Building hippocampal circuits to learn and remember: Insights into the development of human memory

Behavioural Brain Research 254 (2013) 8–21

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Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr

Review

Building hippocampal circuits to learn and remember: Insights into the development of human memory Pierre Lavenex a,b,c,d,∗ , Pamela Banta Lavenex a,b a

Laboratory for Experimental Research on Behavior, University of Lausanne, Switzerland Institute of Psychology, University of Lausanne, Switzerland Laboratory of Brain and Cognitive Development, University of Fribourg, Switzerland d Fribourg Center for Cognition, University of Fribourg, Switzerland b c

h i g h l i g h t s

g r a p h i c a l

a b s t r a c t

 Distinct hippocampal circuits exhibit distinct developmental profiles.  The subiculum, presubiculum and parasubiculum support path integration.  Direct entorhinal cortex projections to CA1 support basic allocentric spatial memory.  Dentate gyrus and CA3 support pattern separation and high-resolution spatial memory.  Maturation of all hippocampal circuits underlies the emergence of episodic memory.

a r t i c l e

i n f o

Article history: Received 24 November 2012 Received in revised form 5 February 2013 Accepted 8 February 2013 Available online 18 February 2013 Keywords: Amnesia Spatial memory Development Hippocampus Neural networks Gene expression

a b s t r a c t The hippocampal formation is essential for the processing of episodic memories for autobiographical events that happen in unique spatiotemporal contexts. Interestingly, before 2 years of age, children are unable to form or store episodic memories for recall later in life, a phenomenon known as infantile amnesia. From 2 to 7 years of age, there are fewer memories than predicted based on a forgetting function alone, a phenomenon known as childhood amnesia. Here, we discuss the postnatal maturation of the primate hippocampal formation with the goal of characterizing the development of the neurobiological substrates thought to subserve the emergence of episodic memory. Distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural and molecular development during early postnatal life. The protracted period of neuronal addition and maturation in the dentate gyrus is accompanied by the late maturation of specific layers in different hippocampal regions that are located downstream from the dentate gyrus, particularly CA3. In contrast, distinct layers in several hippocampal regions, particularly CA1, which receive direct projections from the entorhinal cortex, exhibit an early maturation. In addition, hippocampal regions that are more highly interconnected with subcortical structures, including the subiculum, presubiculum, parasubiculum and CA2, mature even earlier. These findings, together with our studies of the development of human spatial memory, support the hypothesis that the differential maturation of distinct hippocampal circuits might underlie the differential emergence of specific “hippocampus-dependent” memory processes, culminating in the emergence of episodic memory concomitant with the maturation of all hippocampal circuits. © 2013 Elsevier B.V. All rights reserved.

∗ Corresponding author at: Laboratory for Experimental Research on Behavior, Institute of Psychology, University of Lausanne, Geopolis 4343, CH-1015 Lausanne, Switzerland. Tel.: +41 21 692 32 62; fax: +41 21 692 32 60. E-mail address: [email protected] (P. Lavenex). 0166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2013.02.007

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Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postnatal development of the primate hippocampal formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Dentate gyrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. CA3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. CA2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. CA1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Subiculum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Presubiculum and parasubiculum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Entorhinal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Evidence at the molecular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A model linking brain and behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Basic allocentric spatial memory in 2-year-old children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Improved allocentric spatial processing after 2 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Emergence and maturation of episodic memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The hippocampal formation is comprised of a group of cortical regions located in the medial temporal lobe that includes the dentate gyrus, hippocampus, subiculum, presubiculum, parasubiculum and entorhinal cortex [1,2] (Fig. 1). The hippocampal formation, as a whole functional unit, is essential for the processing of episodic memories [3], which are the memories for autobiographical events that happen in unique spatiotemporal contexts [4]. These memories comprise the representations of unique personal experiences that are central to defining who we are [5]. In humans, significant changes in the capacity for episodic memory occur within the first 7 years of life. Prior to about 2 years of age, children are unable to form or store episodic memories for recall later in life, a phenomenon known as infantile amnesia [6]. The 3–5 years that follow this period are characterized by fewer episodic memories than would be predicted based on a simple forgetting function alone, a phenomenon referred to as childhood amnesia [6]. Until recently, the neurobiological basis for such early-life changes in episodic memory had remained highly speculative due to the lack of

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systematic, quantitative studies of postnatal brain development at the cellular or systems levels [7–9]. As the hippocampal formation is the central component of a large neural network subserving memory processes, we first review recent data from our laboratory and from the laboratories of other researchers on the structural and molecular development of the primate hippocampal formation. Second, we propose a model suggesting how the differential maturation of distinct hippocampal circuits might contribute to the emergence of distinct memory processes in humans. Finally, we discuss the results of recent behavioral studies supporting the predictions of this model. 2. Postnatal development of the primate hippocampal formation Historically, neuroanatomical data has indicated that there is significant postnatal maturation of the primate hippocampal formation. However, since much of this data derived from largely qualitative reports, it has been difficult to summarize and assimilate this data into a coherent, definitive picture. To rectify this, our laboratory has recently undertaken a series of comprehensive and systematic analyses of the postnatal structural and molecular development of the rhesus macaque monkey (Macaca mulatta) hippocampal formation [8,10–14]. Our quantitative data provide a fundamental framework within which to integrate the piecemeal or qualitative information reported previously. In this section, we consider the existing data regarding the postnatal development of distinct regions and putative functional circuits of the primate hippocampal formation. For this description, we follow the classical view of information flow through the hippocampal loop of information processing, starting with the dentate gyrus, moving to CA3, then to CA1, then to the subiculum and the entorhinal cortex. We show that the sequential maturation of distinct hippocampal regions or layers does not follow this principal circuit, but, instead, is characterized by the differential maturation of parallel hippocampal pathways. 2.1. Dentate gyrus

Fig. 1. Schematic representation of the hierarchical organization of the main serial and parallel pathways through the different regions of the rhesus macaque monkey (Macaca mulatta) hippocampal formation. EC: entorhinal cortex; DG: dentate gyrus; CA3, CA2, CA1: fields of the hippocampus proper; Sub: subiculum; PrS: presubiculum; PaS: parasubiculum. Scale bar = 1 mm.

The primate hippocampal formation, in general, and the primate dentate gyrus, specifically, are far from mature at birth (Fig. 2). Indeed, the dentate gyrus is one of only two regions of the mammalian brain in which neurogenesis has been shown unequivocally to occur postnatally under normal conditions ([15]; the olfactory bulb being the other). Although granule cell

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Fig. 2. Coronal, Nissl-stained sections and corresponding line drawings at mid rostrocaudal level of the newborn (A) and adult (B) rhesus monkey hippocampal formation. DG, dentate gyrus; ml, molecular layer; gcl, granule cell layer; pl, polymorphic layer; CA3, CA2, CA1, fields of the hippocampus proper; CA3prox, proximal portion of CA3; CA3dist, distal portion of CA3; so, stratum oriens; pcl, pyramidal cell layer; sl, stratum lucidum; end, end bulb; sr, stratum radiatum; slm, stratum lacunosum-moleculare; Sub, subiculum; PrS, presubiculum; PaS, parasubiculum; EC, entorhinal cortex. Scale bar = 1 mm, applies to all panels.

Fig. 3. Stereological measurements of the postnatal development of the rhesus monkey dentate gyrus. (A) Number of neurons in the granule cell layer. (B) Volume of distinct layers of the dentate gyrus at different ages during early postnatal development (expressed as percentage of the volume of the layer observed in 5–10-year-old monkeys: average ± standard error of the mean). (C) Distribution of neuronal soma size in the monkey granule cell layer through early postnatal development and in adulthood. Gray areas indicate two modes: mode 1, corresponding to immature granule cells (soma < 150 ␮m3 ); mode 2, corresponding to the median size of mature granule cells (400–550 ␮m3 ).

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neuron production decreases considerably after the first few postnatal months in monkeys, a substantial number of neurons continue to be generated throughout juvenile, adolescent [12,16–18] and adult life [12,19,20]. Indeed, we have recently shown that about 40% of the total number of granule cells observed in adult (5–10-year-old) rhesus macaque monkeys (M. mulatta) are added to the granule cell layer postnatally (Fig. 3A) [12,13]; and, although 25% of these neurons are added in the first 3 months of life, the period when the greatest number of postnatally-generated neurons are added to the dentate gyrus, the number of granule cells at 1 year of age still does not equate that of adults. This protracted period of neuron addition in the dentate gyrus is accompanied by a late maturation of the granule cell population, which continues beyond the first postnatal year in rhesus macaque monkeys [12]. Specifically, there is a large population of small cells that is most prominent during the first 3 months after birth, coinciding temporally with the peak in postnatal neurogenesis described above, that gradually decreases over the first year (Fig. 3C). Nevertheless, the number of small cells is still significantly higher in 1-year-old monkeys as compared to 5–10-year-old monkeys, indicating that developmental processes are not yet terminated at one year of age in monkeys. In parallel, although the mature-sized cell population exhibits a gradual increase in number between birth and one year of age, there are still fewer mature-sized cells in 1-year-old monkeys as compared to 5–10-year-olds (Fig. 3C). These data indicate that monkey granule cell neurons undergo a gradual but substantial structural maturation from birth until beyond the first year after birth in order to achieve mature morphological characteristics. As a result of these increases in cell number and cell volume, the volume of the granule cell layer itself increases gradually during this same postnatal period (Fig. 3B). At birth, the volume of the granule cell layer in Nissl-stained preparations (6.43 ± 0.60 mm3 ) is about 60% of that observed in 5–10-year-old monkeys (10.77 ± 0.66 mm3 ). It increases linearly (0.008 mm3 /day, R2 = 0.4667, P < 0.001) between birth and 1 year of age (9.46 ± 0.55 mm3 ), when it reaches 88% of the volume observed in 5–10-year-old monkeys. Paralleling this gradual development of the granule cell layer, the molecular and polymorphic layers exhibit gradual increases in volume during this same postnatal period, suggesting a protracted development of the functional circuits to which the granule cells contribute. Our volumetric findings are consistent with results from previous studies reporting that the dendritic length and spine density of individual granule cells increase until at least the fifth postnatal month in monkeys [21,22]. In rats, the number of dendritic spines per unit length increases between 2 and 7 months of age [23], which suggests a protracted postnatal development of the rat molecular layer, parallel to that observed volumetrically in monkeys. Unfortunately, there are no data regarding the postnatal maturation of the afferent projections of the dentate gyrus in rodents or primates. Although it has been shown that entorhinal and subcortical projections innervate the dentate gyrus during fetal development in both species [24], no study has evaluated the possible postnatal maturation of these projections in either rats or monkeys. We published preliminary findings showing that entorhinal cortex fibers innervate the appropriate target zones in the dentate gyrus and hippocampus of 3-week-old monkeys [8], but we have yet to perform quantitative analyses of these projections in infant and adult monkeys in order to evaluate their possible postnatal maturation. In humans, there is to our knowledge no information regarding the developmental state of entorhinal-dentate gyrus projections at birth. Nevertheless, the myelination of these projections appears to occur largely during the postnatal period and is thought to continue even after the first decade of life in humans [25]. Altogether, these data suggest that although the main afferent connections of the dentate gyrus are already present at birth in primates, they

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undergo important morphological maturation during postnatal life that might impact the functional properties of these pathways. With respect to the late maturation of the granule cells, we might expect that their axons continue to mature and influence the development of their target cells in the polymorphic layer of the dentate gyrus and the CA3 field of the hippocampus during postnatal life. Indeed, we showed that the polymorphic layer exhibits an increase in volume beyond the first year of life in monkeys (Fig. 3B) [12,13], suggesting a protracted maturation of its cellular components. Interestingly, it has been reported that the mossy cells, the major targets of the granule cell projections in the polymorphic layer [26,27], exhibit clear morphological changes in soma and dendritic structure until at least 9 months of age in monkeys [28] and at least 30 months of age in humans [22]. In addition, the number of spines per 100 ␮m of mossy cell dendrite appears to increase by about 10% between 1 year and 4–20 years of age in monkeys [28]. Our analyses revealed a 25% increase in the volume of the polymorphic layer between 1 year and 5–10 years of age. Although the mossy cells and the axons of granule cells represent a major component of the polymorphic layer, there are a variety of other neuronal types and afferent projections targeting this area [1,29]. Despite the early establishment of subcortical projections to the polymorphic layer of the dentate gyrus [24], myelination occurs relatively late in the polymorphic layer, as compared to other hippocampal regions, in humans [25]. In sum, the circuits established by the projections from the dentate gyrus to the polymorphic layer (and CA3, see below) exhibit a slow and protracted development that persists well after the first year of life in macaque monkeys, and may persist for the first decade of life in humans. Nevertheless, detailed analyses of the postnatal maturation of the different cell types contained in the dentate gyrus will be necessary to provide a definitive answer regarding the functional consequences of this delayed maturation of distinct circuits within the dentate gyrus. 2.2. CA3 Located downstream from the dentate gyrus in the hippocampal loop of information processing (Fig. 1), it is not surprising that we found that the developmental increase in volume of CA3 generally parallels that of the dentate gyrus (Fig. 4A). Interestingly, however, the distal portion of CA3, which receives direct projections from entorhinal cortex layer II neurons, matures volumetrically earlier than the proximal portion of CA3 (Fig. 4B). At the cellular level, we found that the proximal CA3 pyramidal neurons exhibit significant changes in soma size within the first three to six postnatal months [13]. In contrast, the size of distal CA3 pyramidal neurons does not vary during postnatal development, suggesting that they have already reached an adult-like size by birth. Our quantitative data are thus in agreement with the description by Seress and Ribak [30] that the somas and dendrites of distal CA3 pyramidal neurons exhibit adult-like ultrastructural features at birth. There is, unfortunately, no published information on the ultrastructural characteristics of developing proximal CA3 pyramidal neurons. Functionally, proximal and distal CA3 pyramidal neurons might contribute to different hippocampal circuits. Proximal CA3 pyramidal cells typically display no or very few dendrites extending into stratum lacunosum-moleculare in 33–57-day-old rats [31] or 10-month- to 21-year-old monkeys [27], and are therefore not in a position to receive significant, direct inputs from the entorhinal cortex [32]. In contrast, pyramidal neurons located in the proximal portion of CA3 receive large numbers of mossy fiber terminals on both their apical and basal dendrites and are thus under greater influence of the granule cells than distally located CA3 cells that receive only apical mossy fiber inputs [1,33]. As mentioned above, various aspects of the dentate gyrus structure mature late during

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Fig. 4. Volume of individual regions/layers of the rhesus monkey hippocampal formation at different ages during early postnatal development (expressed as percentage of the volume of the layer/region observed in 5–10-year-old monkeys: average ± standard error of the mean). (A) Comparison between the dentate gyrus, CA3, CA2, CA1, Subiculum, Presubiculum, Parasubiculum. (B) CA3: proximal and distal portions. (C) CA1: strata oriens, pyramidale and radiatum (so/pcl/sr), stratum lacunosum-moleculare (slm).

postnatal development; this is also the case for the mossy fiber projections. Indeed, Timm-stained mossy fiber terminals, although visible at birth, become more heavily stained in 3-month-old and adult monkeys [30], and the width of CA3 stratum lucidum (in which the mossy fibers travel and terminate) continues to increase after 6 months of age [30]. Our own measurements of the volume of the endbulb (the zone of stratum lucidum located distally in CA3, where the mossy fibers bend rostrally and travel longitudinally [33]) also reveal a continued increase in size between 9 months and 1 year of age [13]. Consequently, the earlier structural maturation of distal CA3 pyramidal neurons, as compared to proximal CA3 pyramidal neurons, suggests a differential maturation of presumably distinct functional circuits within CA3: a relatively early-maturing system associated with projections arising from the entorhinal cortex (see also below for CA1 and the subiculum) and a rather late-maturing system associated with mossy fiber projections arising from dentate granule cells. 2.3. CA2 Surprisingly, our volumetric measurements revealed that CA2 develops earlier than the dentate gyrus and CA3. These data are consistent with our observations based on the immunohistochemical detection of non-phosphorylated high-molecular-weight neurofilament expression, a marker of structural maturity, suggesting an early maturation of CA2 (Fig. 5) [34]. Interestingly, CA2 differs from the dentate gyrus, CA3 and CA1 based on its connectivity with subcortical structures [1]. CA2 projects extensively to the hippocampus proper (CA3, CA2 and CA1), has no known projections toward the neocortex and does not project extensively to subcortical structures. However, CA2 receives a particularly

prominent innervation from the posterior hypothalamus, especially from the supramammillary area and the tuberomammillary nucleus [1]. These projections terminate mainly in and around the CA2 pyramidal cell layer and mainly on principal cells, a region that exhibits early expression of non-phosphorylated high-molecularweight neurofilament immunoreactivity [34]. Interestingly, CA2 pyramidal neurons are also more strongly excited by entorhinal cortex inputs onto their distal dendrites in stratum lacunosummoleculare than are CA3 and CA1 pyramidal neurons [35]. CA2 neurons, in turn, make strong excitatory synaptic contacts with CA1 neurons and could contribute, together with direct inputs from entorhinal cortex layer III neurons to the CA1 stratum lacunosummoleculare, to the firing of CA1 pyramidal neurons in the absence of excitatory inputs from CA3 pyramidal neurons. The early maturation of both subcortical and direct entorhinal cortex inputs to CA2 might explain why we did not observe a differential maturation of individual layers within CA2 (in contrast to what was observed in CA3, CA1 and the subiculum). Altogether, these data suggest how CA2 might form distinct functional pathways that mature both structurally and functionally earlier than CA3, the main source of the excitatory inputs to CA2 arising within the adult hippocampal formation. 2.4. CA1 Similarly, our quantitative volumetric analyses reveal that CA1 matures earlier than the dentate gyrus and CA3 (Fig. 4A), despite the fact that the largest input to the CA1 pyramidal neurons comes from CA3 pyramidal neurons via the Schaffer collaterals [1,36]. Indepth analysis of the separate layers of CA1, however, revealed that despite the overall, relatively early maturation of CA1, distinct

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Fig. 5. Nonphosphorylated high-molecular-weight neurofilament (NF-H) immunoreactivity in the hippocampal formation and mammillary nuclei of infant and adult rhesus monkeys. We employed the monoclonal antibody SMI-32, a well-characterized antibody raised against nonphosphorylated NF-H, the expression of which is believed to reflect the maturation of certain neuronal populations [34]. (A) Heavy labeling in CA3, CA2, and the subiculum of an 11-year-old adult male. (B) Heavy labeling in the entorhinal cortex of a 13-year-old adult male. (C) Heavy labeling in the medial mammillary nuclei of a 13-year-old adult male. (D) Heavy labeling in the subiculum of a 3-month-old infant male. Note the moderate labeling in CA2. (E) NF-H immunoreactivity in the entorhinal cortex of a 3-month-old infant male. (F) Heavy labeling in the medial mammillary nuclei of a 3-month-old infant male. (G) Heavy labeling in the subiculum of a 3-week-old infant male. Note the absence of immunoreactivity in the CA3 and CA2 fields of the hippocampus. (H) NF-H immunoreactivity in the entorhinal cortex of a 3-week-old infant male. (I) Moderate labeling in the medial mammillary nuclei of a 3-week-old infant male. CA1, CA1 field of the hippocampus; CA2, CA2 field of the hippocampus; CA3, CA3 field of the hippocampus; DG, dentate gyrus; EC, entorhinal cortex; LM, lateral mammillary nucleus; MM, medial mammillary nucleus; Sub, subiculum. Scale bar = 1 mm (in A, applies to A–I).

layers within the CA1 exhibit differential maturation (Fig. 4C). The most superficial layer of CA1, stratum lacunosum-moleculare, in which the projections from the entorhinal cortex layer III neurons terminate, matures earlier than the deeper layers of CA1, strata oriens, pyramidale and radiatum, in which the CA3 projections terminate. Our quantitative measurements are in agreement with recent reports of a tardive myelination of fibers in strata pyramidale and radiatum, as compared to stratum lacunosum-moleculare, in CA1 of humans [25]. Similarly, in rats, the length and number of dendritic segments reach adult values as early as postnatal day 10 in CA1 stratum lacunosum-moleculare, whereas they continue to develop until postnatal day 48 in CA1 stratum radiatum [37]. Furthermore, axon terminals, spines and synapses mature earlier in CA1 stratum lacunosum-moleculare than in stratum radiatum. Altogether these data suggest a differential maturation of distinct, putative functional circuits within CA1: a relatively early-maturing system associated with the entorhinal cortex projections reaching stratum lacunosum-moleculare and a rather late-maturing system associated with the Schaffer collateral projections from CA3 to strata radiatum, pyramidale and oriens. 2.5. Subiculum Volumetric measures indicate that the subiculum develops earlier than the dentate gyrus and CA3, and at about the same time as CA2. In addition, the subiculum is relatively more mature than CA1 until 6 months of age (Fig. 4A). However, similar to what is observed in CA1, the molecular layer of the subiculum, in which the projections from entorhinal cortex layer III neurons terminate, is overall

more mature within the first postnatal year, as compared to the stratum pyramidale in which most of the CA1 projections terminate (not shown). Our quantitative data therefore also suggest a differential maturation of distinct, putative functional circuits within the subiculum: a relatively early-maturing system associated with the entorhinal cortex projections and a rather late-maturing system associated with the CA1 projections. These data are also consistent with our observations based on the immunohistochemical detection of non-phosphorylated high-molecular-weight neurofilaments, which revealed an early maturation of the subiculum (Fig. 5) [34]. Interestingly, the subiculum differs from the dentate gyrus, CA3 and CA1 based on its connectivity with subcortical structures [1]. The subiculum is one of the two primary output structures of the hippocampal formation [i.e., the entorhinal cortex being the other; 1] and the major source of efferent projections toward subcortical structures [38]. The most prominent subcortical projections of the subiculum reach the lateral septal nuclei, the nucleus accumbens and the mammillary nuclei. Altogether, these data suggest that distinct functional pathways between the subiculum and subcortical structures mature both structurally and functionally earlier than the main excitatory pathways within the adult hippocampal formation. 2.6. Presubiculum and parasubiculum The volumetric developmental profile of the presubiculum is unique. Unlike all of the other hippocampal fields, there is evidence for regressive events in the structural maturation of presubicular neurons and circuits as suggested by decreases in the soma size of

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Fig. 6. Stereological estimates of neuronal soma size in the different layers of the intermediate division (Ei) of the rhesus monkey entorhinal cortex in 3-month-old and 5–10-year-old monkeys.

layer II neurons, as well as the overall volume of layer I, from birth to 5–10 years of age (Fig. 4A). We do not know, however, what specific cellular changes could contribute to this particular maturational profile. Our volumetric measurements also suggest an early maturation of the parasubicular circuits, as compared to the rest of the hippocampal formation (Fig. 4A). Two unique features of these structures, as compared to other hippocampal regions, are their reciprocal connections with the anterior thalamic nuclear complex and their heavy cholinergic innervation. It is interesting to note that both the presubiculum and the parasubiculum also receive direct inputs from the retrosplenial cortex and give rise to a direct, albeit minor, projection to the molecular layer of the dentate gyrus. Functionally, experiments in rats have shown that the presubiculum contains so-called “head-direction cells”, whereas some neurons in the parasubiculum are classified as “place-cells” because they discharge in relation to the rat’s location in the environment, although the majority of all place-cells are found in the hippocampus proper [39] (i.e., CA3, CA2 and CA1). Accordingly, cells in the presubiculum and parasubiculum might contribute to the elaboration of a primitive spatial representation of the environment before other hippocampal circuits become functional [40]. The exact nature of this representation remains to be determined. 2.7. Entorhinal cortex The findings discussed above indicate that distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural development during early postnatal life. Another critical question is to determine whether distinct layers and subdivisions of the primate entorhinal cortex, which contribute to different hippocampal functional circuits, also exhibit differential maturation during early postnatal development. Indeed, this is particularly important to know because the entorhinal cortex constitutes the gateway for bi-directional interaction between the neocortical areas comprised in the extended brain network subserving episodic memory processes and the hippocampal formation, which is the central component of this network [41]. The majority of neocortical inputs reaching the entorhinal cortex target preferentially its superficial layers [1]. In turn, entorhinal cortex layer II neurons project toward the dentate gyrus, CA3 and CA2, whereas layer III neurons project toward CA1 and the subiculum. In contrast, layer V and VI neurons receive reciprocal connections from CA1 and the subiculum, and project back to most of the neocortical areas that project to the entorhinal cortex. Given the different developmental profiles of the dentate gyrus, CA3, CA2, CA1 and subiculum [12,13], it is particularly important to

determine whether the neurons in the superficial entorhinal cortex layers II and III exhibit distinct profiles of structural maturation. It is equally important to evaluate whether neurons in the deep layers V and VI of the entorhinal cortex, classically considered as the principal elements of the output circuitry toward neocortical regions [1], exhibit different patterns of postnatal maturation. Indeed recent functional studies of the role of the entorhinal cortex in the spatial representation of the environment have questioned this linear representation of entorhinal-hippocampal interaction [42]. Preliminary evidence based on our qualitative observations of non-phosphorylated, high-molecular-weight neurofilament immunostaining suggests that the neurons located in the superficial layers of the entorhinal cortex (layers II and III) mature earlier that those located in the deep layers (layers V and VI; Fig. 5B, E and H). This finding is supported by our preliminary, quantitative analysis of neuronal soma size in area Ei of the entorhinal cortex (Fig. 6). We found no significant differences in the size of neurons located in the superficial layers between 3-month-old and 5–10-year-old monkeys, whereas neurons located in the deep layers are significantly smaller in 3-month-olds, as compared to 5–10-year-olds. This suggests that neocortical inputs might reach and be processed within hippocampal circuits relatively early, but that hippocampal outputs might be directed mainly toward subcortical structures via the subiculum at early ages and only reach neocortical areas via the entorhinal cortex during later stages of postnatal development. However, in the absence of systematic, quantitative information it is difficult to extrapolate this observation to other subdivisions of the entorhinal cortex that receive different sets of cortical afferents (see review in [41]), nor is it possible to determine the exact ages at which such morphological changes take place, thus reflecting the structural maturation of distinct functional circuits. This is particularly important in order to determine whether distinct functional circuits processing different types of sensory inputs mature simultaneously or at different times. Indeed, experiments carried out in rats suggest that memory for associations between objects and their spatial locations is slower to develop than memory for objects alone ([43]; and references therein). One might thus predict that the rostral portion of the primate entorhinal cortex, which is more highly interconnected with the perirhinal cortex (and is therefore considered to be more significantly involved in object memory processing [41,44,45]) would mature earlier than the more caudal portion of the entorhinal cortex, which is more highly interconnected with the parahippocampal cortex (and thus more significantly involved in spatial memory processing [41,44,45]). We are currently carrying out a stereological analysis of cell number, cell size and neuropil volume in the different layers of the different subdivisions of the monkey entorhinal cortex, in order to determine the ages at which principal neuron populations of the main input/output structure of the monkey hippocampal formation achieve adult morphological characteristics. Our future findings should help to determine whether distinct functional circuits processing different types of sensory inputs, and perhaps different types of memory outputs, within the entorhinal cortex mature simultaneously or at different times during postnatal development. 2.8. Evidence at the molecular level In parallel with our stereological studies, we have carried out genome-wide analyses of gene expression in distinct regions of the monkey hippocampal formation from birth to adulthood [10,11,14]. Of particular interest is our finding that a large number of genes in CA3 and CA1 exhibit developmental-specific regulation that leads to a lower level of gene expression in older mature monkeys, as compared to young developing monkeys. Most importantly, the developmental changes observed at the molecular level

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confirm that CA1 matures earlier than CA3. In this section, we consider how the decrease in the expression of certain functional groups of genes might regulate synaptic plasticity in hippocampal circuits and thus contribute to the emergence of more selective and efficient memory processes. In a first gene expression study [14], we found that a large number of genes associated with glycolysis and glutamate metabolism in astrocytes exhibit a lower expression level in CA1 of adult animals, as compared to other hippocampal regions. In addition, the expression of genes associated with glycolysis and glutamate metabolism in astrocytes decreases and reaches adult-like levels earlier during postnatal development in CA1, as compared to CA3 (Fig. 7A), corroborating our previously described anatomical evidence suggesting that CA1 matures earlier than the dentate gyrus and CA3. Accordingly, immunohistochemical analyses of the distribution of glial acidic fibrillary proteins revealed a differential developmental decrease of astrocytic processes in CA1 and CA3 (Fig. 7B), with levels in CA1 decreasing before those in CA3. Finally, electron microscope analyses revealed that the coverage of excitatory synapses by astrocytic processes undergoes significant decreases in CA1 from birth to adulthood (Fig. 7C). Although at first glance decreased astrocytic coverage may seem maladaptive, and may indeed underlie the adult hippocampus’ sensitivity to hypoxic/ischemic insult [14], other more important benefits that are subject to selective pressures might result. In particular, decreased astrocytic coverage may increase synaptic efficacy in a manner that is advantageous for learning [46]. Specifically, a reduction in glutamate clearance associated with a

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relative decrease in astrocytic processes in the vicinity of synapses has been shown to affect transmitter release through modulation of presynaptic metabotropic glutamate receptors [47]. Reduced glutamate clearance results in increased glutamate concentration in the extracellular space [48,49], which in turn increases the activation of presynaptic metabotropic glutamate receptors [50], thus leading to a lower probability of glutamate release by the presynaptic terminal [47]. Presynaptic inhibition can be overcome by high-frequency bursts of afferent synaptic potentials [51], thus serving as a high-pass filter increasing the signal-to-noise ratio for information transmitted through these synapses [47]. Thus, the decreased astrocytic coverage of excitatory synapses that we observed in the adult CA1 could serve to ensure that only the most salient information generates synaptic activity in the hippocampal circuits that contribute to learning and memory processes. A developmental decrease of astrocytic processes and functions may therefore contribute to the emergence of adult-like, selective memory function. In a second gene expression study [11], we identified another important functional group involved in protein metabolism amongst the genes that were down-regulated in CA1 and CA3 with age. This group of genes can be subdivided into two subgroups: one involved in protein synthesis and the other in protein degradation. The importance of protein synthesis in synaptic plasticity is well established. Indeed, as early as the 1960s, researchers showed that protein synthesis inhibitors impair memory performance, as well as LTP and LTD induction in CA1 [52,53]. Demonstration of the role of protein degradation pathways in synaptic plasticity is more recent.

Fig. 7. (A) Microarray analysis of gene expression in the rhesus monkey hippocampal formation: GFAP gene expression decreased from birth to 6 months of age in CA1. GFAP gene expression decreased after 1 year of age in CA3. GFAP gene expression did not differ between CA3 and CA1 at birth, but differed at all other ages. EC, entorhinal cortex; DG, dentate gyrus; CA3 and CA1, fields of the hippocampus; Sub, subiculum. (B) GFAP immunostaining in the rhesus monkey hippocampus: GFAP immunostaining decreased from birth to 6 months of age in CA1. GFAP immunostaining decreased after 1 year of age in CA3. GFAP immunostaining did not differ between CA3 and CA1 at birth, but differed at all other ages. (C) Electron microscope evaluation of astrocytic processes around excitatory synapses in the stratum radiatum of CA1 in rhesus monkeys. The surface area occupied by astrocytic processes decreased from birth to adulthood.

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For example, the proteasome inhibitor lactacystin, which prevents protein degradation, also leads to impaired memory performance and decreased LTP in CA1 [54]. From these two series of experiments, it has become clear that the regulation of protein synthesis and degradation impacts synaptic plasticity, as well as learning and memory processes. The down-regulation of both protein synthesis and protein degradation genes likely impacts the plasticity mechanisms that regulate synaptic transmission [55]. For example, the concomitant down-regulation of genes involved in protein synthesis and protein degradation that we have observed might reflect or underlie an increase in protein lifespan (i.e., if fewer proteins are degraded, fewer proteins need to be made). Increased protein lifespan might, in turn, lead to more stable and longer lasting changes in the efficacy of synaptic transmission, which could be beneficial for learning and the maintenance of long-term memories. Again, as discussed above, the developmental changes in gene expression occur earlier in CA1, as compared to CA3. Finally, we also identified other functional groups of down-regulated genes that are preferentially expressed in neurons including genes involved in the MAPK signaling pathway, LTP, LTD, glutamate and GABA neurotransmitter pathways, regulation of dendritic processes and ion channels [11]. The MAPK signaling pathway has been shown to be necessary for processes like LTP and is therefore essential for the mechanisms of synaptic plasticity [56]. MAPK pathway over-activation in transgenic mice leads to deficits in hippocampal plasticity and hippocampal-dependent learning, which correlate with an increase in GABA release in the hippocampus [56–58]. The relative overexpression of genes involved in the MAPK signaling pathway in young individuals, as compared to adults, might be associated with lower learning and memory abilities in young individuals. The down-regulation of the expression of genes involved in the MAPK signaling pathway as the individual ages would thus lead to improved hippocampal function, leading to the increase in learning and memory performance typically observed during normal postnatal development [6,7,59].

3. A model linking brain and behavior The hippocampal formation, as a whole functional unit, is the central component of a large brain network essential for the processing of episodic memory. Yet, it has become increasingly clear that different hippocampal structures and circuits contribute to different types of information processing. In this section, we discuss our findings of differential maturation of distinct hippocampal circuits from a functional perspective that takes into consideration the work of many other researchers, some of whom have also contributed to this special issue on MTL Memory Networks. Our neuroanatomical and molecular data discussed above suggest that the differential maturation of distinct hippocampal circuits might underlie the emergence and maturation of different “hippocampus-dependent” memory processes, ultimately leading to the emergence of episodic memory concomitant with the maturation of all hippocampal circuits (Fig. 8). This hypothesis is founded on the emerging principle that specific types of information processing are subserved by different hippocampal circuits. These processes can be summarized as follows: (1) The dentate gyrus contributes to pattern separation, treating both spatial and non-spatial information [60,61]. (2) Postnatal neurogenesis in the dentate gyrus contributes to the encoding of temporal associations, linking events that happened at the same time and distinguishing events that happened at different times [62]. (3) CA3 contributes to pattern completion and the rapid and flexible acquisition of spatial memories [63,64]. (4) CA1 contributes to the integration of all sensory and memory inputs; it enables slow and gradual learning and the elaboration of an internal

representation of the relations between more than two different items experienced simultaneously. As such, CA1 is fundamental for the establishment of allocentric spatial memory [65], a fundamental component of episodic memory. (5) The subiculum, presubiculum and parasubiculum contribute to the integration of self-generated movement information [66]. As such, these structures can contribute to the process of path integration (dead reckoning) [67] and the elaboration or maintenance of spatial representations that subserve spatial navigation in absence of external information [68]. 3.1. Basic allocentric spatial memory in 2-year-old children Our model makes predictions that are consistent with the concept of a hierarchical development of different types of spatial capacities in children [69]. Egocentric capacities emerge first in the newborn child, and tend to dominate the child’s spatial world for at least the first 6 months [70–72]. The use of cues or landmarks to remember spatial locations begins to appear between 8.5 and 12 months [70–74]. Path integration becomes apparent in children from 6 to 12 months of age [70,75,76]. Finally, allocentric spatial memory abilities in children appear to emerge last, although studies have yielded disparate and seemingly conflicting results with respect to exactly when allocentric spatial competence emerges and when it becomes adult-like in children, with estimates ranging from 2 to 7 years depending on the task used. An important exception, however, is one study by Newcombe et al. suggesting that from 22 months of age children demonstrate the ability to use allocentric spatial information [77]. Recent experiments in our laboratory using some of the most stringent methods to date [78] have confirmed the previous findings by Newcombe et al. [77] that allocentric place learning does not begin to emerge until after 20 months of age and is only reliably expressed by a majority of children after 2 years of age (Fig. 9A). In our experiments, children were asked to locate a hidden candy hidden under one of four inverted cups placed at the distal cardinal points in a 4 m × 4 m arena (Experiment 2 in [78]). The arena was surrounded on three sides by opaque curtains, thus precluding children from using aligned or adjacent objects as uncontrolled visual guidance cues. Four separate entry/exit points precluded children from using an egocentric strategy to solve the task. In the local cue condition, a red cup concealed the candy, thus allowing us to assess children’s use of a controlled visual guidance cue. In the allocentric spatial condition, all four cups were identical, and children had to use an allocentric spatial representation of the environment to learn and remember the rewarded cup’s location. Whereas 80% of the children between 20 and 24 months of age found the candy when it was hidden under the red cup, only 30% of these same children could find the candy in the allocentric spatial condition, in the absence of the local cue. In contrast, for children 25–39 months of age, 100% found the candy in the local cue condition, and 84% in the allocentric spatial condition. Although it may seem reasonable to predict that the emergence of certain spatial capacities would parallel motor development, with capacities such as path integration and allocentric processing emerging around the same time, or shortly after, infants begin independent locomotion and can experience their environment in an autonomous manner, this view is insufficient to explain the whole developmental spectrum of spatial memory capacities observed in children, especially considering the apparent delayed emergence of allocentric capacities. Instead, as described above, we propose that the differential maturation of distinct circuits within the hippocampal formation contributes to the gradual emergence of specific spatial memory abilities with age. We elaborate the neuroanatomical and neurophysiological findings supporting this proposition below.

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Fig. 8. Hierarchical model of the postnatal maturation of the primate hippocampal formation. (A) The maturation of hippocampal circuits involving the subiculum, presubiculum and parasubiculum might support path integration abilities before 1 year of age in children. (B) The maturation of hippocampal circuits involving the direct projections from the superficial layers of the entorhinal cortex to CA1 (and CA2) might support basic allocentric spatial memory abilities at 2 years of age in children. (C) The protracted maturation of hippocampal circuits involving the dentate gyrus and CA3 might support high-resolution allocentric spatial memory abilities after 3 years of age in children. (D) The more complete maturation of all hippocampal circuits might support episodic memory abilities after 7 years of age in children. The dentate gyrus is thought to contribute to pattern separation. Neurogenesis in the dentate gyrus is thought to contribute to the encoding of temporal associations. CA3 is thought to contribute to pattern completion and the rapid and flexible acquisition of spatial memories. CA1 is thought to contribute to the integration of all sensory and memory inputs; it might enable slow and gradual learning of allocentric spatial memory. The subiculum, presubiculum and parasubiculum are thought to contribute to the integration of self-generated movement information, enabling path integration. See main text for details. ATN: anterior thalamic nuclei; DG: dentate gyrus; CA3, CA2, CA1: fields of the hippocampus proper; Sub: subiculum; PrS: presubiculum; PaS: parasubiculum; II, III, V–VI: layers of the entorhinal cortex.

Historically, the hippocampal formation, including the entorhinal cortex, the dentate gyrus, CA3, CA2, CA1, the subiculum, presubiculum and parasubiculum [41], has been considered as a functional brain circuit critical for processing declarative memories, as well as allocentric spatial memories [3,79–81]. Entorhinal cortex layer II neurons project to the dentate gyrus, which projects to CA3, which projects to CA1, which projects to the subiculum and the deep layers of the entorhinal cortex, thus closing the prominent hippocampal loop of information processing (Fig. 1). However, in addition to their primary projection toward the dentate gyrus, entorhinal cortex layer II neurons also project directly to CA3 and CA2, and entorhinal cortex layer III neurons project directly to CA1 and the subiculum.

Over the past decade, research in rodents has revealed that different hippocampal regions serve computationally distinct but complementary roles during memory processing. For example, a basic allocentric representation of the environment can be maintained in CA1 and is subserved by the direct monosynaptic pathway from the entorhinal cortex to CA1. Mizumori et al. first showed that CA1 place cell coding is maintained during reversible suppression of CA3 output to CA1 [82]. Brun et al. showed that CA1 place cell coding persists following direct lesion of CA3 and that CA3lesioned animals display place recognition [83]. In contrast, specific lesion of the entorhinal cortex input to CA1 impairs CA1 place cell coding [84]. Finally, transgenic mice lacking NMDA receptors in CA3 pyramidal cells, thus functionally deafferenting CA1 from its

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Fig. 9. Behavioral testing of children’s allocentric spatial memory abilities. (A) Picture of a participant in the arena with four potential locations in the local cue and allocentric spatial conditions, only one location is rewarded (location 2 or 4). Percentage of 20–39-month-old children exhibiting a performance above chance level with one rewarded location among four possible locations. White bars: children who failed to discriminate the rewarded cup in the local cue and allocentric spatial conditions. Gray bars: children who succeeded in the local cue condition, but not in the allocentric spatial condition. Black bars: children who succeeded in both the local cue and allocentric spatial conditions. (B) Picture of a participant in the arena with three rewarded locations (locations 7, 10, 14) among 18 potential locations in the local cue and allocentric spatial conditions. Percentage of 25–61-month-old children exhibiting a performance above chance level with three reward locations among 18 possible locations. Gray bars: children who succeeded in the local cue condition, but not in the allocentric spatial condition. Black bars: children who succeeded in the local cue and allocentric spatial conditions. Note: All children discriminated the reward locations in the local cue condition.

CA3 inputs, exhibit essentially normal CA1 place cells and are capable of acquiring and remembering allocentric spatial memories experienced over repeated trials [63,85]. Altogether, these experiments carried out in rodents indicate that CA1 place cell activity and a basic allocentric representation of the environment can be maintained by direct inputs from the entorhinal cortex to CA1. As described above, our recent structural and molecular studies indicate that CA1 exhibits an early and rapid development, achieving adult-like volumes and levels of gene expression around 6 months of age in the rhesus macaque monkey. In contrast, the dentate gyrus and CA3 exhibit slower and prolonged developmental time courses, and do not achieve adult-like volumes or levels of gene expression until after 1 year of age in the rhesus macaque monkey. Importantly, the early volumetric maturation of CA1 is primarily due to the early maturation of one specific layer, the stratum lacunosum-moleculare, in which the direct projections from the entorhinal cortex terminate. If one considers that 1 year of life in the monkey corresponds to approximately 4 years of life in the human [86,87], the neuroanatomical and molecular data in monkeys suggests that CA1 likely achieves an adult-like volume around 2 years of age in the human. This corresponds precisely to the age at which a qualitative shift in the spatial capacities of children can be observed, with the emergence of their ability to learn, remember and use an allocentric representation of the environment (Fig. 9A). These behavioral findings in children, when combined with the

neuroanatomical and molecular data in monkeys and electrophysiological findings in rats, lead us to propose that it is the maturation of the CA1 region of the hippocampus, specifically, that underlies the emergence of allocentric spatial processing that is reliably observed in children at 2 years of age [77,78]. 3.2. Improved allocentric spatial processing after 2 years of age Despite our finding that basic allocentric capacities emerge after 20 months of age and are reliably expressed after 2 years of age, additional experiments (Experiment 1 in [78]) found that children of this same age, between 25 and 41 months, were not capable of solving a complex allocentric spatial memory task. The only difference between the previously described experiment testing basic allocentric capacities and this experiment testing more complex allocentric capacities is that the latter required children to discriminate between three reward locations from amongst 18 spatially distinct locations (rather than one location amongst four in the former). Nevertheless, in both the four-location task and the 18-location task, each location occupies a unique position in space, and is thus discriminable using allocentric processes. How, then, can we explain these seemingly contradictory results showing success in one allocentric spatial task by children older than 24 months, and failure in another by these same-aged children?

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As described above, a direct projection from the entorhinal cortex to CA1 is thought to be able to subserve basic allocentric spatial processing. In contrast, computational models, in vivo studies carried out in rats, and imaging studies in humans support the hypothesis that the dentate gyrus, together with its connections with CA3, subserve a process known as pattern separation [60,61], which might be necessary to discriminate individual items, episodes or spatial locations that are very similar or close to one another [60,61,88,89]. In accordance with this hypothesis, studies have shown that disrupting the CA3 input to CA1 results in decreased spatial tuning of CA1 place cells [83,90], suggesting the necessity of the main trisynaptic hippocampal pathway (i.e., entorhinal cortex to dentate gyrus, dentate gyrus to CA3, CA3 to CA1) for maintaining high-resolution spatial discrimination (i.e., spatial pattern separation). Our neuroanatomical data indicate that the monkey dentate gyrus exhibits a late and protracted development, and has not yet reached an adult volume at 1 year of age (which corresponds to approximately 4 years of age in humans). This leads us to hypothesize that the improvement in allocentric spatial memory capacities with age (better spatial resolution) might result from the gradual functional maturation of the dentate gyrus and trisynaptic hippocampal pathway, which contribute to improved spatial pattern separation abilities from 2 to 5 years of life in humans. Indeed, studies of both spatial and autobiographical episodic memories suggest that these forms of hippocampus-dependent memory mature significantly within the same age range [7,69,91–94]. Previous findings by Acredolo et al. [91] are in agreement with our proposed hypothesis that the improvements that occur in children’s allocentric spatial memory after 2 years of age (i.e., after the basic capacity to learn and remember an allocentric representation of the environment has emerged) correspond to improvements in children’s ability to more precisely calculate the spatial coordinates of individual locations based on distal environmental objects. Their study found that the accuracy of children under 5 years of age to replace items where they found them improved when landmarks were located close to the target locations, whereas the performance of older children was already optimal in absence of adjacent landmarks. Age-dependent maturation in spatial pattern separation capacities can also explain the age-dependent improvements in children’s performance in tasks such as the Morris search task [95], the radial arm maze [95–98], open-field tasks [95], and sandbox search tasks that test children’s representation of multiple locations, relations between objects, and short-term (2 min) retention of a spatial location [94]. 3.3. Emergence and maturation of episodic memory The lack of autobiographical memories from our infancy has often been hypothesized to result from the immaturity of the neurobiological substrates subserving these memories in adult individuals [7,99], although concrete neurobiological evidence for these theories has been notably absent [8]. We have shown that from 2 years of age, children are capable of solving a spatial task using a basic allocentric representation of the surrounding environment (Fig. 9A). The emergence of this capacity coincides temporally with the end of infantile amnesia, and as we have proposed, likely coincides with the structural and functional maturation of the CA1 region of the hippocampus. It is possible that mature CA1 processing confers the overall capacity to form relational memories, including both spatial and episodic memories. We have also shown that by 3.5 years of age, children are capable of solving a complex allocentric spatial task, which necessitates a high degree of spatial pattern separation in order to discriminate goal locations from closely apposed decoy locations (Fig. 9B). This capacity likely coincides with the structural and functional maturation of the dentate gyrus and trisynaptic hippocampal pathway. However, it has

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also been shown that the trisynaptic pathway is critical for rapid single-trial contextual learning [90]. The encoding of autobiographical memories, by definition, requires rapid, single-trial contextual learning. Our recent structural findings [12,13] revealed that the potential structural impact of postnatal neurogenesis differs in developing and mature individuals. We found a prolonged period of developmental neurogenesis and granule cell addition and a further protracted maturation of distinct dentate gyrus circuits beyond 1 year of age in monkeys. We thus previously proposed [78] that the immaturity of the dentate gyrus underlies the phenomenon of childhood amnesia, and the gradual maturation of the trisynaptic hippocampal pathway subserves the gradual improvement, from 2 to 7 years of age, in our ability to create autobiographical memories that can be recalled later in life. Computational models have proposed that continued neurogenesis in the adult dentate gyrus plays a fundamental role in the temporal coding of events and the formation of episodic memories [100,101]. Newly generated immature neurons might contribute to increased association of events occurring close in time, whereas events occurring several days apart would be encoded separately by distinct groups of newly generated neurons that are not yet fully mature. In conjunction with the reported role of the dentate gyrus in pattern separation (see above), adult neurogenesis could help to disambiguate new events happening in familiar contexts and therefore contribute to the encoding of individual episodic memories [102]. This might explain the inability to form enduring episodic memories until the dentate gyrus has become fully structurally mature. Indeed, very high levels of plasticity are typically associated with the normal development of the brain [103,104], and the dentate gyrus is likely no exception [105]. Dentate gyrus circuits, and in particular the balance between highly plastic, immature neurons born later during development and less plastic, mature neurons born earlier during development, might not be optimally tuned to contribute to the separate encoding of distinct episodes until late postnatal development. The population of dentate gyrus granule cells, which continue to mature beyond 1 year of age in monkeys, might be too responsive to neuronal activity and undergoing continuous changes in synaptic plasticity that are important for normal development but are inadapted for learning and the establishment of long-term memories.

4. Conclusion Our systematic, quantitative studies of the postnatal development of the monkey hippocampal formation indicate that distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural and molecular development during early postnatal life. The protracted period of neuronal addition and maturation in the dentate gyrus is accompanied by the late maturation of specific layers in different hippocampal regions that are located downstream from the dentate gyrus, particularly CA3. In contrast, distinct layers in several hippocampal regions, particularly CA1, which receive direct projections from the entorhinal cortex, exhibit an early maturation. In addition, hippocampal regions that are more highly interconnected with subcortical structures, including the subiculum, presubiculum, parasubiculum and CA2 mature even earlier. In parallel, our behavioral studies of the emergence of spatial memory processes in humans indicate that the ability to form a basic allocentric representation of the environment is present by 2 years of age; its emergence coincides temporally with the offset of infantile amnesia, and we propose coincides with the specific maturation of the CA1 region of the hippocampus. From 2 to 3.5 years of age the ability of children to distinguish and remember closely related spatial locations improves; although this developmental period is marked by

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persistent deficits in long-term episodic memory, a phenomenon referred to as childhood amnesia, improvements in long-term episodic memory are occurring. We propose that these improvements in both spatial and episodic memory are specifically correlated with the maturation of the dentate gyrus and CA3. In sum, it is highly probable that a causal relationship between the structural and functional maturation of the hippocampal formation and infantile and childhood amnesia exists. Altogether, our findings support the hypothesis that the differential maturation of distinct hippocampal circuits might underlie the emergence of specific “hippocampus-dependent” memory processes during early childhood, culminating in the emergence of episodic memory concomitant with the maturation of all hippocampal circuits. Future research should prioritize investigations of the relationships between the maturation of specific hippocampal circuits and the development of high-resolution allocentric spatial representations, single-trial contextual learning and the emergence of episodic memory in children and experimental animals. Acknowledgments We thank all members of our laboratories and other collaborators and colleagues who contributed to the work presented in this article. In particular, we thank David G. Amaral for his precious collaboration on the neuroanatomical studies. This research was supported by grants from the Swiss National Science Foundation to Pierre Lavenex (PP00A 106701, PP00P3 124536) and Pamela Banta Lavenex (PMPDP3 122844, PMPDP3 128996). Work reported in this article was also supported by a Joe P. Tupin award (Dept of Psychiatry and Behavioral Sciences, UC Davis) and a NARSAD Young Investigator Award (National Alliance for Research on Schizophrenia and Depression) to Pierre Lavenex; as well as by NIH Grant R01-NS16980 to David G. Amaral. The work with monkeys was conducted, in part, at the California National Primate Research Center (RR00169). References [1] Amaral DG, Lavenex P. Hippocampal neuroanatomy. In: Amaral DG, Andersen P, Bliss T, Morris RGM, O’Keefe J, editors. The hippocampus book. New York: Oxford University Press; 2007. p. 37-114. [2] Lavenex P, Amaral DG. Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 2000;10:420–30. [3] Squire LR. Memory and the hippocampus – a synthesis from findings with rats, monkeys, and humans. Psychological Review 1992;99:195–231. [4] Tulving E. Episodic and semantic memory. In: Tulving E, Donaldson W, editors. Organization of memory. New York: Academic Press; 1972. p. 381-403. [5] Tulving E. Episodic memory: from mind to brain. Annual Review in Psychology 2002;53:1–25. [6] Newcombe NS, Lloyd ME, Ratliff KR. Development of episodic and autobiographical memory: a cognitive neuroscience perspective. Advances in Child Development and Behavior 2007;35:37–85. [7] Bauer PJ. Constructing a past in infancy: a neuro-developmental account. Trends in Cognitive Sciences 2006;10:175–81. [8] Lavenex P, Banta Lavenex P, Amaral DG. Postnatal development of the primate hippocampal formation. Developmental Neuroscience 2007;29:179–92. [9] Richmond J, Nelson CA. Accounting for change in declarative memory: a cognitive neuroscience perspective. The Development Review 2007;27:349–73. [10] Favre G, Banta Lavenex P, Lavenex P. Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. Translational Psychiatry 2012;2:e173. [11] Favre G, Banta Lavenex P, Lavenex P. miRNA regulation of gene expression: a predictive bioinformatics analysis in the postnatally developing monkey hippocampus. PLoS ONE 2012;7:e43435. [12] Jabès A, Banta Lavenex P, Amaral DG, Lavenex P. Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gyrus. European Journal of Neuroscience 2010;31:273–85. [13] Jabès A, Banta Lavenex P, Amaral DG, Lavenex P. Postnatal development of the hippocampal formation: a stereological study in macaque monkeys. Journal of Comparative Neurology 2011;519:1051–70. [14] Lavenex P, Sugden SG, Davis RR, Gregg JP, Banta Lavenex P. Developmental regulation of gene expression and astrocytic processes may explain selective hippocampal vulnerability. Hippocampus 2011;21:142–9.

[15] Feliciano DM, Bordey A. Newborn cortical neurons: only for neonates? Trends in Neurosciences 2013;36(1):51–61. [16] Eckenhoff MF, Rakic P. Nature and fate of proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey. Journal of Neuroscience 1988;8:2729–47. [17] Nowakowski RS, Rakic P. The site of origin and route and rate of migration of neurons to the hippocampal region of the rhesus monkey. Journal of Comparative Neurology 1981;196:126–54. [18] Rakic P, Nowakowski RS. The time of origin of neurons in the hippocampal region of the rhesus monkey. Journal of Comparative Neurology 1981;196:99–128. [19] Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E. Hippocampal neurogenesis in adult Old World primates. Proceedings of the National Academy of Sciences of the United States of America 1999;96:5263–7. [20] Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey. Proceedings of the National Academy of Sciences of the United States of America 1999;96:5768–73. [21] Duffy CJ, Rakic P. Differentiation of granule cell dendrites in the dentate gyrus of the rhesus monkey: a quantitative Golgi study. Journal of Comparative Neurology 1983;214:224–37. [22] Seress L, Mrzljak L. Postnatal development of mossy cells in the human dentate gyrus: a light microscopic Golgi study. Hippocampus 1992;2: 127–41. [23] Duffy CJ, Teyler TJ. Development of potentiation in the dentate gyrus of rat: physiology and anatomy. Brain Research Bulletin 1978;3:425–30. [24] Frotscher M, Seress L. Morphological development of the hippocampus. In: Amaral DG, Andersen P, Bliss T, Morris RGM, O’Keefe J, editors. The hippocampus book. New York: Oxford University Press; 2007. p. 115–31. [25] Abraham H, Vincze A, Jewgenow I, Veszpremi B, Kravjak A, Gomori E, et al. Myelination in the human hippocampal formation from midgestation to adulthood. International Journal of Developmental Neuroscience 2010;28:401–10. [26] Amaral DG. A Golgi study of cell types in the hilar region of the hippocampus in the rat. Journal of Comparative Neurology 1978;182:851–914. [27] Buckmaster PS, Amaral DG. Intracellular recording and labeling of mossy cells and proximal CA3 pyramidal cells in macaque monkeys. Journal of Comparative Neurology 2001;430:264–81. [28] Seress L, Ribak CE. Postnatal development and synaptic connections of hilar mossy cells in the hippocampal dentate gyrus of rhesus monkeys. Journal of Comparative Neurology 1995;355:93–110. [29] Amaral DG, Scharfman HE, Lavenex P. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). Progress in Brain Research 2007;163:3–22. [30] Seress L, Ribak CE. Postnatal development of CA3 pyramidal neurons and their afferents in the Ammon’s horn of rhesus monkeys. Hippocampus 1995;5:217–31. [31] Ishizuka N, Cowan WM, Amaral DG. A quantitative analysis of the dendritic organization of pyramidal cells in the rat hippocampus. Journal of Comparative Neurology 1995;362:17–45. [32] Witter MP, Amaral DG. Entorhinal cortex of the monkey: V. Projections to the dentate gyrus, hippocampus, and subicular complex. Journal of Comparative Neurology 1991;307:437–59. [33] Kondo H, Lavenex P, Amaral DG. Intrinsic connections of the macaque monkey hippocampal formation: I. Dentate gyrus. Journal of Comparative Neurology 2008;511:497–520. [34] Lavenex P, Banta Lavenex P, Amaral DG. Nonphosphorylated high-molecularweight neurofilament expression suggests early maturation of the monkey subiculum. Hippocampus 2004;14:797–801. [35] Chevaleyre V, Siegelbaum SA. Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron 2010;66:560–72. [36] Kondo H, Lavenex P, Amaral DG. Intrinsic connections of the macaque monkey hippocampal formation: II. CA3 connections. Journal of Comparative Neurology 2009;515:349–77. [37] Pokorny J, Yamamoto T. Postnatal ontegenesis of hippocampal CA1 area in rats, II. Development of ultrastructure in stratum lacunosum and moleculare. Brain Research Bulletin 1981;7:121–30. [38] Naber PA, Witter MP. Subicular efferents are organized mostly as parallel projections: a double-labeling, retrograde-tracing study in the rat. Journal of Comparative Neurology 1998;393:284–97. [39] O’Keefe J. Hippocampal neurophysiology in the behaving animal. In: Amaral DG, Andersen P, Bliss T, Morris RGM, O’Keefe J, editors. The hippocampus book. New York: Oxford University Press; 2007. p. 475-548. [40] Langston RF, Ainge JA, Couey JJ, Canto CB, Bjerknes TL, Witter MP, et al. Development of the spatial representation system in the rat. Science 2010;328:1576–80. [41] Lavenex P. Functional anatomy, development and pathology of the hippocampus. In: Bartsch T, editor. The clinical neurobiology of the hippocampus: an integrative view. Oxford: Oxford University Press; 2012. [42] Witter MP, Moser EI. Spatial representation and the architecture of the entorhinal cortex. Trends in Neurosciences 2006;29:671–8. [43] Ainge JA, Langston RF. Ontogeny of neural circuits underlying spatial memory in the rat. Frontiers in Neural Circuits 2012;6:8. [44] Davachi L. Item, context and relational episodic encoding in humans. Current Opinion in Neurobiology 2006;16:693–700. [45] Suzuki WA. Untangling memory from perception in the medial temporal lobe. Trends in Cognitive Sciences 2010;14:195–200.

P. Lavenex, P. Banta Lavenex / Behavioural Brain Research 254 (2013) 8–21 [46] Karlsson MP, Frank LM. Network dynamics underlying the formation of sparse, informative representations in the hippocampus. Journal of Neuroscience 2008;28:14271–81. [47] Oliet SH, Piet R, Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 2001;292:923–6. [48] Bergles DE, Jahr CE. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. Journal of Neuroscience 1998;18:7709–16. [49] Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997;276:1699–702. [50] Scanziani M, Salin PA, Vogt KE, Malenka RC, Nicoll RA. Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors. Nature 1997;385:630–4. [51] Grover LM, Kim E, Cooke JD, Holmes WR. LTP in hippocampal area CA1 is induced by burst stimulation over a broad frequency range centered around delta. Learning and Memory 2009;16:69–81. [52] Flexner JB, Flexner LB, Stellar E. Memory in mice as affected by intracerebral puromycin. Science 1963;141:57–9. [53] Stanton PK, Sarvey JM. Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis. Journal of Neuroscience 1984;4:3080–8. [54] Lopez-Salon M, Alonso M, Vianna MR, Viola H, Mello e Souza T, Izquierdo I, et al. The ubiquitin-proteasome cascade is required for mammalian long-term memory formation. European Journal of Neuroscience 2001;14:1820–6. [55] Mabb AM, Ehlers MD. Ubiquitination in postsynaptic function and plasticity. Annual Review of Cell and Developmental Biology 2010;26:179–210. [56] Peng S, Zhang Y, Zhang J, Wang H, Ren B. ERK in learning and memory: a review of recent research. International Journal of Molecular Sciences 2010;11:222–32. [57] Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y, Gutmann DH, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 2008;135:549–60. [58] Denayer E, Ahmed T, Brems H, Van Woerden G, Borgesius NZ, Callaerts-Vegh Z, et al. Spred1 is required for synaptic plasticity and hippocampus-dependent learning. Journal of Neuroscience 2008;28:14443–9. [59] Lavenex P, Banta Lavenex P. Spatial relational memory in 9-month-old macaque monkeys. Learning and Memory 2006;13:84–96. [60] Bakker A, Kirwan CB, Miller M, Stark CE. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 2008;319:1640–2. [61] Kesner RP. A behavioral analysis of dentate gyrus function. Progress in Brain Research 2007;163:567–76. [62] Aimone JB, Wiles J, Gage FH. Potential role for adult neurogenesis in the encoding of time in new memories. Nature Neuroscience 2006;9:723–7. [63] Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 2002;297:211–8. [64] Rolls ET, Kesner RP. A computational theory of hippocampal function, and empirical tests of the theory. Progress in Neurobiology 2006;79:1–48. [65] Remondes M, Schuman EM. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature 2004;431:699–703. [66] Rolls ET. Neurophysiological and computational analyses of the primate presubiculum, subiculum and related areas. Behavioural Brain Research 2006;174:289–303. [67] O’Mara SM, Commins S, Anderson M, Gigg J. The subiculum: a review of form, physiology and function. Progress in Neurobiology 2001;64:129–55. [68] Sharp PE. Complimentary roles for hippocampal versus subicular/entorhinal place cells in coding place, context, and events. Hippocampus 1999;9:432–43. [69] Newcombe NS, Drummey AB, Fox NA, Lie EH, Ottinger-Alberts W. Remembering early childhood: how much, how, and why (or why not). Current Directions in Psychological Science 2000;9:55–8. [70] Acredolo LP. Development of spatial orientation in infancy. Developmental Psychology 1978;14:224–34. [71] Acredolo LP, Evans D. Developmental changes in the effects of landmarks on infant spatial behavior. Developmental Psychology 1980;16:312–8. [72] Bremner JG. Egocentric versus allocentric spatial coding in nine-month-old infants: factors influencing the choice of code. Developmental Psychology 1978;14:346–55. [73] Bushnell EW, McKenzie BE, Lawrence DA, Connell S. The spatial coding strategies of one-year-old infants in a locomotor search task. Child Development 1995;66:937–58. [74] Lew AR, Bremner JG, Lefkovitch LP. The development of relational landmark use in six- to twelve-month-old infants in a spatial orientation task. Child Development 2000;71:1179–90. [75] Bremner JG, Knowles L, Andreasen G. Processes underlying young children’s spatial orientation during movement. Journal of Experimental Child Psychology 1994;57:355–76. [76] Rieser JJ, Heiman ML. Spatial self-reference systems and shortest-route behavior in toddlers. Child Development 1982;53:524–33.

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[77] Newcombe NS, Huttenlocher J, Bullock Drummey A, Wiley JG. The development of spatial location coding: place learning and dead reckoning in the second and third years. Cognitive Development 1998;13: 185–200. [78] Ribordy F, Jabes A, Banta Lavenex P, Lavenex P. Development of allocentric spatial memory abilities in children from 18 months to 5 years of age. Cognitive Psychology 2012;66:1–29. [79] Milner B, Squire LR, Kandel ER. Cognitive neuroscience and the study of memory. Neuron 1998;20:445–68. [80] Morris RGM. Theories of hippocampal function. In: Andersen P, Morris RGM, Amaral DG, Bliss TV, O’Keefe J, editors. The hippocampus book. Oxford: Oxford University Press; 2007. p. 581-713. [81] O’Keefe J, Nadel L. The hippocampus as a cognitive map. Oxford: Clarendon Press; 1978. [82] Mizumori SJ, Barnes CA, McNaughton BL. Reversible inactivation of the medial septum: selective effects on the spontaneous unit activity of different hippocampal cell types. Brain Research 1989;500:99–106. [83] Brun VH, Otnass MK, Molden S, Steffenach HA, Witter MP, Moser MB, et al. Place cells and place recognition maintained by direct entorhinalhippocampal circuitry. Science 2002;296:2243–6. [84] Brun VH, Leutgeb S, Wu HQ, Schwarcz R, Witter MP, Moser EI, et al. Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron 2008;57:290–302. [85] Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 2003;38:305–15. [86] Fortman JD, Hewett TA, Bennett BT. The laboratory nonhuman primate. Boca Raton: CRC Press; 2001. [87] Van Zutphen LFM, Baumans V, Beynen AC. Principles of laboratory animal science. Amsterdam: Elsevier; 1993. [88] Gilbert PE, Kesner RP, DeCoteau WE. Memory for spatial location: role of the hippocampus in mediating spatial pattern separation. Journal of Neuroscience 1998;18:804–10. [89] Morris AM, Churchwell JC, Kesner RP, Gilbert PE. Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations. Neurobiology of Learning and Memory 2012;97:326–31. [90] Nakashiba T, Young JZ, McHugh TJ, Buhl DL, Tonegawa S. Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning. Science 2008;319:1260–4. [91] Acredolo LP, Pick HL, Olsen MG. Environmental differentiation and familiaritiy as determinants of children’s memory for spatial location. Developmental Psychology 1975;11:495–501. [92] Balcomb F, Newcombe NS, Ferrara K. Finding where and saying where: developmental relationships between place learning and language in the first year. Journal of Cognition and Development 2011;12:315–31. [93] Herman JF, Siegel AW. The development of cognitive mapping of the large-scale environment. Journal of Experimental Child Psychology 1978;26:389–406. [94] Sluzenski J, Newcombe NS, Satlow E. Knowing where things are in the second year of life: implications for hippocampal development. Journal of Cognitive Neuroscience 2004;16:1443–51. [95] Overman WH, Pate BJ, Moore K, Peuster A. Ontogeny of place learning in children as measured in the radial arm maze, Morris search task, and open field task. Behavioral Neuroscience 1996;110:1205–28. [96] Aadland J, Beatty WW, Maki RH. Spatial memory of children and adults assessed in the radial maze. Developmental Psychobiology 1985;18:163–72. [97] Foreman N, Arber M, Savage J. Spatial memory in preschool infants. Developmental Psychobiology 1984;17:129–37. [98] Foreman N, Warry R, Murray P. Development of reference and working spatial memory in preschool children. Journal of General Psychology 1990;117:267–76. [99] Newcombe N, Lloyd ME, Ratliff KR. Development of episodic and autobiographical memory: a cognitive neuroscience perspective. Advances in Child Development and Behavior 2007;35:37–85. [100] Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory. Nature Reviews Neuroscience 2010;11:339–50. [101] Weisz VI, Argibay PF. A putative role for neurogenesis in neuro-computational terms: inferences from a hippocampal model. Cognition 2009;112: 229–40. [102] Aimone JB, Wiles J, Gage FH. Computational influence of adult neurogenesis on memory encoding. Neuron 2009;61:187–202. [103] Hensch TK. Critical period regulation. Annual Review of Neuroscience 2004;27:549–79. [104] Knudsen EI. Early experience and critical periods. In: Squire LR, Bloom FE, McConnell SK, Roberts JL, Spitzer NC, Zigmond MJ, editors. Fundamental neuroscience. London: Academic Press; 2003. p. 555–73. [105] Josselyn SA, Frankland PW. Infantile amnesia: a neurogenic hypothesis. Learning and Memory 2012;19:423–33.