The role of the hippocampus in generalizing configural relationships

The hippocampus has been implicated in integrating information across separate events in support of mnemonic generalizations. These generalizations may be underpinned by processes at both encoding (linking similar information across events) and retrieval (“on‐the‐fly” generalization). However, the relative contribution of the hippocampus to encoding‐ and retrieval‐based generalizations is poorly understood. Using fMRI in humans, we investigated the hippocampal role in gradually learning a set of spatial discriminations and subsequently generalizing them in an acquired equivalence task. We found a highly significant correlation between individuals’ performance on a generalization test and hippocampal activity during the test, providing evidence that hippocampal processes support on‐the‐fly generalizations at retrieval. Within the same hippocampal region there was also a correlation between activity during the final stage of learning (when all associations had been learnt but no generalization was required) and subsequent generalization performance. We suggest that the hippocampus spontaneously retrieves prior events that share overlapping features with the current event. This process may also support the creation of generalized representations during encoding. These findings are supportive of the view that the hippocampus contributes to both encoding‐ and retrieval‐based generalization via the same basic mechanism; retrieval of similar events sharing common features. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Neural activity in the hippocampus predicts individual visual short‐term memory capacity

Although the hippocampus had been traditionally thought to be exclusively involved in long‐term memory, recent studies raised controversial explanations why hippocampal activity emerged during short‐term memory tasks. For example, it has been argued that long‐term memory processes might contribute to performance within a short‐term memory paradigm when memory capacity has been exceeded. It is still unclear, though, whether neural activity in the hippocampus predicts visual short‐term memory (VSTM) performance. To investigate this question, we measured BOLD activity in 21 healthy adults (age range 19–27 yr, nine males) while they performed a match‐to‐sample task requiring processing of object‐location associations (delay period = 900 ms; set size conditions 1, 2, 4, and 6). Based on individual memory capacity (estimated by Cowan's K‐formula), two performance groups were formed (high and low performers). Within whole brain analyses, we found a robust main effect of “set size” in the posterior parietal cortex (PPC). In line with a “set size × group” interaction in the hippocampus, a subsequent Finite Impulse Response (FIR) analysis revealed divergent hippocampal activation patterns between performance groups: Low performers (mean capacity = 3.63) elicited increased neural activity at set size two, followed by a drop in activity at set sizes four and six, whereas high performers (mean capacity = 5.19) showed an incremental activity increase with larger set size (maximal activation at set size six). Our data demonstrated that performance‐related neural activity in the hippocampus emerged below capacity limit. In conclusion, we suggest that hippocampal activity reflected successful processing of object‐location associations in VSTM. Neural activity in the PPC might have been involved in attentional updating. © 2013 Wiley Periodicals, Inc.     

Intracranial EEG correlates of implicit relational inference within the hippocampus

Drawing inferences from past experiences enables adaptive behavior in future situations. Inference has been shown to depend on hippocampal processes. Usually, inference is considered a deliberate and effortful mental act which happens during retrieval, and requires the focus of our awareness. Recent fMRI studies hint at the possibility that some forms of hippocampus‐dependent inference can also occur during encoding and possibly also outside of awareness. Here, we sought to further explore the feasibility of hippocampal implicit inference, and specifically address the temporal evolution of implicit inference using intracranial EEG. Presurgical epilepsy patients with hippocampal depth electrodes viewed a sequence of word pairs, and judged the semantic fit between two words in each pair. Some of the word pairs entailed a common word (e.g., “winter–red,” “red–cat”) such that an indirect relation was established in following word pairs (e.g., “winter–cat”). The behavioral results suggested that drawing inference implicitly from past experience is feasible because indirect relations seemed to foster “fit” judgments while the absence of indirect relations fostered “do not fit” judgments, even though the participants were unaware of the indirect relations. A event‐related potential (ERP) difference emerging 400 ms post‐stimulus was evident in the hippocampus during encoding, suggesting that indirect relations were already established automatically during encoding of the overlapping word pairs. Further ERP differences emerged later post‐stimulus (1,500 ms), were modulated by the participants' responses and were evident during encoding and test. Furthermore, response‐locked ERP effects were evident at test. These ERP effects could hence be a correlate of the interaction of implicit memory with decision‐making. Together, the data map out a time‐course in which the hippocampus automatically integrates memories from discrete but related episodes to implicitly influence future decision making. © 2015 Wiley Periodicals, Inc.     

Spatial reconstruction by patients with hippocampal damage is dominated by relational memory errors

Hippocampal damage causes profound yet circumscribed memory impairment across diverse stimulus types and testing formats. Here, within a single test format involving a single class of stimuli, we identified different performance errors to better characterize the specifics of the underlying deficit. The task involved study and reconstruction of object arrays across brief retention intervals. The most striking feature of patients' with hippocampal damage performance was that they tended to reverse the relative positions of item pairs within arrays of any size, effectively “swapping” pairs of objects. These “swap errors” were the primary error type in amnesia, almost never occurred in healthy comparison participants, and actually contributed to poor performance on more traditional metrics (such as distance between studied and reconstructed location). Patients made swap errors even in trials involving only a single pair of objects. The selectivity and severity of this particular deficit creates serious challenges for theories of memory and hippocampus. © 2013 Wiley Periodicals, Inc.     

Medial temporal contributions to successful face-name learning

The brain mechanisms that enable us to form durable associations between different types of information are not completely understood. Although the hippocampus is widely thought to play a substantial role in forming associations, the role of surrounding cortical regions in the medial temporal lobe, including perirhinal and parahippocampal cortex, is controversial. Using anatomically constrained functional magnetic resonance imaging, we assessed medial temporal contributions to learning arbitrary associations between faces and names. By sorting learning trials based on subsequent performance in associative and item-specific memory tests, we characterized brain activity associated with successful face-name associative learning. We found that right hippocampal activity was greater when corresponding face-name associations were subsequently remembered than when only a face or a name, but not both, were remembered, or when single-item information or associative information was not remembered. Neither perirhinal nor parahippocampal cortex encoding activity differed across these same conditions. Furthermore, right hippocampal activity during successful face-name association learning was strongly correlated with activity in cortical regions involved in multimodal integration, supporting the idea that interactions between the hippocampus and neocortex contribute to associative memory. These results specifically implicate the hippocampus in associative memory formation, in keeping with theoretical formulations in which contributions to across-domain binding differ among brain structures in the medial temporal region.     

The hippocampus is critical for value‐based decisions guided by dissociative inference

The hippocampus supports flexible decision‐making through memory integration: bridging across episodes and inferring associations between stimuli that were never presented together (‘associative inference’). A pre‐requisite for memory integration is flexible representations of the relationships between stimuli within episodes (AB) but also of the constituent units (A,B). Here we investigated whether the hippocampus is required for parsing experienced episodes into their constituents to infer their re‐combined within‐episode associations (‘dissociative inference’). In three experiments male rats were trained on an appetitive conditioning task using compound auditory stimuli (AB+, BA+, CD?, DC?). At test either the compound or individual stimuli were presented as well as new stimuli. Rats with hippocampal lesions acquired and retained the compound discriminations as well as controls. Single constituent stimuli (A, B, C, D) were presented for the first time at test, so the only value with which they could be associated was the one from the compound to which they belonged. Controls inferred constituent tones’ corresponding values while hippocampal rats did not, treating them as merely familiar stimuli with no associated value. This finding held whether compound training occurred before or after hippocampal lesions, suggesting that hippocampus‐dependent inferential processes more likely occur at retrieval. The findings extend recent discoveries about the role of the hippocampus in intrinsic value representation, demonstrating hippocampal contributions to allocating value from primary rewards to individual stimuli. Importantly, we discovered that dissociative inferences serve to restructure or reparse patterns of directly acquired associations when animals are faced with environmental changes and need to extract relevant information from a multiplex memory. The hippocampus is critical for this fundamental flexible use of associations.     

The effects of study task on prestimulus subsequent memory effects in the hippocampus

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre‐stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as “Remembered,” “Known,” or “New.” As expected, “deep” animacy judgments led to better memory for study items than did “shallow” syllable judgments. In both study tasks, pre‐stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre‐stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre‐stimulus hippocampal subsequent memory effects depends on whether an optimal pre‐stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories. © 2015 Wiley Periodicals, Inc.     

Mnemonic strategy training partially restores hippocampal activity in patients with mild cognitive impairment

Learning and memory deficits typify patients with mild cognitive impairment (MCI) and are generally attributed to medial temporal lobe dysfunction. Although the hippocampus is perhaps the most commonly studied neuroanatomical structure in these patients, there have been few attempts to identify rehabilitative interventions that facilitate its functioning. Here, we present results from a randomized, controlled, single‐blind study in which patients with MCI and healthy elderly controls (HEC) were randomized to either three sessions of mnemonic strategy training (MS) or a matched‐exposure control group (XP). All participants underwent pre‐ and posttraining fMRI scanning as they encoded and retrieved object–location associations. For the current report, fMRI analyses were restricted to the hippocampus, as defined anatomically. Before training, MCI patients showed reduced hippocampal activity during both encoding and retrieval, relative to HEC. Following training, the MCI MS group demonstrated increased activity during both encoding and retrieval. There were significant differences between the MCI MS and MCI XP groups during retrieval, especially within the right hippocampus. Thus, MS facilitated hippocampal functioning in a partially restorative manner. We conclude that cognitive rehabilitation techniques may help mitigate hippocampal dysfunction in MCI patients. © 2012 Wiley Periodicals, Inc.     

Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy

One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task), between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. We discuss the role of the hippocampus and its interactions with the prefrontal cortex in serving working memory.     

Medial septal cholinergic neurons are necessary for context‐place memory but not episodic‐like memory

Loss of cholinergic cortical input is associated with diseases in which episodic memory impairment is a prominent feature, but the degree to which this neurochemical lesion can account for memory impairment in humans with neurodegenerative diseases remains unclear. Removal of cholinergic input to hippocampus impairs some of its functions in memory, perhaps by reducing the plasticity of information representation within the hippocampus, but the role of cholinergic hippocampal input in episodic‐like memories has not been investigated. To address this question, we tested rats with selective lesions of basal forebrain neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), which contains hippocampal‐projecting cholinergic neurons, on a task of integrated memory for objects, places, and contexts (“what–where–which” memory). This task serves as a rodent model of human episodic memory (episodic‐like memory) and is sensitive to damage to the hippocampal system. Rats with lesions of cholinergic MS/VDB neurons performed as well on the what–where–which task as controls, but were impaired in a task that simply required them to associate places with contexts (“where–which” memory). Thus, episodic‐like memories that rely on the hippocampus do not require cholinergic neuromodulation to be formed. Nevertheless, some more specific aspects of where–which memory, which may be more dependent on the plasticity of hippocampal spatial representations, require acetylcholine. These results suggest that cholinergic projections to hippocampus are not necessary for episodic memory and, furthermore, that hippocampal spatial representations may be to some extent dissociable from episodic memory function. © 2010 Wiley‐Liss, Inc.     

Lesions affecting the right hippocampal formation differentially impair short‐term memory of spatial and nonspatial associations

Converging evidence from behavioral and imaging studies suggests that within the human medial temporal lobe (MTL) the hippocampal formation may be particularly involved in recognition memory of associative information. However, it is unclear whether the hippocampal formation processes all types of associations or whether there is a specialization for processing of associations involving spatial information. Here, we investigated this issue in six patients with postsurgical lesions of the right MTL affecting the hippocampal formation and in ten healthy controls. Subjects performed a battery of delayed match‐to‐sample tasks with two delays (900/5,000 ms) and three set sizes. Subjects were requested to remember either single features (colors, locations, shapes, letters) or feature associations (color‐location, color‐shape, color‐letter). In the single‐feature conditions, performance of patients did not differ from controls. In the association conditions, a significant delay‐dependent deficit in memory of color‐location associations was found. This deficit was largely independent of set size. By contrast, performance in the color‐shape and color‐letter conditions was normal. These findings support the hypothesis that a region within the right MTL, presumably the hippocampal formation, does not equally support all kinds of visual memory but rather has a bias for processing of associations involving spatial information. Recruitment of this region during memory tasks appears to depend both on processing type (associative/nonassociative) and to‐be‐remembered material (spatial/nonspatial). © 2010 Wiley‐Liss, Inc.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.     

Episodic memory: Neuronal codes for what,where, and when

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent (“where”), sequence of events (“when”), and the content of the experience itself (“what”). Second, the code should arise instantly thereby being able to support memory formation of one‐shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory‐based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object‐coding and odor‐selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.     

Dorsal hippocampal lesions boost performance in the rat sequential reaction time task

It is commonly accepted that the hippocampus plays a major role in declarative memory across species and that it is of particular relevance for spatial memory in rodents. However, the interplay between hippocampal function and nondeclarative memory systems, such as procedural stimulus-response (S-R) or sequential learning, is less clear: depending on task requirements, an interaction, dissociation or interference between hippocampal function and other memory systems may occur. This study was conducted to investigate the influence of dorsal ibotenic hippocampal lesions on learning and performance of sequential behavior in a rat version of the serial reaction time task (SRTT). Magnetic resonance imaging (MRI) analyses of the lesions revealed a bilateral volume reduction of ≈ 46% (histological analyses: ≈ 59%) of the total hippocampus. They were largely confined to its dorsal part and led to an expected spatial memory deficits in an object place recognition test as compared to healthy controls, even though sham lesions had the same effect. Our earlier studies on sequential learning had revealed substantial impairments in case of dorsal striatal dopaminergic lesions. In the present study, however, hippocampal lesioned animals unexpectedly showed superior performance throughout SRTT testing and training as compared to controls, which resulted in a higher degree of subsequent automated sequential behavior. Thus, our data reveal the infrequent case where hippocampal lesions lead to long-term improvements in test performance of a type of rather complex procedural behavior. One possible explanation for this effect is that hippocampal activity in rodents can interfere with other memory systems during the acquisition of procedural tasks with very low spatial requirements, as used here. Alternative explanations for the observed superior SRTT performance in lesioned animals, such as hyperactivity or increased exploratory drive are also topic of the discussion.     

Hippocampus NMDA receptors selectively mediate latent extinction of place learning

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical “response extinction,” animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In “latent extinction,” animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)‐dependent response learning and hippocampus‐dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long‐Evans rats were trained in a response learning task in a water plus‐maze, in which animals were reinforced to make a consistent body‐turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra‐hippocampal infusions of the NMDA receptor antagonist 2‐amino‐5‐phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were effective at extinguishing memory in the place learning task. In addition, intra‐hippocampal AP5 (7.5 µg) impaired latent extinction, but not response extinction, suggesting that hippocampal NMDA receptors are selectively involved in latent extinction. © 2016 Wiley Periodicals, Inc.     

Age- and performance-related differences in hippocampal contributions to episodic retrieval

The goal of the present study was to investigate whether hippocampal contribution to episodic memory retrieval varies as a function of age (8–9 versus 10–11 versus adults), performance levels (high versus low) and hippocampal sub-region (head, body, tail). We examined fMRI data collected during episodic retrieval from a large sample (N = 126). Participants judged whether a stimulus had been encoded previously, and, if so, which of three scenes it had been paired with (i.e., source judgment). For 8- to 9-years-olds as well as low-performing 10- to 11-year-olds, hippocampal activations did not reliably differentiate between trials on which item-scene associations were correctly recalled (correct source), incorrectly recalled (incorrect source), or trials on which the item was forgotten (miss trials). For high-performing 10–11-year olds and low-performing adults, selective hippocampal activation was observed for correct source relative to incorrect source and miss trials; this effect was observed across the entire hippocampus. For high-performing adults, hippocampal activation also distinguished between correct and incorrect source trialsl, but only in the hippocampal head, suggesting that good performance in adults is associated with more focal hippocampal recruitment. Thus, both age and performance are important factors for understanding the development of memory and hippocampal function.     

Factors that influence the relative use of multiple memory systems

Neurobehavioral evidence supports the existence of at least two anatomically distinct “memory systems” in the mammalian brain that mediate dissociable types of learning and memory; a “cognitive” memory system dependent upon the hippocampus and a “stimulus‐response/habit” memory system dependent upon the dorsolateral striatum. Several findings indicate that despite their anatomical and functional distinctiveness, hippocampal‐ and dorsolateral striatal‐dependent memory systems may potentially interact and that, depending on the learning situation, this interaction may be cooperative or competitive. One approach to examining the neural mechanisms underlying these interactions is to consider how various factors influence the relative use of multiple memory systems. The present review examines several such factors, including information compatibility, temporal sequence of training, the visual sensory environment, reinforcement parameters, emotional arousal, and memory modulatory systems. Altering these parameters can lead to selective enhancements of either hippocampal‐dependent or dorsolateral striatal‐dependent memory, and bias animals toward the use of either cognitive or habit memory in dual‐solution tasks that may be solved adequately with either memory system. In many learning situations, the influence of such experimental factors on the relative use of memory systems likely reflects a competitive interaction between the systems. Research examining how various factors influence the relative use of multiple memory systems may be a useful method for investigating how these systems interact with one another. © 2013 Wiley Periodicals, Inc.     

Stress and the engagement of multiple memory systems: Integration of animal and human studies

Learning and memory can be controlled by distinct memory systems. How these systems are coordinated to optimize learning and behavior has long been unclear. Accumulating evidence indicates that stress may modulate the engagement of multiple memory systems. In particular, rodent and human studies demonstrate that stress facilitates dorsal striatum‐dependent “habit” memory, at the expense of hippocampus‐dependent “cognitive” memory. Based on these data, a model is proposed which states that the impact of stress on the relative use of multiple memory systems is due to (i) differential effects of hormones and neurotransmitters that are released during stressful events on hippocampal and dorsal striatal memory systems, thus changing the relative strength of and the interactions between these systems, and (ii) a modulatory influence of the amygdala which biases learning toward dorsal striatum‐based memory after stress. This shift to habit memory after stress can be adaptive with respect to current performance but might contribute to psychopathology in vulnerable individuals. © 2013 Wiley Periodicals, Inc.     

Hippocampal‐cortical contributions to strategic exploration during perceptual discrimination

The hippocampus is crucial for long‐term memory; its involvement in short‐term or immediate expressions of memory is more controversial. Rodent hippocampus has been implicated in an expression of memory that occurs on‐line during exploration termed “vicarious trial‐and‐error” (VTE) behavior. VTE occurs when rodents iteratively explore options during perceptual discrimination or at choice points. It is strategic in that it accelerates learning and improves later memory. VTE has been associated with activity of rodent hippocampal neurons, and lesions of hippocampus disrupt VTE and associated learning and memory advantages. Analogous findings of VTE in humans would support the role of hippocampus in active use of short‐term memory to guide strategic behavior. We therefore measured VTE using eye‐movement tracking during perceptual discrimination and identified relevant neural correlates with functional magnetic resonance imaging. A difficult perceptual‐discrimination task was used that required visual information to be maintained during a several second trial, but with no long‐term memory component. VTE accelerated discrimination. Neural correlates of VTE included robust activity of hippocampus and activity of a network of medial prefrontal and lateral parietal regions involved in memory‐guided behavior. This VTE‐related activity was distinct from activity associated with simply viewing visual stimuli and making eye movements during the discrimination task, which occurred in regions frequently associated with visual processing and eye‐movement control. Subjects were mostly unaware of performing VTE, thus further distancing VTE from explicit long‐term memory processing. These findings bridge the rodent and human literatures on neural substrates of memory‐guided behavior, and provide further support for the role of hippocampus and a hippocampal‐centered network of cortical regions in the immediate use of memory in on‐line processing and the guidance of behavior.     

Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the “satiety hormone” leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years ± 7 SD) were compared to 40 healthy controls (HC) that were pair‐wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T‐neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539–4549, 2016. © 2016 Wiley Periodicals, Inc.