EEG markers of successful allocentric spatial working memory maintenance in humans.

Several brain regions in the frontal, occipital and medial temporal lobes are known to contribute to spatial information processing. In contrast, the oscillatory patterns contributing to allocentric spatial working memory maintenance are poorly understood, especially in humans. Here, we tested twenty-three 21- to 32-year-old and twenty-two 64- to 76-year-old healthy right-handed adults in a real-world, spatial working memory task and recorded electroencephalographic (EEG) activity during the maintenance period. We established criteria for designating recall trials as perfect (no errors) or failed (errors and random search) and identified 8 young and 13 older adults who had at least 1 perfect and 1 failed trial amongst 10 recall trials. Individual alpha frequency-based analyses were used to identify oscillatory patterns during the maintenance period of perfect and failed trials. Spectral scalp topographies showed that individual theta frequency band relative power was stronger in perfect than in failed trials in the frontal midline and posterior regions. Similarly, gamma band (30-40 Hz) relative power was stronger in perfect than in failed trials over the right motor cortex. Exact low-resolution brain electromagnetic tomography in the frequency domain identified greater theta power in perfect than in failed trials in the secondary visual area (BA19) and greater gamma power in perfect than in failed trials in the right supplementary motor area. The findings of this exploratory study suggest that theta oscillations in the occipital lobe and gamma oscillations in the secondary motor cortex (BA6) play a particular role in successful allocentric spatial working memory maintenance.

Well-designed manufacturing work improves some cognitive abilities in individuals with cognitive impairments.

Introduction: Employment is recognized as a fundamental human right, which correlates with better physical and mental health. Importantly, well-designed work, which considers the physical, social, and psychological impacts of work, can serve to enhance the cognitive abilities of workers. Although often overlooked, work for individuals with disabilities, including cognitive impairments, is equally important for their physical and mental well-being. What has not been established, however, is whether well-designed work can also enhance the cognitive abilities of individuals with cognitive impairments. Methods: Using a longitudinal study design, we investigated the impact of well-designed work on the cognitive abilities of 60 participants (operators) at the AMIPI Foundation factories, which employ individuals with cognitive impairments to produce electrical cables and harnesses for the automobile industry. The same operators were assessed at three different time points: upon hiring (n = 60), and after working in the factory for 1 year (n = 41, since 19 left the factory) and 2 years (n = 28, since 13 more left the factory). We used five cognitive tests evaluating: (1) finger and manual dexterity, bimanual dexterity, and procedural memory using the Purdue Pegboard; (2) sustained and selective attention using the Symbol Cancellation Task; (3) short- and long-term declarative verbal memory and long-term verbal recognition memory using Rey's Audio-Verbal Learning Test; (4) short- and long-term visual recognition memory using the Continuous Visual Memory Test; and (5) abstract reasoning using Raven's Standard Progressive Matrices. Results: We observed improvements in procedural memory, sustained and selective attention, and short- and long-term visual recognition memory after working in the factory for 1 or 2 years. We did not observe improvements in finger or manual dexterity or bimanual dexterity, nor short- or long-term declarative verbal memory or verbal recognition memory, nor abstract reasoning. Discussion: We conclude that, in addition to improving physical and mental well-being, well-designed manufacturing work can serve as a training intervention improving some types of cognitive functioning in individuals with cognitive impairments.

Why do individuals with Williams syndrome or Down syndrome fail the Weather Prediction Task?

Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental disorders with distinct genetic origins characterized by mild to moderate intellectual disability. Individuals with WS or DS exhibit impaired hippocampus-dependent place learning and enhanced striatum-dependent spatial response learning. Here, we used the Weather Prediction Task (WPT), which can be solved using hippocampus- or striatum-dependent learning strategies, to determine whether individuals with WS or DS exhibit similar profiles outside the spatial domain. Only 10% of individuals with WS or DS solved the WPT. We further assessed whether a concurrent memory task could promote reliance on procedural learning to solve the WPT in individuals with WS but found that the concurrent task did not improve performance. To understand how the probabilistic cue-outcome associations influences WPT performance, and whether individuals with WS or DS can ignore distractors, we assessed performance using a visual learning task with differing reward contingencies, and a modified WPT with unpredictive cues. Both probabilistic feedback and distractors negatively impacted the performance of individuals with WS or DS. These findings are consistent with deficits in hippocampus-dependent learning and executive functions, and reveal the importance of congruent feedback and the minimization of distractors to optimize learning in these two populations.

When and how do children solve the Weather Prediction Task?

The Weather Prediction Task (WPT) can be solved by adults using several strategies dependent on different memory systems. One developmental study reported that 8-12-year-old children can solve WPT-like tasks but, because of inadequate analyses, the cognitive processes involved in solving the task have not been established. The present study aimed to determine at what age children can first solve the WPT and identify the strategies used by children of different ages. We tested 3-12-year-old typically developing children and 20-30-year-old adults on a modified WPT. We performed detailed analyses of performance for each pattern of cue-outcome associations to decipher the strategies used by participants. None of the 3-5.5-year-old children solved the task. About one third of 5.5-7.5-year-old children performed above chance, relying only on the two most predictive cues. In contrast, about 80% of 7.5-12-year-old children performed above chance, relying on a conditional hierarchical strategy. Similar to 20-30-year-old adults, 7.5-12-year-old children considered the highly predictive cues primarily and the less predictive cues secondarily. These findings indicate that the learning strategies used to solve the WPT evolve from middle to late childhood and reflect an increasing ability to use a conditional strategy concomitant with the development of the hippocampus-dependent memory system.

Structural plasticity in the entorhinal and perirhinal cortices following hippocampal lesions in rhesus monkeys.

Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2-positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl-stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate-lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate-lesioned monkeys but no differences were found in layer II of area 36. In adult-lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age-dependent manner.

What Is the Weather Prediction Task Good for? A New Analysis of Learning Strategies Reveals How Young Adults Solve the Task.

The Weather Prediction Task (WPT) was originally designed to assess probabilistic classification learning. Participants were believed to gradually acquire implicit knowledge about cue-outcome association probabilities and solve the task using a multicue strategy based on the combination of all cue-outcome probabilities. However, the cognitive processes engaged in the resolution of this task have not been firmly established, and despite conflicting results, the WPT is still commonly used to assess striatal or procedural learning capacities in various populations. Here, we tested young adults on a modified version of the WPT and performed novel analyses to decipher the learning strategies and cognitive processes that may support above chance performance. The majority of participants used a hierarchical strategy by assigning different weights to the different cues according to their level of predictability. They primarily based their responses on the presence or absence of highly predictive cues and considered less predictive cues secondarily. However, the influence of the less predictive cues was inconsistent with the use of a multicue strategy, since they did not affect choices when both highly predictive cues associated with opposite outcomes were present simultaneously. Our findings indicate that overall performance is inadequate to draw conclusions about the cognitive processes assessed by the WPT. Instead, detailed analyses of performance for the different patterns of cue-outcome associations are essential to determine the learning strategies used by participants to solve the task.

Age-Related Differences in Resting-State EEG and Allocentric Spatial Working Memory Performance.

During normal aging resting-state brain activity changes and working memory performance declines as compared to young adulthood. Interestingly, previous studies reported that different electroencephalographic (EEG) measures of resting-state brain activity may correlate with working memory performance at different ages. Here, we recorded resting-state EEG activity and tested allocentric spatial working memory in healthy young (20-30 years) and older (65-75 years) adults. We adapted standard EEG methods to record brain activity in mobile participants in a non-shielded environment, in both eyes closed and eyes open conditions. Our study revealed some age-group differences in resting-state brain activity that were consistent with previous results obtained in different recording conditions. We confirmed that age-group differences in resting-state EEG activity depend on the recording conditions and the specific parameters considered. Nevertheless, lower theta-band and alpha-band frequencies and absolute powers, and higher beta-band and gamma-band relative powers were overall observed in healthy older adults, as compared to healthy young adults. In addition, using principal component and regression analyses, we found that the first extracted EEG component, which represented mainly theta, alpha and beta powers, correlated with spatial working memory performance in older adults, but not in young adults. These findings are consistent with the theory that the neurobiological bases of working memory performance may differ between young and older adults. However, individual measures of resting-state EEG activity could not be used as reliable biomarkers to predict individual allocentric spatial working memory performance in young or older adults.

Life and Death of Immature Neurons in the Juvenile and Adult Primate Amygdala.

In recent years, a large population of immature neurons has been documented in the paralaminar nucleus of the primate amygdala. A substantial fraction of these immature neurons differentiate into mature neurons during postnatal development or following selective lesion of the hippocampus. Notwithstanding a growing number of studies on the origin and fate of these immature neurons, fundamental questions about the life and death of these neurons remain. Here, we briefly summarize what is currently known about the immature neurons present in the primate ventral amygdala during development and in adulthood, as well as following selective hippocampal lesions. We provide evidence confirming that the distribution of immature neurons extends to the anterior portions of the entorhinal cortex and layer II of the perirhinal cortex. We also provide novel arguments derived from stereological estimates of the number of mature and immature neurons, which support the view that the migration of immature neurons from the lateral ventricle accompanies neuronal maturation in the primate amygdala at all ages. Finally, we propose and discuss the hypothesis that increased migration and maturation of neurons in the amygdala following hippocampal dysfunction may be linked to behavioral alterations associated with certain neurodevelopmental disorders.

A Critical Review of Spatial Abilities in Down and Williams Syndromes: Not All Space Is Created Equal.

Down syndrome (DS, Trisomy 21) and Williams syndrome (WS) are two neurodevelopmental disorders of genetic origin that are accompanied by mild to moderate intellectual disability but exhibit distinct cognitive profiles. In this review we discuss our recent work characterizing the real-world spatial learning and memory abilities of adult individuals with DS and WS. We used several different paradigms in which participants locomote freely and have access to coherent input from all sensory modalities to investigate their fundamental egocentric (body-centered or viewpoint-dependent) and allocentric (world-centered or viewpoint-independent) spatial abilities. We found unequivocal evidence that most individuals with DS exhibit low-resolution egocentric and allocentric spatial learning and memory abilities similar to typically developing (TD) children in the same mental age range. In contrast, most individuals with DS exhibit impaired high-resolution allocentric spatial learning and facilitated response learning as compared to TD children. In comparison, whereas most individuals with WS also exhibit facilitated response learning, their low-resolution allocentric spatial learning and memory abilities are severely impaired as compared to both TD children and individuals with DS. Together with work from other laboratories using real-world or virtual reality paradigms, these findings indicate that in order to navigate in their environment most individuals with DS may use either egocentric route learning that does not integrate individual landmarks, or a low-resolution allocentric spatial representation that encodes the relationships between different locations (i.e., cognitive mapping). In contrast, since most individuals with WS are unable to build or use a low-resolution allocentric or configural representation of the environment they may use visually and verbally encoded landmarks as beacons to learn routes. Finally, we discuss the main neural structures implicated in these different spatial processes and explain how the relative preservation or impairment of specific brain functions may engender the unique cognitive profiles observed in individuals with these neurodevelopmental disorders.

Resting-State EEG Microstates Parallel Age-Related Differences in Allocentric Spatial Working Memory Performance.

Alterations of resting-state EEG microstates have been associated with various neurological disorders and behavioral states. Interestingly, age-related differences in EEG microstate organization have also been reported, and it has been suggested that resting-state EEG activity may predict cognitive capacities in healthy individuals across the lifespan. In this exploratory study, we performed a microstate analysis of resting-state brain activity and tested allocentric spatial working memory performance in healthy adult individuals: twenty 25-30-year-olds and twenty-five 64-75-year-olds. We found a lower spatial working memory performance in older adults, as well as age-related differences in the five EEG microstate maps A, B, C, C' and D, but especially in microstate maps C and C'. These two maps have been linked to neuronal activity in the frontal and parietal brain regions which are associated with working memory and attention, cognitive functions that have been shown to be sensitive to aging. Older adults exhibited lower global explained variance and occurrence of maps C and C'. Moreover, although there was a higher probability to transition from any map towards maps C, C' and D in young and older adults, this probability was lower in older adults. Finally, although age-related differences in resting-state EEG microstates paralleled differences in allocentric spatial working memory performance, we found no evidence that any individual or combination of resting-state EEG microstate parameter(s) could reliably predict individual spatial working memory performance. Whether the temporal dynamics of EEG microstates may be used to assess healthy cognitive aging from resting-state brain activity requires further investigation.

Path Integration and Cognitive Mapping Capacities in Down and Williams Syndromes.

Williams (WS) and Down (DS) syndromes are neurodevelopmental disorders with distinct genetic origins and different spatial memory profiles. In real-world spatial memory tasks, where spatial information derived from all sensory modalities is available, individuals with DS demonstrate low-resolution spatial learning capacities consistent with their mental age, whereas individuals with WS are severely impaired. However, because WS is associated with severe visuo-constructive processing deficits, it is unclear whether their impairment is due to abnormal visual processing or whether it reflects an inability to build a cognitive map. Here, we tested whether blindfolded individuals with WS or DS, and typically developing (TD) children with similar mental ages, could use path integration to perform an egocentric homing task and return to a starting point. We then evaluated whether they could take shortcuts and navigate along never-traveled trajectories between four objects while blindfolded, thus demonstrating the ability to build a cognitive map. In the homing task, 96% of TD children, 84% of participants with DS and 44% of participants with WS were able to use path integration to return to their starting point consistently. In the cognitive mapping task, 64% of TD children and 74% of participants with DS were able to take shortcuts and use never-traveled trajectories, the hallmark of cognitive mapping ability. In contrast, only one of eighteen participants with WS demonstrated the ability to build a cognitive map. These findings are consistent with the view that hippocampus-dependent spatial learning is severely impacted in WS, whereas it is relatively preserved in DS.

Children five-to-nine years old can use path integration to build a cognitive map without vision.

Although spatial navigation competence improves greatly from birth to adulthood, different spatial memory capacities emerge at different ages. Here, we characterized the capacity of 5-9-year-old children to use path integration to build egocentric and allocentric spatial representations to navigate in their environment, and compared their performance with that of young adults. First, blindfolded participants were tested on their ability to return to a starting point after being led on straight and two-legged paths. This egocentric homing task comprising angular and linear displacements allowed us to evaluate path integration capacities in absence of external landmarks. Second, we evaluated whether participants could use path integration, in absence of visual information, to create an allocentric spatial representation to navigate along novel paths between objects, and thus demonstrate the ability to build a cognitive map of their environment. Ninety percent of the 5-9-year-old children could use path integration to create an egocentric representation of their journey to return to a starting point, but they were overall less precise than adults. Sixty-four percent of 5-9-year-old children were capable of using path integration to build a cognitive map enabling them to take shortcuts, and task performance was not dependent on age. Imprecisions in novel paths made by the children who built a cognitive map could be explained by poorer integration of the experienced turns during the learning phase, as well as greater individual variability. In sum, these findings demonstrate that 5-9-year-old children can use path integration to build a cognitive map in absence of visual information.

Postnatal development of the entorhinal cortex: A stereological study in macaque monkeys.

The entorhinal cortex is the main gateway for interactions between the neocortex and the hippocampus. Distinct regions, layers, and cells of the hippocampal formation exhibit different profiles of structural and molecular maturation during postnatal development. Here, we provide estimates of neuron number, neuronal soma size, and volume of the different layers and subdivisions of the monkey entorhinal cortex (Eo, Er, Elr, Ei, Elc, Ec, Ecl) during postnatal development. We found different developmental changes in neuronal soma size and volume of distinct layers in different subdivisions, but no changes in neuron number. Layers I and II developed early in most subdivisions. Layer III exhibited early maturation in Ec and Ecl, a two-step/early maturation in Ei and a late maturation in Er. Layers V and VI exhibited an early maturation in Ec and Ecl, a two-step and early maturation in Ei, and a late maturation in Er. Neuronal soma size increased transiently at 6 months of age and decreased thereafter to reach adult size, except in Layer II of Ei, and Layers II and III of Ec and Ecl. These findings support the theory that different hippocampal circuits exhibit distinct developmental profiles, which may subserve the emergence of different hippocampus-dependent memory processes. We discuss how the early maturation of the caudal entorhinal cortex may contribute to path integration and basic allocentric spatial processing, whereas the late maturation of the rostral entorhinal cortex may contribute to the increased precision of allocentric spatial representations and the temporal integration of individual items into episodic memories.

Stereological analysis of the rhesus monkey entorhinal cortex.

The entorhinal cortex is a prominent structure of the medial temporal lobe, which plays a pivotal role in the interaction between the neocortex and the hippocampal formation in support of declarative and spatial memory functions. We implemented design-based stereological techniques to provide estimates of neuron numbers, neuronal soma size, and volume of different layers and subdivisions of the entorhinal cortex in adult rhesus monkeys (Macaca mulatta; 5-9 years of age). These data corroborate the structural differences between different subdivisions of the entorhinal cortex, which were shown in previous connectional and cytoarchitectonic studies. In particular, differences in the number of neurons contributing to distinct afferent and efferent hippocampal pathways suggest not only that different types of information may be more or less segregated between caudal and rostral subdivisions, but also, and perhaps most importantly, that the nature of the interaction between the entorhinal cortex and the rest of the hippocampal formation may vary between different subdivisions. We compare our quantitative data in monkeys with previously published stereological data for the rat and human, in order to provide a perspective on the relative development and structural organization of the main subdivisions of the entorhinal cortex in two model organisms widely used to decipher the basic functional principles of the human medial temporal lobe memory system. Altogether, these data provide fundamental information on the number of functional units that comprise the entorhinal-hippocampal circuits and should be considered in order to build realistic models of the medial temporal lobe memory system.

Functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion in rhesus monkeys.

Hippocampal damage in adult humans impairs episodic and semantic memory, whereas hippocampal damage early in life impairs episodic memory but leaves semantic learning relatively preserved. We have previously shown a similar behavioral dissociation in nonhuman primates. Hippocampal lesion in adult monkeys prevents allocentric spatial relational learning, whereas spatial learning persists following neonatal lesion. Here, we quantified the number of cells expressing the immediate-early gene c-fos, a marker of neuronal activity, to characterize the functional organization of the medial temporal lobe memory system following neonatal hippocampal lesion. Ninety minutes before brain collection, three control and four adult monkeys with bilateral neonatal hippocampal lesions explored a novel environment to activate brain structures involved in spatial learning. Three other adult monkeys with neonatal hippocampal lesions remained in their housing quarters. In unlesioned monkeys, we found high levels of c-fos expression in the intermediate and caudal regions of the entorhinal cortex, and in the perirhinal, parahippocampal, and retrosplenial cortices. In lesioned monkeys, spatial exploration induced an increase in c-fos expression in the intermediate field of the entorhinal cortex, the perirhinal, parahippocampal, and retrosplenial cortices, but not in the caudal entorhinal cortex. These findings suggest that different regions of the medial temporal lobe memory system may require different types of interaction with the hippocampus in support of memory. The caudal perirhinal cortex, the parahippocampal cortex, and the retrosplenial cortex may contribute to spatial learning in the absence of functional hippocampal circuits, whereas the caudal entorhinal cortex may require hippocampal output to support spatial learning.

The "when" and the "where" of single-trial allocentric spatial memory performance in young children: Insights into the development of episodic memory.

Allocentric spatial memory, "where" with respect to the surrounding environment, is one of the three fundamental components of episodic memory: what, where, when. Whereas basic allocentric spatial memory abilities are reliably observed in children after 2 years of age, coinciding with the offset of infantile amnesia, the resolution of allocentric spatial memory acquired over repeated trials improves from 2 to 4 years of age. Here, we first show that single-trial allocentric spatial memory performance improves in children from 3.5 to 7 years of age, during the typical period of childhood amnesia. Second, we show that large individual variation exists in children's performance at this age. Third, and most importantly, we show that improvements in single-trial allocentric spatial memory performance are due to an increasing ability to spatially and temporally separate locations and events. Such improvements in spatial and temporal processing abilities may contribute to the gradual offset of childhood amnesia.

Human short-term spatial memory: precision predicts capacity.

Here, we aimed to determine the capacity of human short-term memory for allocentric spatial information in a real-world setting. Young adults were tested on their ability to learn, on a trial-unique basis, and remember over a 1-min interval the location(s) of 1, 3, 5, or 7 illuminating pads, among 23 pads distributed in a 4m×4m arena surrounded by curtains on three sides. Participants had to walk to and touch the pads with their foot to illuminate the goal locations. In contrast to the predictions from classical slot models of working memory capacity limited to a fixed number of items, i.e., Miller's magical number 7 or Cowan's magical number 4, we found that the number of visited locations to find the goals was consistently about 1.6 times the number of goals, whereas the number of correct choices before erring and the number of errorless trials varied with memory load even when memory load was below the hypothetical memory capacity. In contrast to resource models of visual working memory, we found no evidence that memory resources were evenly distributed among unlimited numbers of items to be remembered. Instead, we found that memory for even one individual location was imprecise, and that memory performance for one location could be used to predict memory performance for multiple locations. Our findings are consistent with a theoretical model suggesting that the precision of the memory for individual locations might determine the capacity of human short-term memory for spatial information.

The human hippocampus beyond the cognitive map: evidence from a densely amnesic patient.

We tested a densely amnesic patient (P9), with bilateral hippocampal damage resulting from an autoimmune disorder, and 12 age- and sex-matched controls on a series of memory tasks designed to characterize allocentric spatial learning and memory abilities. We compared P9's ability to perform spatial memory tasks with her ability to perform non-spatial, color memory tasks. First, P9's performance was impaired as compared to controls even in the simplest versions of an allocentric spatial memory task, in which she had to find repeatedly over 10 trials the same location(s) of one, two or three illuminating foot pad(s) among 23 pads distributed in an open-field arena. In contrast, she performed as well as controls when she had to find repeatedly over 10 trials the same one, two or three pad(s) marked by color cue(s), whose locations varied between trials. Second, P9's performance was severely impaired in working memory tasks, when she had to learn on a trial-unique basis and remember the location(s) or the color(s) of one, two or three pad(s), while performing an interfering task during the 1-min interval separating encoding and retrieval. Without interference during the retention interval of the trial-unique tasks, P9's performance was partially preserved in the color tasks, whereas it remained severely impaired in the allocentric spatial tasks. Detailed behavioral analyses indicate that P9's memory representations are more limited than those of controls both in their precision (metric coding) and in the number of items that can be maintained in memory (capacity). These findings are consistent with the theory that the hippocampus contributes to the integration or binding of multiple items, in order to produce high-resolution/high-capacity representations of spatial and non-spatial information in the service of short-term/working and long-term memory.

What animals can teach clinicians about the hippocampus.

Abnormalities in hippocampal structure and function have been reported in a number of human neuropathological and neurodevelopmental disorders, including Alzheimer's disease, autism spectrum disorders, Down syndrome, epilepsy, and schizophrenia. Given the complexity of these disorders, animal studies are invaluable and remain to date irreplaceable, providing fundamental knowledge regarding the basic mechanisms underlying normal and pathological human brain structure and function. However, there is a prominent ill-conceived view in current research that scientists should be restricted to using animal models of human diseases that can lead to results applicable to humans within a few years. Although there is no doubt that translational studies of this kind are important and necessary, limiting animal studies to applicable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems. Here, we discuss findings regarding the normal postnatal development of the monkey hippocampal formation, which provide an essential framework to consider the etiologies of different neuropathological disorders affecting human hippocampal structure and function. We focus on studies of gene expression in distinct hippocampal regions that shed light on some basic mechanisms that might contribute to the etiology of schizophrenia. We argue that researchers, as well as clinicians, should not consider the use of animals in research only as 'animal models' of human diseases, as they will continue to need and benefit from a better understanding of the normal structure and functions of the hippocampus in 'model animals'.

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

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.