spatial memory, CA3 was at least reported toplay a critical role in trace eye-blinking conditioning, non-spatialassociative recognition memory and object recognition memory[131,133,142,143: for a review see 8]. Interestingly, tracing studiesfirst and electrophysiological and IEG reports later, have suggestedthat the most distal part of CA1 (close to the subiculum) prefer-entially processes non-spatial information provided by the LEC.In contrast a more proximal part of CA1 (close to CA2) wouldprincipally deal with spatial information provided by MEC inputs,indicating a segregation of spatial and non-spatial informationwithin CA1 [13–15,24,87,144–147,148]. In addition, a vast numberof anatomical studies have suggested that CA3 could also be seg-regated following a similar pattern. Indeed, the cytoarchitecture,the gene expression and the connectivity patterns are quite differ-ent in proximal CA3 (close to the dentate gyrus; DG) and distalCA3 (close to CA2) [for reviews see 149,150]. Of specific inter-est for this section, proximal CA3 preferentially projects to distalCA1 (receiving LEC inputs) whereas distal CA3 primarily projectsto proximal CA1 (which receives MEC inputs) [108,151,152]. Inaddition, proximal and distal CA3 receive preferential projectionsfrom different parts of the DG. Proximal CA3 primarily receives pro-jections from the exposed blade of the DG, which is not recruitedduring exposure to new spatial contexts, while distal CA3 is morestrongly connected to the enclosed blade of the DG, which isstrongly recruited in the same spatial task [153,154]. Altogether,these studies have strongly suggested that CA3 could be function-ally segregated along its proximodistal axis, and that CA3 (and
in particular its proximal part) could play a critical role in non-spatial memory, in addition to its well-documented role in spatialmemory. However, functional evidence of such a segregation waslacking.
M.M. Sauvage et al. / Behavioural Brain Research 254 (2013) 22– 33 29
Fig. 5. Delayed non-matching to odor task.(A) Ten odors are presented to the animal during the ‘study’ phase (one at a time). After a 20 min delay, the memory for the studied odors is tested by presenting the sameo elayet od rei
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.2. Testing the hypothesis of a functional segregation of CA3 andA1 during non-spatial memory
The delayed non-matching to odor paradigm described in155,156] was used to evaluate the contribution of the distal androximal parts of CA1 and CA3 during non-spatial memory. Briefly,ach training session consisted of a ‘study’ phase, a delay, and a
recognition’ phase (see Fig. 5). Each day, rats were presented with astudy’ list of ten different household spices (thyme, coriander etc.)
ixed in sand contained in a transparent cup. During the recog-ition phase, animals were tested for their ability to distinguishetween the odors presented during the study phase (‘old’ odors)nd ten additional odors (‘new’ odors) that they had been familiar-zed with, but were not presented during the study phase. Whennimals were presented with an odor that was part of the studyist (‘old’ odor), animals had to refrain digging and go to the back ofhe cage to receive a food reward if they were correct. Conversely,hen the odor was not part of the study list (‘new odor’), animalsad to dig in the test cup to get the reward, if correct. Animals thateached 75–80% correct choices over three sessions in a row wereacrificed on the third session immediately after the recognitionhase, and Arc pre-mRNAs were detected in the distal and proximalarts of CA1 and CA3 along the transverse axis, as well as at septalnd temporal levels of the hippocampus [for more details see [157].
.3. A preferential involvement of proximal CA3 and distal CA1 inon-spatial recognition memory
This study reported for the first time evidence of a functionalegregation of the CA3 hippocampal subfield in non-spatial recog-ition memory, and showed that proximal CA3 was more recruiteduring non-spatial memory than distal CA3. In addition, distalA1 was found to be more involved in the processing of non-patial information than proximal CA1. Since proximal CA3 projectsainly to distal CA1, it was speculated that a selective proximal
A3-distal CA1 hippocampal sub-network could preferentially sup-ort high-order non-spatial memory [157].
In this study, proximal CA3 was more activated than distal CA3
long the transverse and mediolateral axes of the hippocampus,hich suggested that non-spatial information is processed pref-rentially by proximal CA3 throughout the hippocampus. Givenhat proximal CA3 receives little direct input from the EC when
d non-matching-to-sample rule. If the odor belonged to the ‘study’ list (‘old’ odor),ward (B). If the odor did not belong to the ‘study’ list (‘new’ odor), the rat could dig
compared to distal CA3 (because the lacunosum moleculare layeris virtually absent at this level), non-spatial information processedby proximal CA3 was hypothesized to primarily originate from theDG [152,158–160]. Granule cells of the DG receive inputs fromboth the LEC and the MEC, albeit at different levels of the den-dritic tree (closer to the cell body for the MEC, further away for theLEC [159,161]). Whether this information is integrated, or remainssegregated, is not known. However, the exposed and the enclosedblades of the DG show strikingly different electrophysiological andneuroanatomical profiles [162,163]. It is unclear how exactly thetwo blades functionally differ. However, an Arc imaging study hasshown that the exposed blade of the DG was not recruited duringexposure to new spatial contexts, whereas the enclosed blade was[154]. In addition, in further support of a segregation of spatial andnon-spatial information between the two blades, a recent studyfound that the exposed blade could be more important for cuedfreezing and the enclosed blade for freezing to context [164]. Aspreviously mentioned, the exposed blade of the DG projects prin-cipally to proximal CA3, while the enclosed blade preferentiallyprojects to distal CA3 [149: for a review see 153]. Hence, since prox-imal CA3 was more activated than distal CA3 during the delayednon-matching to odor task (DNMO), it is tempting to speculatethat the exposed blade of the DG could preferentially relay non-spatial information to proximal CA3, while projections from theenclosed blade of the DG to distal CA3 would rather relay spatialinformation.
As a further piece of the puzzle, distal CA1 was found to be morerecruited than proximal CA1 during the DNMO task, a finding thatconfirms recent electrophysiological and IEGs reports using sponta-neous exploration tasks, but this time with a task involving a highermemory load [14,15; of note Burke et al. did not study proximalCA1]. This result combined with the existence of LEC inputs to distalCA1, and the preferential proximal CA3-distal CA1 projections, ledto the hypothesis that distal CA1 activation (and maybe proximalCA3) could possibly reflect non-spatial pattern separation betweenthe representations created during the ‘study’ phase and those gen-erated during the ‘recognition’ phase of the task. This hypothesisis at least partially supported by studies reporting a critical role
of CA1 and CA3 in non-spatial pattern separation, and a stronginvolvement of CA1 in the interpretation/recoding of CA3 inputsin the context of less spatially relevant information [for reviewssee 165–167].
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In summary, this study reports a preferential recruitment ofroximal CA3 and distal CA1 (over their counterparts distal CA3nd proximal CA1) during non-spatial memory, which suggests thatot only CA1 is functionally segregated along its proximodistal axis,ut also CA3, which is a rather new concept. Given that proximalA3 and distal CA1 share direct projections, it might be possiblehat proximal CA3 and distal CA1 belong to a selective functionalub-network in the hippocampus which would preferentially sup-ort memory function when the salient part of a representation
s restricted to its non-spatial content. These intriguing findingsotentially open the door to an alternative way of conceptualizingpatial and non-spatial information processing in the hippocam-us, according to which spatial and non-spatial information coulde either: 1) integrated at the level of hippocampus when bothypes of information are salient (the current view), or 2) whennly one type of information is meaningful for the representationt stake (spatial or non-spatial), this salient information could berocessed through a more ‘efficient/direct’ network specialized inhe processing of this type of information. Further investigationsocusing on differential processing of spatial and non-spatial infor-
ation at CA3 and CA1’s proximodistal levels will be necessary tourther test this hypothesis [for more details on this study see [157].
. Conclusion and future directions
Prior to the studies mentioned in this review, Arc imagingad been principally used to get further insight on hippocam-al function by studying CA1 and CA3 contributions to spatialnd contextual information processing [for reviews see 9,28,29].n the present review, we described studies which addition-lly investigated the contribution of CA1 and CA3 to non-spatialemory, and the contribution of other MTL areas to spatial and
on-spatial memory by investigating the functional segregationetween parahippocampal areas, and within CA1 and CA3 alonghe dorsoventral and proximodistal axes.
This ‘systems’ approach was made possible because Arc imag-ng is optimally suited to the simultaneous detection of patterns ofctivation in multiple brain areas independently of whether theyre adjacent or very distant, which still represents a major chal-enge for other technical approaches. The studies we have describedn the present review have adopted this approach and led to theonclusions that, within the frame of memory function, 1) thearahippocampal region is not strictly segregated into anatomicaltreams preferentially processing spatial or non-spatial informa-ion as originally described, since only the PrC showed evidence ofreferential tuning (to the type of stimulus), while the POR, the LECnd the MEC processed spatial and non-spatial information to theame level; 2) that CA3 function is rather homogenous along theorsoventral axis of the hippocampus (more recruited during spa-ial tasks than non-spatial tasks, albeit still significantly recruited)ut not CA1’s, since dorsal CA1 is recruited to a similar extent duringpatial and non-spatial tasks but CA1 displays a preferential spatialuning in the ventral part; 3) that CA3 is functionally segregatedlong its proximodistal axis in a way that mirror’s CA1’s, whichuggests the existence of a proximal CA3-distal CA1 hippocampalub-network that could preferentially support non-spatial mem-ry. These findings suggest that the well-accepted hypothesis of aivision of the MTL areas, and that of the dorsal and ventral parts ofhe hippocampus into spatial and non-spatial domains may needo be revisited. In addition, they also bring evidence for a new typef segregation within CA3 that is observable not only along the
ransverse axis, but also along the mediolateral axis at septal andemporal levels of the hippocampus.Arc studies have originally focused on uncovering the mech-nisms sustaining information processing within the frame of
in Research 254 (2013) 22– 33
cognitive tasks with a strong plasticity component and a low mem-ory load (for example: a single exposure to a spatial context),which led to results consistent with electrophysiological stud-ies. Progressively, this imaging technique was also adapted to thedetection of patterns of activation in tasks with increasing mem-ory demands such as spontaneous item recognition memory tasks,water maze tasks, fear conditioning and delayed non-matching tosample tasks. Findings that emerge from those studies have beenrelevant to the discussion of concepts going beyond the frame of theprocessing of information content, and have implications for ourunderstanding of more abstract cognitive processes, such as pat-tern separation/completion, or the familiarity and the recollectionprocesses.
A deeper understanding of the functional relevance of therecruitment of MTL areas during memory still depends at leastpartially on a further characterization of the specific molecularmechanisms Arc contributes to. However, the fact that Arc has beenreported to be a major player in synaptic and cell-wide plasticityprocesses, give us already a unique opportunity to further bridgecognitive performance and those plasticity processes.
In summary, Arc imaging appears to have become a newstandard in brain imaging. Given the high level of convergencebetween lesion, mutagenesis and electrophysiological outputs andArc imaging findings, much hope is put into a combination ofthose techniques to unravel the specific contribution of the dif-ferent areas of the medial temporal lobe to distinct types ofmemory (spatial/non-spatial), different stages of memory forma-tion (encoding, consolidation, retrieval etc.) and different memoryprocesses (pattern separation/completion, recollection/familiarityprocesses).
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