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There are currently a number of theories of rodent hippocampal function. They fall into two major groups that differ in the role they impute to space in hippocampal information processing. On one hand, the cognitive map theory sees space as crucial and central, with other types of nonspatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored, and manipulated. One crucial difference, therefore, is the extent to which theories see hippocampal pyramidal cells as representing nonspatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to nonspatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards, and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these nonspatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this article, we argue that when tested in multiple locations, the hippocampal response to nonspatial stimuli is almost invariably dependent on the animal’s location. Looked at collectively, the data provide strong support for the cognitive map theory.

Introduction: A sequence of time-dependent changes can affect the brain’s functional capacity. This study aimed at investigating the effects of Forced Aerobic Exercise (FAE) versus the Rosemary Extract (RE) on the learning abilities and oxidative stress modulation in rats. Methods: Young and old rats received daily FAE and RE for 3 months. Using the Passive Avoidance (PA) test, we evaluated the learning and memory of the rats by Step-Through Latency (STL) score. We measured the Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), Catalase (CATA), Malondialdehyde (MDA) enzymes levels, and Total Antioxidant Capacity (TAC) in the hippocampus Results: FAE could significantly increase the STL score (P

Transgenic rodent models were created to decipher pathogenic mechanisms associated with Alzheimer’s disease (AD), and behavioral apparatuses such as the Morris water maze (MWM) are used to assess cognition in mice. The IntelliCage was designed to circumvent issues of traditional behavioral tests, such as frequent human handling. The motivation to complete IntelliCage tasks is water consumption, which is less stressful than escaping from a pool in the MWM. Here, we examined behavioral performances of mice in the IntelliCage and MWM tasks. Twelve-month-old male and female APP/PS1 and non-transgenic mice first underwent 42 days of IntelliCage testing to assess prefrontal cortical and hippocampal function followed by MWM testing for six days. We found that females performed better in the IntelliCage while males performed superiorly in the MWM. Mechanistically, female APP/PS1 mice had a higher Amyloid-β plaque load throughout the brain, which is inconsistent with their performance in the IntelliCage. Collectively, these results inform scientists about the sex-based differences when testing animals in different behavioral paradigms that tap similar cognitive functions.

The dentate gyrus (DG) of the hippocampus is evolutionarily conserved as one of the few sites of adult neurogenesis in mammals. Although there is clear evidence that neurogenesis is necessary for healthy hippocampal function, whether adult-born neurons are simply integrated into existing hippocampal networks to serve a similar purpose to that of developmentally born neurons or whether they represent a discrete cell population with unique functions remains less clear. In this review, we consider evidence for discrete cellular, synaptic, and structural features of adult-born DG neurons, suggesting that neurogenesis contributes to the formation of a heterogeneous DG. We therefore propose that hippocampal neurogenesis creates a specialized neuronal subpopulation that may play a key role in hippocampal functions like episodic memory. We note critical gaps in this extensive body of work, including a general failure to include female animals in relevant research and a need for more precise consideration of intrahippocampal neuroanatomy.

Prevailing theories of hippocampal function argue that memories are rapidly encoded by non-overlapping memory traces. Concurrently, the hippocampus has been argued to integrate across related experiences, enabling generalization. The cognitive neuroscience of memory has been transformed by the recent proliferation of studies using pattern similarity analyses to investigate the neural substrates of memory in humans, marking an exciting and significant advance in our understanding of population-level neural representations. We provide an overview of hippocampal pattern similarity studies published to date. By considering the effects of stimulus type, time-scale, and hippocampal subregions, we account for both increases and decreases in representational similarity. We argue that hippocampal representations for related memories are not fixed. Instead, the evoked representations are flexibly modulated, depending on whether the current goal is to extract generalities or to reinstate specific experiences. In the first comprehensive review of hippocampal pattern similarity analyses, we provide insight into the mechanisms of memory representation and implications for the interpretation of pattern similarity more generally.

Bisphenol A (BPA) is widely used in industrial production. It is closely related to the growth and development of the nervous system, and can enter the fetal circulation through the placental barrier, and can be secreted through breast milk. The development of nervous system is very important in fetus and neonatal period. The purpose of this study is to investigate the effects of different doses of BPA on learning and memory function of nervous system in rats. Pregnant rats were randomly divided into three treatment groups (control group, 5 mg/kg/d, 50 mg/kg/d). All animals received BPA from the discovery of pregnancy to 21 days after birth. Results had shown that after high concentration BPA exposure, the increase of PS amplitude and f-EPSP slope in hippocampal CA1 area of male offspring was lower than that of control group. High concentration of BPA could inhibit Nestin, Cyclin D1, bcl-2 and Rac1 in male offspring rats and the expression of bax and RhoA was promoted by BPA. In summary, our study indicated that BPA exposure during pregnancy and lactation could impair the hippocampal function of male offspring by affecting the growth and apoptosis of hippocampal neurons, which might be due to the abnormal regulation of RhoA and Rac1.

Depression is characterized by impairments in adult neurogenesis. Reduced hippocampal function, which is suggestive of neurogenesis impairments, is associated with depression-related phenotypes. As adult neurogenesis operates in an activity-dependent manner, disruption of hippocampal neurogenesis in depression may be a consequence of neural circuitry impairments. In particular, the entorhinal cortex is known to have a regulatory effect on the neural circuitry related to hippocampal function and adult neurogenesis. However, a comprehensive understanding of how disruption of the neural circuitry can lead to neurogenesis impairments in depression remains unclear with respect to the regulatory role of the entorhinal cortex. This review highlights recent findings suggesting neural circuitry-regulated neurogenesis, with a focus on the potential role of the entorhinal cortex in hippocampal neurogenesis in depression-related cognitive and emotional phenotypes. Taken together, these findings may provide a better understanding of the entorhinal cortex-regulated hippocampal neurogenesis model of depression.

The hippocampus has long been considered as a key structure for memory processes. Multilevel alterations of hippocampal function have been identified as a common denominator of memory impairments in a number of psychiatric and neurodegenerative diseases. For many years, the glutamatergic and cholinergic systems have been the main targets of therapeutic treatments against these symptoms. However, the high rate of drug development failures has left memory impairments on the sideline of current therapeutic strategies. This underscores the urgent need to focus on new therapeutic targets for memory disorders, such as type 4 serotonin receptors (5-HT4Rs). Ever since the discovery of their expression in the hippocampus, 5-HT4Rs have gained growing interest for potential use in the treatment of learning and memory impairments. To date, much of the researched information gathered by scientists from both animal models and humans converge on pro-mnesic and anti-amnesic properties of 5-HT4Rs activation, although the mechanisms at work require more work to be fully understood. This review addresses a fundamental, yet poorly understood set of evidence of the potential of 5-HT4Rs to re-establish or limit hippocampal alterations related to neurological diseases. Most importantly, the potential of 5-HT4Rs is translated by refining hypotheses regarding the benefits of their activation in memory disorders at the hippocampal level.

Transgenic rodent models of Alzheimer’s disease (AD) were designed to study mechanisms of pathogenesis and connect these mechanisms with cognitive decline. Measurements of cognition in rodents can be confounded, however, by human handling and interaction; the IntelliCage was created to circumvent these issues while measuring various facets of cognition in a social environment with water consumption as the primary motivator for task completion. Here, for the first time, we examined the behavioral performance of 3xTg-AD mice in the IntelliCage. Seven- to 9-month-old female 3xTg-AD and non-transgenic (NonTg) mice were tested for 29 days in the IntelliCage to measure prefrontal cortical and hippocampal function. We found that a higher percentage of NonTg mice (86.96%) were able to successfully complete the training (adaptation) phases compared to their 3xTg-AD (57.14%) counterparts. Furthermore, the 3xTg-AD mice showed impairments in attention and working memory. Interestingly, we found that differences in body and brain weight between NonTg and 3xTg-AD mice were associated with whether mice were able to complete the IntelliCage tasks. 3xTg-AD mice that completed IntelliCage tasks had lower cortical insoluble amyloid-β40 fractions than their 3xTg-AD counterparts who failed to complete the tasks. Collectively, these results demonstrate deficits in cognition in the 3xTg-AD mouse and inform scientists of important factors to consider when testing this transgenic model in the IntelliCage.

The hippocampus, which engages in the process of consolidating long-term memories and learning, shows active development during childhood and adolescence. The hippocampus also functionally influences attention. Based on the influence of hippocampal function on attention, it was expected that the volume of the hippocampus would be associated with the difference in attention during childhood and adolescence, in which the brain develops actively. Thus, this study examined the association between hippocampal volume and attention metrics measured by the continuous performance test (CPT) in 115 children and adolescents (mean age = 12.43 ± 3.0, 63 male and 52 female). In association studies with both auditory and visual attention, we found that the bilateral hippocampal volumes showed negative relationships with auditory omission errors. A smaller volume of the left hippocampus also led to a longer auditory response time. However, visual attention did not show any significant relationship with the hippocampal volume. These findings were consistent even after adjusting for the effects of the related covariates (e.g., age, insomnia, and depression). Taken together, this study suggested that the increase in hippocampal volume during childhood and adolescence was associated significantly with better auditory attention.

A number of theories of hippocampal function have placed spatial context at the center of richly recollected memories, but the subjective and objective ways that spatial context underlies the recollection of single words has been largely overlooked and underexplained. In this study, we conducted three experiments to investigate the involvement of spatial context in the recollection of single words. In all three experiments, participants encoded single words with varying features such as location and color. The subjective experience of recollection was measured using remember/know judgments and participant self-report of the types of information they recollected about the words. Objectively, recollection was measured using source memory judgments for both spatial and non-spatial features associated with the words. Our results provide evidence that spatial context frequently accompanies the recollection of single, isolated words, reviving discussions on the role of the hippocampus in spatial and detailed recollection.

Studies in school-aged children and adults consistently implicate hippocampus, cortical regions, and their interaction as being critical for memory. However, few studies have examined this neural network in younger children (8 years), despite the fact that behavioral studies consistently report substantial improvements in memory earlier in life. This study aimed to fill this gap by integrating task-based (i.e., memory encoding task) and task-free fMRI scans in 4- to 8-year-old children. Results showed that during memory encoding the hippocampus and several cortical regions (e.g., inferior frontal gyrus, IFG) were activated, consistent with findings in older individuals. Novel findings during memory encoding showed: 1) additional regions (i.e., orbital frontal gyrus, OFG) were recruited, 2) hippocampal activation varied due to age and performance, and 3) differentiation of connectivity between hippocampal subregions and IFG was greater in older versus younger participants, implying increased speicalization with age. Novel findings from task-free fMRI data suggested the extent of functional differentiation along the longitudinal axis of the hippocampus, particularly between hippocampus and OFG, was moderated by both age and performance. Our findings support and extend previous research, suggesting that maturation of hippocampal activity, connectivity, and differentiation may all contribute to development of memory during early childhood.

A clue to hippocampal function has been the discovery of place cells, leading to the ‘spatial map’ theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate-early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a ‘cluster-type’ organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a ‘cluster-type’ functional organization of hippocampal neurons encoding for space.

BackgroundCross-sectional studies indicate that hippocampal function is abnormal across stages of psychosis. Neural theories of psychosis pathophysiology suggest that dysfunction worsens with illness stage. Here, we test the hypothesis that hippocampal function is impaired in the early stage of psychosis and declines further over the next 2 years.MethodsWe measured hippocampal function over 2 years using a scene processing task in 147 participants (76 individuals in the early stage of a non-affective psychotic disorder and 71 demographically similar healthy control individuals). Two-year follow-up was completed in 97 individuals (50 early psychosis, 47 healthy control). Voxelwise longitudinal analysis of activation in response to scenes was carried out within a hippocampal region of interest to test for group differences at baseline and a group by time interaction.ResultsAt baseline, we observed lower anterior hippocampal activation in the early psychosis group relative to the healthy control group. Contrary to our hypothesis, hippocampal activation remained consistent and did not show the predicted decline over 2 years in the early psychosis group. Healthy controls showed a modest reduction in hippocampal activation after 2 years.ConclusionsThe results of this study suggest that hippocampal dysfunction in early psychosis does not worsen over 2 years and highlight the need for longer-term longitudinal studies.

Highlights • Two-year-olds played tablet games requiring them to remember locations visited by characters and the temporal order with which they visited them. • Two-year-olds remembered spatial locations better than temporal order immediately after learning, and after a 20-minute and one-week delay. • Song-related hippocampal activation during sleep is associated with memory for temporal order., Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but research in humans has been constrained by the difficulty of examining hippocampal function during early development. In the present study, we assessed 48 2-year-olds with a novel paradigm in which participants completed two games on a tablet that required remembering associations between unique characters, the places they visited, and the temporal order with which they did so. At the completion of each game, a unique, novel song played. Toddlers remembered spatial locations better than temporal order during an immediate test, after a 20-minute delay, and after a week delay. After the last behavioral session, toddlers underwent an fMRI task during natural nocturnal sleep evaluating hippocampal activation in response to learned and novel songs. We found that the extent of hippocampal activation for learned songs compared to novel songs during sleep was correlated with memory for temproal order across all time delays, but not with memory for spatial locations. The results confirm that that the functional contribution of the hippocampus to early memory can be assessed during sleep and suggest that assessment of temporal aspects of memory in the current task best capture this contribution.

Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance late in life is not known. Here, we labelled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population by long-term memory recall in young adult, cognitively impaired-and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance in aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

We propose that a major contribution of juvenile and adult hippocampal neurogenesis is to allow behavioral experience to sculpt dentate gyrus connectivity such that sensory attributes that are relevant to the animal's environment are more strongly represented. This "specialized" dentate is then able to store a larger number of discriminable memory representations. Our hypothesis builds on accumulating evidence that neurogenesis declines to low levels prior to adulthood in many species. Rather than being necessary for ongoing hippocampal function, as several current theories posit, we argue that neurogenesis has primarily a prospective function, in that it allows experience to shape hippocampal circuits and optimize them for future learning in the particular environment in which the animal lives. Using an anatomically-based simulation of the hippocampus (BACON), we demonstrate that environmental sculpting of this kind would reduce overlap among hippocampal memory representations and provide representation cells with more information about an animal's current situation; consequently, it would allow more memories to be stored and accurately recalled without significant interference. We describe several new, testable predictions generated by the sculpting hypothesis and evaluate the hypothesis with respect to existing evidence. We argue that the sculpting hypothesis provides a strong rationale for why juvenile and adult neurogenesis occurs specifically in the dentate gyrus and why it declines significantly prior to adulthood.

Anorexia nervosa (AN) is a serious and persistent eating disorder, characterized by severe dietary restriction and weight loss, with a third of patients developing a severe-enduring form. The factors contributing to this progression are poorly understood, although there is evidence for impairments in neural structures such as the hippocampus, an area particularly affected by malnutrition and chronic stress.This study aimed to map the evidence for alterations in hippocampal volume, function, and related molecular activity in anorexia nervosa. PubMed, PsycINFO, and Web of Science were searched for studies related to hippocampal function and integrity using a range of methodologies, such as neuropsychological paradigms, structural and functional magnetic resonance imaging, and analysis of blood components.Thirty-nine studies were included in this review. The majority were neuroimaging studies, which found hippocampus-specific volumetric and functional impairments. Neuropsychological studies showed evidence for a specific memory and learning impairments. There was some evidence for molecular abnormalities (e.g. cortisol), although these were few studies. Taken together, our review suggests that the hippocampus might be a particular region of interest when considering neurobiological approaches to understanding AN. These findings warrant further investigation and may lead to novel treatment approaches.

Summary: Neuroactive steroids, termed neurosteroids, are synthesized locally in the brain and influence biological functions including cognition and behavior. These neurosteroids are synthesized from cholesterol by a series of cytochrome P450 enzymes, among which a member of P450 hydroxylase, cytochrome P450-7b1 (CYP7B1), catalyzes the formation of 7α-hydroxylated neurosteroids, 7α-hydroxypregnenolone (7α-OH-Preg) and 7α-hydroxydehydroepiandrosterone (7α-OH-DHEA). Here we demonstrated the occurrence of these neurosteroids in the mouse hippocampus after spatial-learning tasks. Cyp7b1 deficiency impaired remote spatial memory with recent memory mostly unaffected. The hippocampal dendritic spine densities were reduced in Cyp7b1-deficient mice, and they were no more increased by the training. Furthermore, chronic intracerebroventricular administration of a mixture of 7α-OH-Preg and 7α-OH-DHEA rescued the deteriorated remote memory performance in Cyp7b1-deficient mice. It is concluded that the 7α-hydroxylated neurosteroids are required for long-term maintenance of spatial memory, and we suggest that these neurosteroids may induce synaptic remodeling to maintain the hippocampal function.

Brain-derived neurotrophic factor (BDNF), which regulates the neuronal survival, differentiation and synaptic plasticity, has been proved to play a critical role in the pathology and treatment of several psychiatric disorders including depression. Dexamethaone (DEX) is indicated for a number of conditions in perinatal medicine, however, the long-term impact of early-life DEX exposure on BDNF expression in hippocampus remains unknown. Here we found that neonatal DEX(ND) exposure leads to insignificant change of BDNF expression levels in the adulthood, albeit increased hyperanxious and depressive-like behaviors. However, the bdnf mRNA and BDNF protein levels were significantly reduced in all the hippocampal subregions during the developmental stages, including the perinatal period and puberty. We conclude that early life DEX exposure leads to a persistent disturbance of BDNF signaling during the developmental stages, which might be associated with the life-long impairment of hippocampal function.

Aging is typically accompanied by both memory decline and changes in hippocampal function. Lasting memory is thought to also require recapitulation of recent memory traces during subsequent rest-a phenomenon termed memory trace reactivation or replay. Replay becomes less synchronized in the CA1 region of aged animals, and while subtle, this deficit may have profound physiological consequences for driving plasticity. Importantly, spike timing changes during replay may impair the induction of plasticity-regulating gene products, such as activity-regulated cytoskeletal protein (Arc). To test this hypothesis, Arc transcription was assessed both during spatial exploration and subsequent memory-related replay in hippocampal CA1 of young and aged animals. A significant age-related difference was observed in the pattern of pyramidal cells expressing Arc during rest, supporting the hypothesis that altered plasticity-related cascade is a major consequence of the changes in coordinated activity that occur during consolidation in older animals.

SummaryHippocampal function relies on the anterior thalamic nuclei, but the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded subicular cells in rats with either permanent (N-methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. Bayesian and other statistical analyses underscored the notable absence of the diverse spatial signals normally found in the subiculum, including place cells, following permanent anterior thalamic lesions. Likewise, there was marked disruption of these diverse spatial signals during transient lesions. By contrast, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Anterior thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance, while leaving a non-spatial recognition memory task unaffected. These findings, which help explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of subiculum function and reveal its dependence on anterior thalamic signalling.Graphical Abstract

Animals fed a Western-style diet (WS-diet) demonstrate rapid impairments in hippocampal function and poorer appetitive control. We examined if this also occurs in humans. One-hundred and ten healthy lean adults were randomized to either a one-week WS-diet intervention or a habitual-diet control group. Measures of hippocampal-dependent learning and memory (HDLM) and of appetitive control were obtained pre- and post-intervention. HDLM was retested at three-week follow-up. Relative to controls, HDLM performance declined in the WS-diet group ( d = 0.43), but was not different at follow-up. Appetitive control also declined in the WS-diet group ( d = 0.47) and this was strongly correlated with HDLM decline ( d = 1.01). These findings demonstrate that a WS-diet can rapidly impair appetitive control in humans—an effect that could promote overeating in consumers of a WS-diet. The study also suggests a functional role for the hippocampus in appetitive control and provides new evidence for the adverse neurocognitive effects of a WS-diet.

Post-Traumatic Stress Disorder (PTSD) is a complex condition that develops after experiencing a severe emotional trauma, with or without physical trauma. There is no known cure and evidence-based treatments, which are effective in reducing symptoms, have low retention rates. It is therefore important, in addition to seeking new therapeutics, to identify ways to reduce the likelihood of developing PTSD. The fact that some, but not all, individuals exposed to the same traumatic event develop PTSD suggests that there is individual susceptibility. Investigating susceptibility and underlying factors will be better guided if there is a coherent framework for such investigations. In this review, we propose that susceptibility is a dynamic state that is comprised of susceptibility factors (before trauma) and sequalae factors (during or after trauma, but before PTSD diagnosis). We define key features of susceptibility and sequalae factors as: (1) they are detectable before trauma (susceptibility factors) or during/shortly after trauma (sequalae factors), (2) they can be manipulated, and (3) manipulation of these factors alters the likelihood of developing PTSD, thus affecting resilience. In this review we stress the importance of investigating susceptibility to PTSD with appropriate animal models, because prospective human studies are expensive and manipulation of susceptibility and sequalae factors for study purposes may not always be feasible. This review also provides a brief overview of a subset of animal models that study PTSD-related behaviors and related alterations in endocrine and brain systems that focus on individual differences, peri- and post-trauma. Attention is drawn to the RISP model (Revealing Individual Susceptibility to a PTSD-like Phenotype) which assesses susceptibility before trauma. Using the RISP model and expression of plasticity-associated immediate early genes, Arc and Homer1a, we have identified impaired hippocampal function as a potential susceptibility factor. We further discuss other putative susceptibility factors and approaches to mitigate them. We assert that this knowledge will guide successful strategies for interventions before, during or shortly after trauma that can decrease the probability of developing PTSD.

Nonlinear microscopy of calcium sensors was used to record hippocampal activity during induced demyelination and remyelination of axons for 100 days. Substantial changes to firing rates were identified during demyelination with partial recovery upon remyelination.